Conditions: Brain Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 716
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate patients with glioblastoma that is MGMT-methylated (the MGMT gene is altered by a chemical change). Patients will receive temozolomide plus radiation therapy. They will be compared to patients receiving nivolumab in addition to temozolomide plus radiation therapy.

Detailed description:

Arms:
arm 1: Nivolumab: specified dose on specified days; IV (intravenous) infusion Temozolomide: 75 mg (milligram)/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units (joule of radiation energy per kilogram) 5 times per week for 6 weeks arm 2: Nivolumab Placebo: specified dose on specified days; IV infusion Temozolomide: 75 mg/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units 5x/week x 6 weeks

Interventions: intervention 1: Nivolumab intervention 2: Temozolomide intervention 3: Radiotherapy intervention 4: Nivolumab Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA209548
IND Number:
119590
Ex-US:
Non-IND
EUDRACT Number:
2015-004722-34
Date:
16-Dec-2015
Revised Date:
02-Sep-2021
Clinical Protocol CA209548
A Randomized Phase 3 Single Blind Study of Temozolomide plus Radiation Therapy combined 
with Nivolumab or Placebo in Newly Diagnosed Adult Subjects with MGMT-Methylated (tumor 
O6-methylguanine DNA methyltransferase) Glioblastoma
(CheckMate 548: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 548)
Protocol Amendment 07
Clinical Scientist
Clinical Trial Physician -Medical Monitor
24-hr Emergency Telephone Number
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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Protocol Amendment No.: 07
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2
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2020 Bristol-Myers Squibb Company
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Protocol Amendment No.: 07
Date: 02-Sep-2021
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 07
02-Sep-2021
Updated Appendix 1 Management Algorithms to include the version from 
Addendum No. 01 to the Nivolumab Investigator Brochure Version 19 (28-
Sep-2020) for studies using CTCAE version 4.0. Amended descriptions of 
DMC activities to clarify that DMC involvement does not continue after 
study unblinding. Updated COVID-19 vaccine risk/benefit and administration 
guidance. Updated text regarding contraception for male subjects with female 
partners.
Protocol 
Amendment 06
26-Feb-2021
The Data Monitoring Committee (DMC) determined that there was no 
possibility for the study to have a positive overall survival (OS) result, and 
recommended to unblind the sites and subjects, which was approved by BMS. 
The study was officially unblinded on 22-Dec-2020. As a consequence, the 
timing of the primary OS analysis, originally planned for when 337 and 494 
events were to be reached respectively for the population without 
corticosteroids at baseline and the overall population, has been updated. To 
prevent any bias due to unblinding of subjects, the primary OS analysis will 
be conducted using the unblinding date of 22-Dec-2020.
Study procedures for subjects remaining on treatment and in safety follow-up 
have been simplified, and OS follow-up after unblinding has been removed. 
Protocol language per BMS standards for nivolumab studies and for 
COVID-19 has been incorporated.
Incorporates approved Administrative Letters 10 and 11.
Administrative 
Letter 14
25-Nov-2020
Study personnel change
Administrative 
Letter 11
22-Jul-2019
Clarification of the timing of on-study contrast-enhanced magnetic resonance 
imaging (MRI) scans, clarification of the use of the term ‘indeterminate’ to 
describe the MGMT status of the tumor in some subjects, corrections to 
hyperlink labels to Table 4.5.2.1-1 in Table 4.5.2.3-2, and clarification that 
baseline MRI scan is the last scan prior to randomization that meets the 
diagnostic quality required in the imaging manual.
Administrative 
Letter 10
18-Jul-2019
Removal of the interim analysis for Progression Free Survival (PFS).
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Protocol Amendment No.: 07
Date: 02-Sep-2021
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Document
Date of Issue
Summary of Change
Revised 
Protocol 05
08-Nov-2018
Major Changes
• Progression Free Survival is now a primary objective of the study, changed 
from secondary.
• Overall survival (OS) rate at 12 and 24 months and PFS based on 
investigator assessment by RANO criteria are added as secondary 
objectives.
• Blinded Independent Central Review (BICR) of study images has been 
added to the study. 
• The statistical section has been revised to support changes in the study 
objectives. The study will now include 1 formal interim analysis for PFS 
and 1 formal interim analysis for OS for superiority.  
Administrative 
Letter 06
19-Jul-2017
Revised 
Protocol 04
17-Jun-2017
Incorporates Amendment 12
Amendment 12
17-Jun-2017
Corrects an error in the Dose Delay Criteria and aligns the Dose Delay 
Criteria and Dose Discontinuation Criteria with the nivolumab program 
standards. 
Revised 
Protocol 03
03-Jun-2017
Incorporates Amendment 11
Amendment 11
03-Jun-2017
Changed to a Phase 3 trial with Primary Objective of OS
Administrative 
Letter 04
08-May-2017
Change in Study Director
Revised 
Protocol 02
26-Oct-2016
Incorporates Amendment 09
Amendment 09
26-Oct-2016
This amendment updates the nivolumab clinical information in GBM and 
safety management algorithms as a result of most recent version of the 
Investigator Brochure (version 15). The amendment also clarifies several 
items as well as corrects minor errors.
•
Renal, Pulmonary, Hepatic, and Skin safety management algorithms 
revised based on IBv.15
•
Time windows and technical descriptions around assessments and 
administration schedule have been added or expanded to allow for 
flexibility at the site level while not affecting the conduct or the analysis 
of the data.
Revised 
Protocol 01
22-Apr-2016
Incorporates Amendment 05
Amendment 05
22-Apr-2016
The main purpose of the first global amendment is to provide additional 
clarification on several items in response to questions arising from 
investigators and IRB/IEC/HAs: 
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Document
Date of Issue
Summary of Change
•
Add any ≥2 creatinine drug-related abnormality. 
•
Delete provision regarding delay in subjects with baseline Grade 1 ALT, 
AST or total bilirubin toxicity to be allowed to continue dosing to Grade ≥
3 toxicity, thus having all subjects delay for ≥Grade 2 drug-related 
toxicity.
•
Modify criteria to specify that subjects with Grade 2 AST/ALT, or total 
bilirubin elevations may resume dosing when lab values return to baseline 
and management with corticosteroids is complete.
•
Modify criteria to specify subjects must discontinue for any Grade 3 non-
skin, drug-related adverse event lasting > 7 days or which recurs with some 
exceptions.
•
Modify criteria for drug-related liver function test abnormality to 
discontinue for AST or ALT > 5 x ULN, Total bilirubin > 3 x ULN or 
concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN.
•
Add a definition for single blind.  
Additional modifications are as described below:
•
Revise resection cutoffs 
•
Clarify time windows and technical descriptions around the infusion, 
examinations, and administration schedule
•
Remove exclusion criteria 2d for subjects with interstitial lung disease 
•
Add exclusion criteria 2k to exclude subjects with prior hypersensitivity to 
dacarbazine (DTIC)
•
Add a Radiotherapy Guideline Appendix
•
Move Highly Effective Methods of Contraception to an Appendix
•
Incorporate other minor changes to correct and/or clarify protocol 
requirements
Original 
Protocol
16-Dec-2015
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
It was determined following finalization of Protocol Amendment 06 that the Protocol Appendix 1 
Management Algorithms were not the current version as included in the Nivolumab Investigator 
Brochure. Appendix 1 has been updated to include the MANAGEMENT ALGORITHMS FOR 
STUDIES UNDER CTCAE VERSION 4.0 from Addendum No. 01 to the Nivolumab Investigator 
Brochure Version 19 (28-Sep-2020).
Descriptions of Data Monitoring Committee (DMC) activities are amended to clarify that DMC 
involvement does not continue after study unblinding. Clarification is added regarding COVID-19 
vaccine benefit risk and administration. The protocol instructions regarding contraception in male 
study participants who are sexually active with women of childbearing potential are updated to 
align with the temozolomide (TMZ) summary of product characteristics (SmPC) or other local 
regulation. Other minor changes are made for consistency throughout the protocol.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Protocol Summary Study 
Design;
Section 3.1: Study Design and 
Duration;
Section 7: Data Monitoring 
Committee and Other External 
Committees
Clarified that subjects may remain on 
nivolumab and TMZ treatment following 
study unblinding.
Clarified that DMC activities cease 
following study unblinding.
Subjects may remain on study 
treatment post-unblinding and 
will be followed only through the 
safety follow-up phase. Limited 
reporting will be completed and 
subject safety will be monitored 
by the sponsor. 
Section 3.1.4: Overall Study 
Duration;
Section 8.5: Interim Analyses
Text regarding a progression free survival 
(PFS) interim analysis (IA) was removed.
The PFS IA was previously 
removed from the protocol, but 
references to it were inadvertently 
left in Section 3.1.4 and Section 
8.
Section 3.3.1: Inclusion Criteria
Inclusion Criterion 3e was revised.
The requirement is updated to 
align with the TMZ summary of 
product characteristics or other 
local regulatory document.
Section 3.4: Concomitant 
Treatments;
Section 3.4.1: Prohibited and/or 
Restricted Treatments
Added text regarding COVID-19 
vaccines.
Clarified that non-live Covid-19 
vaccines are allowed and are to be 
handled in the same manner as 
other non-live vaccines.
Section 4.5.1.7: Management 
Algorithms for Immuno-
Oncology Agents;
Appendix 1: Management 
Algorithms
Added myocarditis to the list of adverse 
event groups for which a management 
algorithm is included in Appendix 1.
Management algorithms updated to 
current version for studies using CTCAE 
Version 4.0.
Updated to align with Addendum 
No. 01 to the nivolumab 
Investigator Brochure Version 19 
(28-Sep-2020) and more-recent 
version of the management 
algorithms.
Section 5.1: Flow Chart/Time 
and Events Schedule;
Table 5.1-2 On-treatment Assessments
adverse event assessment note updated to 
include discontinuation from study.
Aligned with simplified 
procedures following study 
unblinding; subsequent response, 
survival, 
 
are no longer needed.
Protocol Amendment No.: 07
Date: 02-Sep-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 6.4: Pregnancy
Instruction that a pregnancy occurring in 
the female partner of a male subject 
within 3 months of his last dose of TMZ 
must be reported to the Sponsor has been 
updated to 6 months.
The requirement is updated to 
align with the summary of 
product characteristics or other 
local regulatory document.
Protocol Amendment No.: 07
Date: 02-Sep-2021
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PROTOCOL SUMMARY
Clinical Protocol CA209548
Protocol Title: A Randomized Phase 3 Single Blind Study of Temozolomide plus Radiation Therapy combined with 
Nivolumab or Placebo in Newly Diagnosed Adult Subjects with MGMT-Methylated (tumor O6-methylguanine DNA 
methyltransferase) Glioblastoma
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab (BMS-936558) 240 mg IV or placebo as a 30 minute infusion every 2 weeks for 8 doses
followed by nivolumab 480 mg as a 30 minute infusion every 4 weeks beginning after 8 doses until progression, 
unacceptable toxicity (or other reasons), and temozolomide 75 mg/m2 orally daily during radiation therapy followed 
by 4 week break then 6 (28-day) cycles temozolomide on Days 1-5 at 150 mg/m2 in Cycle 1 increasing to 200 mg/m2
as tolerated up to 6 cycles. 
Study Phase: 3
Research Hypothesis: Addition of nivolumab to standard radiotherapy (RT) plus temozolomide (TMZ) will increase 
PFS in subjects with newly-diagnosed GBM of MGMT-methylated or indeterminate subtypes and will increase OS 
in subjects with newly-diagnosed GBM of MGMT-methylated or indeterminate subtypes without baseline 
corticosteroids and regardless of baseline corticosteroids.
Objectives:
Primary Objective:
The two primary objectives are: 
•
To compare PFS of subjects with newly-diagnosed MGMT methylated or indeterminate GBM subtypes 
treated with RT plus TMZ combined with nivolumab or placebo. PFS will be determined by BICR based on 
RANO criteria.
•
To compare OS of subjects with newly-diagnosed MGMT methylated or indeterminate GBM subtypes 
without baseline corticosteroids and regardless of baseline corticosteroids (ie, all-comers) treated with RT 
plus TMZ combined with nivolumab or placebo.
Secondary Objective:
•
To compare OS of subjects with newly-diagnosed MGMT methylated or indeterminate GBM subtypes 
without baseline corticosteroids and regardless of baseline corticosteroids (ie, all comers) treated with RT 
plus TMZ combined with nivolumab or placebo at 12 and 24 months.
•
To compare PFS based on investigator assessment by RANO criteria of subjects with newly-diagnosed 
MGMT methylated or indeterminate GBM subtypes treated with RT plus TMZ combined with nivolumab or 
placebo. 
Protocol Amendment No.: 07
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Study Design:
This study will enroll subjects with newly-diagnosed GBM, following surgical resection of the tumor. Tumor tissue 
will be evaluated for MGMT methylation by a central laboratory assay through the CA209498 study. After enrolling 
in the CA209498 study, the subjects may enroll in the CA209548 study and begin the screening process while they 
wait for the MGMT results. The screening number assigned in the CA209498 IVRS will be the same subject number 
entered by the site to screen the subject into the CA209548 IVRS. Those with a MGMT status of methylated or 
indeterminate may be eligible to randomize in the CA209548 study.
In order to randomize 693 eligible subjects, a total of approximately 780 subjects are expected to be enrolled. After 
signing consent, eligibility for randomization will be documented. When ready to begin study treatment, subjects will 
be randomized in a 1:1 ratio to the RT/TMZ/nivolumab or the RT/TMZ/placebo arm, stratified by partial vs. complete 
resection. All subjects who enter the treatment phase, ie, all randomized subjects, will be followed for safety and 
tolerability, tumor progression and survival. 
A contrast-enhanced MRI should be performed approximately 4 weeks (± 7 days) after completing radiation therapy, 
then every 8 weeks (± 7 days) up to 24 months post randomization, then every 12 weeks until progression regardless 
of treatment schedule or dose delay. Tumor progression will be assessed using Radiologic Assessment in Neuro-
Oncology criteria (RANO). 
 
On 09-Dec-2020 the Data Monitoring Committee (DMC) conducted a pre-planned routine safety review of all 
available safety data, and initially recommended that the study continue unchanged. Subsequently, the DMC noted 
that it is not possible for the study to demonstrate an OS benefit for the investigational treatment arm, and after further 
discussion with the DMC, the decision was made to unblind all study subjects, and inform all investigators, ethics 
committees, and health authorities as required. Following study unblinding, subjects may continue nivolumab and/or 
TMZ (if applicable) treatment, following protocol procedures. After cessation of nivolumab and/or TMZ treatment 
for any reason, all randomized subjects will enter a short follow-up phase for reporting of treatment-related adverse 
events. Subjects in whom disease progression had not been detected at the time study treatment is stopped will no 
longer be followed for progression. All subjects will no longer be followed for survival.
A DMC will meet regularly during the study until study unblinding to ensure that subject safety is carefully monitored.
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Study Schematic:
Following unblinding, subjects may continue on nivolumab and/or temozolomide (if applicable) treatment, 
following protocol procedures. 
Study Population: Subjects must meet all eligibility criteria specified in Sections 3.3.1 and 3.3.2 of the protocol, 
including the following:
Key Inclusion criteria:
•
Males and females age ≥18 years old
•
Newly diagnosed histologically confirmed supratentorial glioblastoma (Grade 4 malignant glioma by World 
Health Organization including gliosarcoma)
a)
No treatment for GBM other than surgery
b)
Post-operative baseline MRI following consensus recommendations must be obtained prior to 
randomization. It is strongly recommended that this scan be obtained <72 hours or >14 days post-surgery 
in order to minimize artifact 
•
Substantial recovery from surgical resection
a)
No major ongoing safety issues (eg infection requiring IV antibiotics) following surgery
b)
For subjects on corticosteroids at the time of Screening: able to taper steroids (preferably discontinued). 
Dose at randomization must be ≤20 mg prednisone daily or ≤3 mg dexamethasone daily (or equivalent)
•
As of Amendment 11, this criterion regarding screen fails from CA209498 is not applicable. 
•
Centrally confirmed (ie, third-party vendor) tumor MGMT-methylated or indeterminate from the CA209498 
study
•
Karnofsky performance status of ≥70
•
Clinically appropriate for concomitant temozolomide plus RT, based on investigator judgement
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Key Exclusion Criteria:
•
Prior treatment for GBM (other than surgical resection)
•
Recurrent GBM
•
MGMT-unmethylated GBM at central laboratory or tumor not available
•
Biopsy-only of GBM at surgery, defined as < 20% resection of enhancing tumor
•
Concomitant use of Gliadel® wafer
•
CNS hemorrhage of Grade > 1 on baseline MRI scan, unless subsequently documented to have resolved
•
Any known metastatic extracranial or leptomeningeal disease
•
Secondary GBM (ie, progression from prior low-grade or anaplastic astrocytoma)
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209548
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Placebo
N/A
IP
Temozolomide
20 mg, 100 mg, 140 mg
IP
Subjects should begin study treatment within 3 days of randomization and chemoradiation within 7 days, but RT 
should begin within 42 days after definitive resection; may be delayed if clinically required. Subjects will continue on 
study treatment until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever comes 
first. 
Study Assessments:
Safety Evaluation: Adverse events will be assessed continuously during the study and for 100 days post last treatment. 
For all treatment discontinuation post unblinding, adverse events will be assessed for 100 days post last nivolumab 
treatment and for 30 days post last temozolomide treatment, whichever is later. Adverse events will be coded using 
the most current version of MedDRA and reviewed for potential significance and importance. Adverse events will be 
evaluated according to the NCI CTCAE Version 4.03. Subjects should be followed until all treatment-related adverse 
events have recovered to baseline or are deemed irreversible by the investigator. 
Efficacy Assessments: Post-operative baseline MRI following consensus recommendations must be obtained prior to 
randomization. It is strongly recommended that this scan be obtained <72 hours or >14 days post-surgery in order to 
minimize artifact. Tumor imaging assessments following recent consensus recommendations will occur 4 weeks 
(± 7 days) after completion of radiotherapy (baseline MRI) then every 8 weeks (± 7 days) up to 24 months post 
randomization, then every 12 weeks until disease progression. Following study unblinding, tumor assessments will 
not continue for subjects who have discontinued all study treatment. Per RANO, assessment of disease progression 
during study requires that MRI scan be performed >12 weeks after RT; it is therefore recommended that second on-
treatment scan be performed at least 84 days after completion of RT.
 
 Subjects will be treated until unacceptable toxicity or disease 
progression. Following discontinuation of therapy, safety will be assessed through post-treatment Follow-up visits 1 
and 2 (~35 and 115 days from last dose); following study unblinding, Follow-up visits 1 and 2 are only required for 
subjects discontinuing nivolumab and/or temozolomide. Survival status will be assessed every 3 months after follow-
up visits are completed and may be completed via telephone or at in person visits; following study unblinding, survival 
status will not be assessed. Images will be submitted to a central imaging vendor for blinded independent central 
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review (BICR) at any time during the study until study unblinding. Prior to scanning first participant, sites should be 
qualified and understand the image acquisition guidelines and submission process as outlined in the CA209-548 
Imaging Manual provided by the central imaging vendor.
Statistical Considerations:
Sample Size: Approximately 693 subjects will be randomized in a 1:1 ratio, stratified by complete or partial resection. 
Of these 693 subjects, 485 subjects are assumed to be considered as no baseline corticosteroids. Accrual is estimated 
to take approximately 25 months based on an observed monthly accrual in CA209548 of approximately 28 subjects 
per month; in the no baseline corticosteroids population, a piecewise accrual of 1, 4, 5, 8, 13, 16, 19, and then 
23 subjects per month thereafter is assumed. At least 337 OS events in no baseline corticosteroid population are needed 
to achieve 88% power using a 2-sided Type 1 error of 4%. This number of events is projected to occur after an 
additional 44 months of follow-up (ie, at 69 months). 
One interim analysis will be conducted on OS in the randomized population with no baseline corticosteroid.  It will 
occur with approximately 70% or 236 OS events is reached. The stopping boundaries at the interim and final analyses 
will be based on the actual number of OS events at the time of the analysis, using Lan DeMets alpha spending function 
with O’Brien-Fleming boundaries. If the planned interim analyses occur exactly at the planned number of events, the 
projected alpha level will be 0.011 and 0.037. The interim analysis will also be conducted in OS in the overall 
randomized population. The interim analysis will be conducted at the same time as the interim for the no baseline 
corticosteroids population in a hierarchy with stopping boundaries at the interim and final analysis based on actual 
number of OS events at the time of the analysis using Lan-DeMets alpha spending function with O’Brien-Fleming 
boundaries. 
The PFS comparisons will be based on first 558 randomized subjects in all-comers. At least 404 PFS events are needed 
to achieve 90% power using a 2-sided Type 1 error of 1%. Accrual is estimated to take approximately 23 months and 
this number of events is projected to occur after an additional 12 months of follow-up (ie, at 35 months).
Endpoints:
The two primary endpoints of the trial will be OS in the randomized population with no corticosteroids at baseline as 
well as in the overall randomized population, and PFS determined by BICR based on RANO criteria.
Secondary endpoints: OS rate at 12 months and 24 months estimated from OS Kaplan-Meier curve. PFS determined 
by investigator assessment based on RANO criteria.
Analyses:
Primary Endpoints
OS is defined as time from the date of randomization to the date of death. Subjects who have not died by the end of 
the study will be censored to last known date alive. OS will be assessed in the randomized population with no 
corticosteroids at baseline population and in the overall randomized population.
The distribution of OS in the sub-population of subjects with no baseline corticosteroids and in all randomized subjects 
will be compared in arms RT + TMZ + nivolumab and RT + TMZ at interim and final analyses via two-sided, log-rank 
tests, stratified by complete resection or partial resection at baseline. The boundaries for declaring superiority at the 
interim and final analyses will be based on the actual number of OS events at the time of the analysis using Lan DeMets 
alpha spending function with O’Brien-Fleming boundaries. For example, if the interim and final analyses occur exactly 
at the planned number of events, superiority of an arm will be declared if P ≤ 0.011 at the interim analysis or P ≤0.037 
at the final analysis. The Kaplan-Meier product limit method will be used to estimate the survival curve in each arm 
including medians and its 95% CI, OS rates at various time points. The HR and the corresponding two sided 
(1-adjusted α) % CIs will be estimated in a Cox proportional hazards model with treatment arm as a single covariate 
stratified by corresponding stratification factor (complete or partial surgical resection at baseline).
PFS is defined as the time from randomization to the date of the first documented tumor progression or death by any 
cause. Subjects who did not have disease progression or die will be censored at the date of the last tumor assessment. 
Subjects who did not have any on study tumor assessment and did not die will be censored at the last tumor assessment. 
Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the 
last tumor assessment prior to initiation of the anti-cancer therapy. Subjects who had surgical resection after start of 
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study treatment will be censored at the last tumor assessment date prior to initiation of surgical resection. PFS will be 
determined by BICR based on RANO criteria. 
The comparison of PFS will be based on a two-sided log-rank test stratified by corresponding stratification factor 
(complete surgical or partial resection at baseline). PFS will be compared in the first 558 subjects out of the (total) 
714 treated subjects. The Kaplan-Meier product limit method will be used to estimate the survival curve in each arm 
including medians and its 95% CI, PFS rates at various time points. The HR and the corresponding two sided 99% 
CIs will be estimated in a Cox proportional hazards model with treatment arm as a single covariate stratified by 
corresponding stratification factor (complete or partial surgical resection at baseline).
PFS (based on BICR) will be analyzed in overall randomized subjects and all randomized subjects without baseline 
corticosteroids.
The CA209548 DMC convened on 09-Dec-2020 to conduct a pre-planned, routine safety review of all data. The OS 
data clearly show that there is no plausible scenario for this study to have a positive OS result at the final analysis 
based on either all randomized subjects or on subjects without baseline corticosteroids. This is based on the DMC’s 
review of the OS results to date, with over 80% of the final required number of events reached and related statistical 
considerations including conditional power of < 1% for a statistically significant final result.
While the group receiving nivolumab has a higher incidence of toxicities, the DMC members believed the increased 
toxicity was expected and did not warrant stopping the study because of safety, and recommended to unblind the sites 
and subjects, which was approved by the Sponsor. The study was officially unblinded to investigators on 22-Dec-2020.
As a consequence, the timing of the primary OS analysis, originally planned when 337 and 494 events were to be 
reached respectively for the population without corticosteroids at baseline and the overall population, has been 
updated. To prevent any bias due to unblinding of subjects, the primary OS analysis will be conducted using the cut-
off date (or last patient last visit [LPLV]) of 22-Dec-2020, which is when the study was unblinded.
Secondary Endpoint
OS rates at 12 and 24 months will be derived from the Kaplan Meier estimate and corresponding confidence interval 
will be derived based on Greenwood formula for variance derivation and on log-log transformation applied on the 
survivor function.
PFS based on investigator assessment will be analyzed in the first 558 subjects, all randomized subjects and all 
randomized subjects who did not receive corticosteroids at baseline.
All secondary endpoints will be analyzed at the same time as the OS and PFS primary analyses using the analysis 
methods already defined in the SAP.
Protocol Amendment No.: 07
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07 ................ 
PROTOCOL SUMMARY ............................................................................................ 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION 
 ..................................................... 
 
1.2 Research Hypothesis ......................................................................................... 
 
1.3 Objective(s) ....................................................................................................... 
 
1.3.1 Primary Objectives .................................................................................. 
 
1.3.2 Secondary Objectives ............................................................................... 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
 
2.1 Good Clinical Practice ...................................................................................... 
 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
 
2.3 Informed Consent.............................................................................................. 
 
3 INVESTIGATIONAL PLAN .................................................................................... 
 
3.1 Study Design and Duration ............................................................................... 
 
3.1.1 Screening Phase ....................................................................................... 
 
3.1.2 Treatment Phase ...................................................................................... 
 
3.1.2.1 Randomization and Initiation of Treatment .................................... 
 
3.1.2.2 Radiotherapy ................................................................................... 
 
3.1.3 Follow-up Phases..................................................................................... 
 
3.1.4 Overall Study Duration ............................................................................ 
 
3.2 Post Study Access to Therapy ........................................................................... 
 
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3.3 Study Population ............................................................................................... 
 
3.3.1 Inclusion Criteria ..................................................................................... 
 
3.3.2 Exclusion Criteria .................................................................................... 
 
3.3.3 Women of Childbearing Potential ........................................................... 
 
3.4 Concomitant Treatments ................................................................................... 
 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
 
3.4.2 Other Restrictions and Precautions ......................................................... 
 
3.4.2.1 Imaging Restriction and Precautions ............................................. 
 
3.4.3 Permitted Therapy ................................................................................... 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
 
3.6 Post Study Drug Follow up ............................................................................... 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
3.6.2 Lost to Follow-Up .................................................................................... 
 
4 STUDY DRUG .......................................................................................................... 
 
4.1 Investigational Product ..................................................................................... 
 
4.2 Non-investigational Product ............................................................................. 
 
4.3 Storage of Study Drug ...................................................................................... 
 
4.3.1 Nivolumab (BMS-936558) ....................................................................... 
 
4.3.2 Temozolomide .......................................................................................... 
 
4.4 Method of Assigning Subject Identification ..................................................... 
 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
 
4.5.1 Nivolumab/Placebo Dosing ..................................................................... 
 
4.5.1.1 Nivolumab/Placebo Dose and Schedule ......................................... 
 
4.5.1.2 Dose Modifications for Nivolumab/Placebo ................................... 
 
4.5.1.3 Dose Delay Criteria for Nivolumab/Placebo ................................. 
 
4.5.1.4 Criteria to Resume Dosing for Nivolumab/Placebo ....................... 
 
4.5.1.5 Treatment Discontinuation Criteria for Nivolumab/Placebo ......... 
 
4.5.1.6 Continuing Nivolumab/Placebo with Suspected Progression ........ 
 
4.5.1.7 Management Algorithms for Immuno-Oncology Agents ................ 
 
4.5.1.8 Treatment of Nivolumab/Placebo-Related Infusion Reactions ....... 
 
4.5.2 Temozolomide Dosing .............................................................................. 
 
4.5.2.1 Temozolomide Dose and Schedule .................................................. 
 
4.5.2.2 Criteria to Start Temozolomide Maintenance Cycles ..................... 
 
4.5.2.3 Dose Modifications or Discontinuation for Temozolomide ............ 
 
4.5.2.4 Supportive Care during Temozolomide .......................................... 
 
4.6 Blinding/Unblinding ......................................................................................... 
 
4.7 Treatment Compliance ...................................................................................... 
 
4.8 Destruction or Return of Investigational Product ............................................. 
 
4.9 Retained Samples for Bioavailability/Bioequivalence ..................................... 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
 
5.2 Study Materials ................................................................................................. 
 
5.3 Safety Assessments ........................................................................................... 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.4.1 Suspected Progression ............................................................................. 
 
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5.4.2 Assessment of Response ........................................................................... 
 
5.6.1 Tumor Samples......................................................................................... 
 
5.6.1.1 Tumor Sample Collection Details ................................................... 
 
5.6.1.2 MGMT Status .................................................................................. 
 
5.8 Other Assessments ............................................................................................ 
 
5.8.1 Results of Central Pathology Reading ..................................................... 
 
5.8.3 Results of Central Radiology Assessments .............................................. 
 
6 ADVERSE EVENTS ................................................................................................. 
 
6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Nonserious Adverse Events .............................................................................. 
 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoint(s) ................................................................................ 
 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
 
8.4 Analyses ............................................................................................................ 
 
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8.4.1 Demographics and Baseline Characteristics .......................................... 
 
8.4.2 Efficacy Analyses ..................................................................................... 
 
8.4.2.1 Analyses of Primary Endpoint ........................................................ 
 
8.4.2.2 Analyses of Secondary Endpoints ................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
8.5 Interim Analyses ............................................................................................... 
 
8.6 End of Study Analyses at Study Closure .......................................................... 
 
9 STUDY MANAGEMENT ........................................................................................ 
 
9.1 Compliance ....................................................................................................... 
 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
 
9.1.2 Monitoring ............................................................................................... 
 
9.1.2.1 Source Documentation .................................................................... 
 
9.2 Records ............................................................................................................. 
 
9.2.1 Records Retention .................................................................................... 
 
9.2.2 Study Drug Records ................................................................................. 
 
9.2.3 Case Report Forms .................................................................................. 
 
9.3 Clinical Study Report and Publications ............................................................ 
 
10 GLOSSARY OF TERMS ........................................................................................ 
 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0 ......................................................................................................... 
 
APPENDIX 2 RADIATION THERAPY GUIDELINES ............................................ 
 
APPENDIX 3 KARNOFSKY PERFORMANCE SCALES ........................................ 
 
APPENDIX 4 HIGHLY EFFECTIVE METHODS OF CONTRACEPTION ............. 
 
APPENDIX 5 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
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1
INTRODUCTION 
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1.2
Research Hypothesis 
Addition of nivolumab to standard radiotherapy (RT) plus temozolomide (TMZ) will increase PFS 
in subjects with newly-diagnosed GBM of MGMT-methylated or indeterminate subtypes and will 
increase OS in subjects with newly-diagnosed GBM of MGMT-methylated or indeterminate 
subtypes without baseline corticosteroids and regardless of baseline corticosteroids.
1.3
Objective(s)
1.3.1
Primary Objectives
•
To compare PFS of subjects with newly-diagnosed MGMT-methylated or indeterminate 
GBM subtypes treated with RT plus TMZ combined with nivolumab or placebo. PFS will be 
determined by blinded independent central review (BICR) based on RANO criteria.
•
To compare OS of subjects with newly-diagnosed MGMT-methylated or indeterminate GBM 
subtypes without baseline corticosteroids and regardless of baseline corticosteroids (ie, all 
comers) treated with RT plus TMZ combined with nivolumab or placebo.
1.3.2
Secondary Objectives
•
To compare OS of subjects with newly-diagnosed MGMT-methylated or indeterminate GBM 
subtypes without baseline corticosteroids and regardless of baseline corticosteroids (ie, all 
comers) treated with RT plus TMZ combined with nivolumab or placebo at 12 and 24 months.
•
To compare PFS based on investigator assessment by RANO criteria of subjects with 
newly-diagnosed MGMT methylated or indeterminate GBM subtypes treated with RT plus 
TMZ combined with nivolumab or placebo.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
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underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC), if applicable, also by local health authority approval/favorable opinion 
prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC and Regulatory Authority(ies), if required by local legislation for the protocol, 
consent form, subject recruitment materials (eg, advertisements), and any other written 
information to be provided to subjects. The investigator or BMS should also provide the IRB/IEC 
or local health authority with a copy of the Investigator Brochure or product labeling information 
to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC or local health authority with 
reports, updates and other information (eg, expedited safety reports, amendments, and 
administrative letters) according to regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
•
Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
•
Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
•
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
•
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia), may 
only be enrolled in the study with the consent of a legally-acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but is capable of forming an opinion and assessing information, to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This study will enroll subjects with newly-diagnosed GBM, following surgical resection of the 
tumor. Tumor tissue will be evaluated for MGMT methylation by a central laboratory assay 
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through the CA209498 study. After enrolling in the CA209498 study, the subjects may enroll in 
the CA209548 study and begin the screening process while they wait for the MGMT results. The 
screening number assigned in the CA209498 IVRS will be the same subject number entered by 
the site to screen the subject into the CA209548 IVRS. Those with a MGMT status of methylated 
or indeterminate may be eligible to randomize in the CA209548 study. In order to randomize 
693 eligible subjects, a total of approximately 780 subjects will be evaluated. For details, see 
Section 3.1.1. 
Subjects with a central laboratory result of MGMT-methylated or indeterminate may continue in 
the screening phase, in which eligibility for randomization will be documented and baseline 
demographic and disease information submitted; for details, see Section 3.1.1. 
When ready to begin study treatment, subjects will proceed to the treatment phase of the study; 
for details, see Section 3.1.2. All subjects who enter the treatment phase, ie, all randomized 
subjects, will be followed for safety and tolerability, tumor progression, and survival. The first 
on-study contrast-enhanced MRI should be performed 4 weeks (± 7 days) after completing 
radiation therapy, then subsequent scans should be every 8 weeks (± 7 days) up to 24 months, then 
every 12 weeks until progression regardless of treatment schedule or dose delays. Tumor 
progression will be assessed using RANO described in Section 5.4.2. 
 
 
 For the purposes of this protocol, each cycle duration is 2 weeks until 8 doses of 
240 mg of nivolumab/placebo are complete. The remaining subsequent cycles (480 mg or placebo 
infusion, starting Week 17 in the absence of delays) are 4 weeks in duration. Cycle 9 should start 
2 weeks after Cycle 8 begins. 
After cessation of all study treatment for any reason, all randomized subjects will enter a follow-up 
phase. In the short-term, visits are defined for reporting of treatment-related adverse events. 
Following study unblinding, subjects who discontinue all treatment will not be followed for 
progression per RANO criteria, or for survival. For details on the follow-up phase, see Section 
3.1.3. 
Baseline and all subsequent scans will be submitted to blinded independent central review (BICR) 
for review, once the subject is randomized and until study unblinding on 22-Dec-2020. 
A Data Monitoring Committee (DMC) will meet regularly during the study until study unblinding 
to ensure that subject safety is carefully monitored, see Section 7.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
Following unblinding, subjects may continue on nivolumab and/or temozolomide (if 
applicable) treatment, following all protocol procedures.
3.1.1
Screening Phase
Subjects will provide consent for enrollment and tumor submission in the peri-operative period in 
the CA209498 study so that MGMT status can be determined. Consent for enrollment in the
CA209548 study will occur while waiting for the MGMT results to be obtained and randomization 
and study treatment will occur once MGMT status of methylated or indeterminate is known and 
eligibility is established (Figure 3.1.1-1).  
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Figure 3.1.1-1:
Screening and Randomization
A centralized tumor tissue assay for MGMT is required as part of the CA209498 MGMT testing. 
Subjects will consent to the MGMT testing and the CA209548 study simultaneously. Following 
informed consent for both studies, subjects will be enrolled via a call to an IVRS system for the 
CA209498 MGMT testing, in order to obtain a subject number. Immediately after the subject 
number is obtained from the CA209498 IVRS, the site will then screen the subject into the 
CA209548 IVRS. The original subject identification number from CA209498 must be entered into 
the eCRF. 
When possible, subjects should not be on corticosteroids at Screening. It is expected that 
corticosteroid therapy will be tapered to the maximum extent possible during this phase. Subjects 
who cannot tolerate tapering of steroids to < 20 mg prednisone or < 3 mg dexamethasone per day 
(or equivalent) are not eligible for randomization.
RT should begin within 42 days of surgical resection but may be delayed if clinically required. 
Typically, the time from screening procedure to treatment should not exceed 28 days, but may be 
longer if clinically indicated. If repeat resection to improve tumor control is performed for 
newly-diagnosed GBM prior to any other therapy (eg, upon referral to research site), the 42-day 
interval should restart at the time of this second surgery and a new post-operative MRI must be 
performed. 
3.1.2
Treatment Phase
3.1.2.1
Randomization and Initiation of Treatment
After eligibility has been confirmed, subjects who are clinically ready to begin study treatment 
(ie, recovered from surgery) will proceed to the treatment phase of the study via a second call into 
the IVRS system. At this call, subjects will be randomized 1:1 to receive radiotherapy, 
temozolomide plus nivolumab or radiotherapy, temozolomide plus placebo. 
Randomization will be prospectively balanced (ie, stratified) according to post-operative MRI 
finding of “complete” versus “partial” resection. For the purposes of this study, a complete 
resection will be defined as ≤5 mm of contrast enhancement in any diameter on T1 images of the 
post tumor surgical region following surgical resection. A partial resection is defined as ≥10 mm 
MGMT Assay 
at Central Lab
Enrollment & 
Tumor 
Submission via 
CA209498
Diagnosis:
Supratentorial
GBM
Randomize 
to CA209548
Clinically eligible 
to enroll in 
CA209548
MGMT 
Methylated or 
indeterminate
MGMT
Unmethylated
Clinically eligible to 
enroll in 
CA209498
Time from surgery to start RT ≤ 42 days
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of residual contrast-enhancing tumor tissue on T1 images following surgical resection. Resections 
with a residual of > 5 and < 10 mm of enhancement will be defined as partial or complete by the 
investigator’s best clinical judgment. 
The total time elapsed from definitive surgery to initiation of RT should not exceed 42 days but 
may be delayed if clinically required. Typically, a delay from randomization to initiation of 
chemoradiation may be up to 7 days, or longer if clinically required. Subjects should begin 
nivolumab or placebo within 3 days after randomization and may be given at any time prior to 
chemoradiation start. 
See Sections 4.5.1 and 4.5.2 for details of dosing for nivolumab and temozolomide; for an 
overview of the treatment phase, see Section 3.1.2. 
3.1.2.2
Radiotherapy
Radiation therapy should begin after substantial recovery from surgical resection, preferably not 
more than 42 days after surgery; however, treatment may be delayed if clinically required. 
External-beam RT to a total dose of 60 Gy will be administered in daily doses of 2 Gy, typically 
on a 5 days on / 2 days off schedule as appropriate for scheduling, over 6-7 weeks. Patients 
considered clinically inappropriate for full dose RT (60 Gy ± 5%) are not eligible, eg, due to older 
age, tumor location. RT is administered to the post-operative tumor volume plus a 2-3 cm margin, 
as directed by a radiation oncologist.
Radiation therapy planning and administration should follow currently-accepted guidelines. 
Additional details are provided in Appendix 2. RT may be administered at a facility more 
convenient to the patient, but approval from Sponsor or designee must be obtained if not part of 
the same practice group as the investigative study site. For adverse events related to RT, see 
Section 6.  
Note: Suspected progression occurring during or within 12 weeks after RT may be 
“pseudoprogression”; in this setting, suspected progression should be confirmed prior to 
discontinuation of treatment. BMS Medical Monitor should be consulted.
3.1.3
Follow-up Phases
The follow-up phase begins when the decision is made to discontinue a subject from study 
treatment, including for adverse events, for maximum clinical benefit (investigator decision), for 
subject request, disease progression, or another reason.
Following study unblinding, subjects who discontinue the experimental arm will be evaluated for 
adverse events with visits at 35 days (± 7 days) and 115 days (± 7 days) after last dose; for details, 
see Table 5.1-3 and Section 6. Subjects on placebo arm who discontinue study temozolomide 
treatment will be evaluated for adverse events with a visit at 35 days (± 7 days) after last dose. All 
adverse events must be documented for a minimum of 100 days after discontinuation of nivolumab
and for 30 days following discontinuation of temozolomide treatment, but drug-related toxicities 
should continue to be followed until they resolve, return to baseline, or are deemed irreversible.
Subjects will not be followed for progression per RANO criteria, or for survival.
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3.1.4
Overall Study Duration
Enrollment and randomization of 693 subjects is expected to require approximately 25 months.
One interim analysis and a final analysis on OS in the no baseline corticosteroid population were 
planned after approximately 236 and 337 deaths have been reported, respectively. Depending on 
assumptions, these analyses were anticipated to occur at approximately 45 and 69 months after 
first subject is randomized, respectively. Following study unblinding, the final analysis on OS will 
use the unblinding date for the data cut-off. One final analysis on PFS in the first 558 randomized 
subjects in all comers is planned after approximately 404 events have been reported. Depending 
on assumptions, this analysis is anticipated to occur at approximately 35 months after first subject 
is randomized. See Statistical Considerations, Section 8 for details. 
Data will be collected after the pivotal OS final analysis has occurred, for subjects remaining on 
treatment. The study will be closed when safety follow-up has completed for the last subjects to 
discontinue study treatment.
3.2
Post Study Access to Therapy 
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be supplied via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study drug if any of the following occur: a) the marketing application is rejected 
by responsible health authority; b) the study is terminated due to safety concerns; c) the subject 
can obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Written informed consent and HIPAA authorization (applies to covered entities in the US 
only) obtained from the subject/legal representative prior to performing any 
protocol-related procedures
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study
2) Target Population
a) Newly-diagnosed histologically-confirmed supratentorial glioblastoma (Grade IV 
malignant glioma by World Health Organization, including gliosarcoma) 47
i)
No treatment for GBM other than surgery
ii) Post-operative baseline MRI following consensus recommendations51 must be 
obtained prior to randomization. It is strongly recommended that this scan be obtained 
<72 hours or >14 days post-surgery in order to minimize artifact.
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b) Substantial recovery from surgical resection 
i)
No major ongoing safety issues (eg, infection requiring IV antibiotics) following 
surgery
ii) For subjects on corticosteroids at the time of Screening: able to taper steroids 
(preferably discontinued). Dose at randomization must be ≤20 mg prednisone or ≤3 
mg dexamethasone daily (or equivalent). Subjects who do not need corticosteroids or 
able to taper down to ≤20 mg prednisone.
c) As of Amendment 11, this criterion regarding screen fails from CA209498 is no longer 
applicable. 
d) Centrally confirmed (ie, third-party vendor) tumor MGMT-methylated or indeterminate 
from the CA209498 study
e) Karnofsky Performance Status of ≥70 (Appendix 3)
f)
Clinically appropriate for concomitant temozolomide plus RT, based on investigator 
judgment 
3) Age and Reproductive Status
a) Males and Females, age ≥18 years old
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of the study treatment with nivolumab/placebo 
and 5 months after the last dose of study treatment (ie, 30 days [duration of ovulatory cycle] 
plus the time required for the investigational drug to undergo approximately five 
half-lives).
i)
As of Amendment 11, this criterion has been merged into 3.d. 
e) As of Protocol Amendment 06, this criterion refers to TMZ treatment. Males who are 
sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of the study treatment with TMZ and for 6 months after the 
last dose of study treatment, or as noted in the locally applicable package insert, summary 
of product characteristics (SmPC), or similar document. 
i)
Males are encouraged to seek advice on cryoconservation of sperm prior to treatment, 
because of the possibility of irreversible infertility due to therapy with TMZ
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
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Investigators shall advise on the use of highly effective methods of contraception (Appendix 4), 
which have a failure rate of < 1% when used consistently and correctly.
4) Physical and Laboratory Test Findings 
a) WBC ≥2,000/μL 
b) Neutrophils ≥1,500/μL
c) Platelets ≥100 x103/μL
d) Hemoglobin ≥9.0 g/dL
e) Serum creatinine ≤1.5 x ULN, unless creatinine clearance (CrCl) ≥50 mL/min (measured 
or calculated using the Cockcroft-Gault formula) 
i)
Female CrCl = (140-age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
ii) Male CrCl = (140-age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
f)
AST ≤3.0 x ULN
g) ALT ≤3.0 x ULN
h) Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who may have a total 
bilirubin < 3.0 x ULN)
3.3.2
Exclusion Criteria
1) Target Disease Exclusions
a) Prior treatment for GBM (other than surgical resection)
b) Recurrent GBM 
c) MGMT-unmethylated GBM at central laboratory or tumor not available
d) Biopsy-only of GBM at surgery, defined as < 20% resection of enhancing tumor
e) Concomitant use of Gliadel® wafer
f)
CNS hemorrhage of Grade > 1 on baseline MRI scan, unless subsequently documented to 
have resolved
g) Any known metastatic extracranial or leptomeningeal disease
h) Secondary GBM (ie, progression from prior low-grade or anaplastic glioma)
2) Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results
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b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll
c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 days 
of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone or equivalent, are permitted in the absence of active autoimmune 
disease
d) Not applicable per Protocol Amendment 05.
e) Subjects with severe renal insufficiency,
ie, glomerular filtration rate (eGFR) 
< 30 mL/min/1.73m2 (who should not receive contrast materials)
f)
Subjects with history of life-threatening toxicity, including hypersensitivity reaction, 
related to prior immunoglobulin treatment for another condition (except those considered 
unlikely to re-occur, with written approval of BMS Medical Monitor) or any other study 
drug component
g) History or evidence upon physical/neurological examination of other central nervous 
system condition (eg, seizures, abscess) unrelated to cancer, unless adequately controlled
by medication or considered not potentially interfering with protocol treatment
h) Surgical procedure < 7 days prior to study treatment (no restriction for vascular access 
device)
i)
Subjects unable (eg, due to pacemaker or ICD device) or unwilling to have a 
contrast-enhanced MRI of the head
j)
Unable to swallow oral medication or any gastrointestinal disease or surgical procedure 
that may impact the absorption of study drug
k) Subjects with a hypersensitivity to Dacarbazine (DTIC)
l)
Subjects who have received a live/attenuated vaccine within 30 days of first treatment.
3) Physical and Laboratory Test Findings
a) Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or history of active 
chronic hepatitis B
b) Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative), or history of 
active chronic hepatitis C 
c) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated by local regulation
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4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast. 
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their judgment 
in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
It is expected that enrolled subjects will have systemic corticosteroids tapered as quickly as 
clinically appropriate during the screening phase, and systemic corticosteroids will be discontinued 
if possible prior to randomization. 
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Supportive care for all disease-related or treatment-related adverse events should be maximized 
for all subjects on this study. See Section 4.5.2.4 for prophylaxis of Pneumocystis pneumonia.
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur during the study, including during the administration of 
the BMS study treatment and after the last administration of the BMS study treatment. 
3.4.1
Prohibited and/or Restricted Treatments
Concurrent anti-neoplastic therapy, including other chemotherapy, immunotherapy, additional 
radiation therapy or investigational agents for treatment of GBM are prohibited during the 
treatment phase. Use of any additional noninvasive medical device treatment of GBM 
(eg, novoTTF, Optune©) is prohibited. The following medications are prohibited during the study 
treatment (unless utilized to treat a drug related adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.4.3) 
•
Any live/attenuated vaccine (eg, live COVID-19, varicella, zoster, yellow fever, rotavirus, oral 
polio and measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
3.4.2
Other Restrictions and Precautions
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone per day or equivalent) or other immunosuppressive medications (including within 
14 days of randomization) are excluded. Subjects continuing to require supra physiologic steroids 
(prednisone > 20 mg daily or > 3 mg dexamethasone per day or equivalent) for increased intra 
cranial pressure may not be randomized. Inhaled or topical steroids and adrenal replacement 
steroid doses > 10 mg daily prednisone per day or equivalent are permitted in the absence of active 
autoimmune disease.
3.4.2.1
Imaging Restriction and Precautions
Study-related MRI imaging of the brain will be performed using contrast materials. It is the local 
imaging facility’s responsibility to determine, based on participant attributes (eg, allergy history, 
diabetic history, and renal status), the appropriate imaging modality and contrast regimen per 
imaging study. Imaging contraindications and contrast risks are to be considered in this 
assessment. Participants with renal insufficiency are to be assessed as to whether or not they should 
receive contrast and if so, which contrast agent and dose is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis, therefore 
MRI contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image acquisition manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator, and standards set by the local Ethics Committee.
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In accordance with TMZ labeling, valproic acid should not be used concomitant with TMZ; at 
investigator discretion, alternative anticonvulsants should be used.
3.4.3
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Steroid use should be minimized prior to randomization. Systemic corticosteroid use or 
physiologic replacement doses of steroids are permitted, even if > 20 mg/day prednisone 
equivalents, for: a) treatment-related AEs; b) symptoms related to GBM, including suspected 
tumor flare or pseudoprogression; or c) treatment of non-autoimmune conditions (eg, prophylaxis 
for contrast dye allergy, contact hypersensitivity). Details regarding corticosteroid use prior to and 
during the study will be collected (name of medication, doses utilized, start and stop dates, 
frequency of use, route of administration). Information regarding concomitant corticosteroid use 
may be analyzed with regard to study outcome measures.
Subjects requiring chronic treatment with corticosteroids may be treated with histamine-2-receptor 
antagonists or proton pump inhibitors as prophylaxis for potential gastrointestinal adverse 
reactions (ulceration, perforation, hemorrhage) unless otherwise contraindicated.
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the CRF. All medications (prescriptions or over the counter 
medications) continued at the start of the study or started during the study and different from the 
study drug must be documented in the concomitant therapy section of the CRF.
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Disease progression, except as described in Section 4.5.1.6
•
Unacceptable toxicity requiring discontinuation of both TMZ and nivolumab/placebo, see 
Sections 4.5.1.5 and 4.5.2.3
•
Maximum clinical benefit, as determined by investigator
•
Subject’s request to stop study treatment (other than for an AE)
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject, see Sections 4.5.1.5 and 4.5.2.3
•
Termination of the study by Bristol-Myers Squibb
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Initiation of other antineoplastic treatment
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In case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, study drug will be permanently discontinued in an appropriate manner. Please 
call the Sponsor or designee within 24 hours of awareness of the pregnancy. If the investigator 
determines a possible favorable benefit/risk ratio that warrants re-initiation of study drug, after 
termination of pregnancy and if allowed by local regulations, a discussion between the investigator 
and the BMS Medical Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form page.
3.6
Post Study Drug Follow up
In this study, overall survival is the primary endpoint of the study. Post study follow-up is of 
critical importance and is essential to preserving subject safety and the integrity of the study.
Following study unblinding, however, subjects who discontinue study drug will only be followed 
for safety as required and in line with Table 5.1-3. BMS may request that survival data be collected 
on all treated/randomized subjects outside of the 3 month specified visit schedule. At the time of 
this request, each subject will be contacted to determine their survival status unless the subject has 
withdrawn consent for all contacts or is lost to follow-up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or 
post treatment study follow-up, and entered on the appropriate CRF page. In the event that vital
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with local 
law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls,
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faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational Medicinal Product (Non-IP/Non-IMP) 
and can consist of the following:
Table 4-1:
Study Drugs for CA209548
Product Description /
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
Nivolumab
[BMS-936558-01] 
Solution for Injectiona
100 mg 
(10 mg/mL)
IP
Open-label
10 mL per vial (5 or 10 vials/carton)
Clear to opalescent colorless to pale yellow liquid. May 
contain particles
2 to 8°C. Protect 
from light and 
freezing
Placeboa
N/A
IP
N/A
Not provided by BMS
Per institution
Temozolomide Capsulesb
20 mg
IP
Open-label
Wallet/blister card containing 5 capsules
White opaque cap and body, imprinted in yellow ink. The 
cap is imprinted with ‘891.’ The body is imprinted with 
‘20 mg’ and two stripes.
Do not store above 
25 °C.
Temozolomide Capsulesb
100 mg
IP
Open-label
Wallet/blister card containing 5 capsules
White opaque cap and body, imprinted in pink ink. The 
cap is imprinted with ‘892.’ The body is imprinted with 
‘100 mg’ and two stripes.
Do not store above 
25 °C.
Temozolomide Capsulesb
140 mg
IP
Open-label
Wallet/blister card containing 5 capsules
White opaque cap and body, imprinted in blue ink. The 
cap is imprinted with ‘929.’ The body is imprinted with 
‘140 mg’ and two stripes.
Do not store above 
25 °C.
a The term “open-label” refers to the medication as it is upon receipt at the pharmacy. The trial will be conducted in a single-blinded fashion, ie, nivolumab/placebo 
blinded to site staff and patients. May be labeled as either “BMS-936558-01” or “Nivolumab.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are nivolumab (BMS-936558), nivolumab placebo
(0.9% sodium chloride for injection or 5% dextrose for injection), and temozolomide. Although 
not a medicinal product, Radiation Therapy is also considered part of study treatment.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
See Section 4.5 for details regarding study drug dosing in combination with RT.
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2 for guidance on IP records and documentation. 
Infusion-related supplies (eg, IV bags, in-line filters (0.2-1.2 micron), 0.9% NaCl or 5% Dextrose 
solution) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for nivolumab 
(BMS-936558).46
4.3.1
Nivolumab (BMS-936558)
For details regarding drug storage, preparation, administration, and use time please refer to the 
nivolumab (BMS-936558) Investigator Brochure46 and/or pharmacy reference sheets.
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4.3.2
Temozolomide
For countries in which BMS is providing packaged/labeled temozolomide, please refer to package 
insert, summary of product characteristics (SmPC), or similar document for details regarding drug 
preparation, administration and use time.
For countries where local sourcing of temozolomide is permitted, product should be stored, 
prepared and administered in accordance to the package insert, summary of product characteristics 
(SmPC) or similar document.
4.4
Method of Assigning Subject Identification
After informed consent has been obtained from both the CA209498 and CA209548 studies, the 
subject must first be enrolled into the CA209498 study by calling an interactive voice response 
system (IVRS) to obtain the subject number. The subject identification number in the CA209498 
study will become the study number for the CA209548 study. Every subject that signs the informed 
consent form must be assigned a subject number in IVRS. The investigator or designee will register 
the subject for enrollment by following the enrollment procedures established by BMS. The 
following information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth of subject
•
Gender (at birth) of subject
•
Patient ID from the CA209498 study
Once enrolled in IVRS, enrolled subjects who meet all eligibility criteria and are clinically ready 
to begin treatment will be randomized through the IVRS. Central lab confirmation of MGMT-
methylated or indeterminate must be received prior to the IVRS randomization call. The following 
information is required for randomization: 
•
Subject number
•
Date of birth of subject
•
Extent of tumor resection: Complete or Partial
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to receive radiotherapy 
plus temozolomide combined with nivolumab or placebo. MGMT-methylation status will be 
transferred from the testing laboratory to the IVRS database. 
The exact procedures for using the IVRS will be detailed in the IVRS manual.
4.5
Selection and Timing of Dose for Each Subject
Dosing schedules for both arms are detailed in Table 4.5-1. All subjects will undergo surgical 
resection and radiotherapy as outlined in Section 3.1. The first dose of nivolumab is to be 
administered within 3 days of randomization. Treatment details are described below. 
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Table 4.5-1:
Selection and Timing of Dose
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Nivolumab/
Placebo 
(BMS-936558)
240 mg
480 mg, after 8 doses 
Every 2 weeks, 
for 8 doses
Every 4 weeks after 
8 doses
30 minute 
intravenous 
(IV)
Until progression, 
unacceptable 
toxicity, or 
discontinuation from 
treatment
Temozolomide 
(TMZ)
75 mg/m2 daily during 
RT 
then 150 mg/m2 D1-5 
for C1 
and increased to 
200 mg/m2 D1-5 for 
C2-C6 as tolerated
Daily from first day of 
RT to last day of RT 
(not to exceed 49 days) 
then 4 week break 
followed by TMZ daily 
for 5 days every 28 days 
x 6 cyclesa
Oral (PO)
Until completion of 
dosing, progression, 
unacceptable 
toxicity or 
discontinuation from 
treatment
a Additional cycles of temozolomide are permitted for subjects enrolled in Japan as well as others with written 
permission of Sponsor 
Treatment modifications (eg, dose delay, reduction, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 4.5.1 and 4.5.2. If the toxicity is 
considered related to either TMZ or nivolumab/placebo, both may be delayed, based on 
investigator judgment. However, if the toxicity is related to one or the other, then that one should 
be delayed or discontinued as appropriate. If the subject continues on either study drug, the visit 
schedule and assessments will continue as described in Table 5.1-2. 
4.5.1
Nivolumab/Placebo Dosing
To reduce bias, this study is blinded for the investigational agent. Therefore, all provisions for 
dosing and dose modification apply equally to the 2 treatment arms until study unblinding. 
The pharmacist will be unblinded to randomized arm; matched infusions (0.9% sodium chloride 
for injection or 5% dextrose for injection) will be provided to subjects on the control arm.
Nivolumab (BMS-936558) is to be administered as an IV infusion over 30 minutes. At the end of 
the infusion, flush the line with a sufficient quantity of 5% dextrose solution or normal saline.
4.5.1.1
Nivolumab/Placebo Dose and Schedule
Subjects should begin study treatment within 3 days of randomization, but RT should begin within 
42 days after definitive resection. Subjects will continue on study treatment until progression, 
unacceptable toxicity, withdrawal of consent, or the study ends, whichever comes first. 
Continuation of nivolumab treatment with suspected progression is permitted; see Section 4.5.1.6. 
Treatment will continue until discontinuation from study treatment for any of the criteria listed in 
Sections 3.5 or 4.5.1.5. 
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Subjects may be dosed no less than 12 days from the previous dose during Q2W cycles. A dose 
given more than 3 days after the intended dose date will be considered a delay. For Q4W dosing 
cycles, subjects may be dosed within a ± 3 day window. Subsequent dosing should be based on 
the actual date of administration of the previous dose of drug. Note: The 480 mg dosing starts at 
Cycle 9, which begins 2 weeks after the start of Cycle 8 (Week 17 in the absence of delays). 
There are no premedications recommended for nivolumab on the first cycle.
Subjects should be monitored for infusion reactions during nivolumab administration. If an acute 
reaction is noted, subjects should be managed according to Section 4.5.1.8.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates treatment. Nivolumab/placebo should be delayed (see Section 4.5.1.3) for 
toxicities considered at least possibly-related to nivolumab. If toxicity is related to TMZ only, then 
only that agent should be interrupted; see Section 4.5.2.3. If the toxicity is considered related to 
either TMZ or nivolumab/placebo, both may be delayed, based on investigator judgment.
No incompatibilities have been observed between nivolumab for injection and polyvinyl chloride 
(PVC), non-PVC/non-DHEP (di(2ethylhexyl)phthalate) IV components or glass bottles.
4.5.1.2
Dose Modifications for Nivolumab/Placebo
Dose modification is not allowed for nivolumab; for dose delay, see Section 4.5.1.3.
4.5.1.3
Dose Delay Criteria for Nivolumab/Placebo
Tumor assessments should continue per protocol schedule, even if dosing is delayed.
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade  2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormality with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST/ALT or total bilirubin will require dose discontinuation (See Section 
4.5.1.5).
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
•
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection, either confirmed or 
suspected
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated. Nivolumab dosing can be resumed on the established dosing schedule (q2 or 
q4 weeks) when retreatment criteria are met (Section 4.5.1.4). 
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4.5.1.4
Criteria to Resume Dosing for Nivolumab/Placebo
Subjects may resume treatment with study drug when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
•
For subjects with Grade 2 AST, ALT, and/or total bilirubin abnormalities, dosing may resume 
when laboratory values return to baseline and management with corticosteroids, if needed, is 
complete
•
Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.5.1.5) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor
•
Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor. Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
•
Subjects with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following:
−
1) at least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive test result (e.g. RT-PCR or viral antigen), 2) resolution of acute 
symptoms (including at least 24 hours has passed since last fever without fever reducing 
medications), 3) evaluation by the Investigator with confirmation that there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment, and 
4) consultation by the Medical Monitor. For suspected cases, treatment may also resume if 
SARS-CoV-2 infection is ruled-out and other criteria to resume treatment are met.
4.5.1.5
Treatment Discontinuation Criteria for Nivolumab/Placebo
Nivolumab treatment should be permanently discontinued for the following: 
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
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−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT, or Total Bilirubin requires discontinuation*
•
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur. 
♦Concurrent AST or ALT > 3 x ULN and Total Bilirubin > 2 x ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor. 
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. 
Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS 
medical monitor must be consulted. Tumor assessments should continue as per protocol even 
if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing delays.
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•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
•
Following study treatment unblinding, a decision by the treating physician and the subject to 
discontinue treatment.
4.5.1.6
Continuing Nivolumab/Placebo with Suspected Progression
Accumulating evidence indicates that a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of disease progression, eg, due to inflammatory 
reaction simulating progression (“tumor flare” or pseudoprogression). At the discretion of the 
investigator, subjects may continue nivolumab in the setting of suspected progression until 
progression is confirmed. [Note: this is not the same as confirmation of progression occurring 
within 12 weeks after RT, which is a component of RANO criteria.] Communication with the BMS 
Medical Monitor is strongly encouraged. If the investigator believes that the subject continues to 
derive clinical benefit by continuing treatment, the subject should continue assessments according 
to Table 5.1-2.
Subjects may continue nivolumab beyond suspected progression only if they meet the following 
criteria:
•
Subject is tolerating nivolumab
•
Treatment will not delay intervention to prevent imminent complications, eg surgery for relief 
of symptomatic intracranial mass effect 
•
Investigator-assessed overall clinical benefit
Radiographic assessment should be repeated after suspected progression as clinically required in 
order to determine whether there has been a decrease in the tumor size or continued progression. 
If possible, perfusion images should also be obtained. All MRI scans should be submitted to the 
imaging vendor as soon as possible. 
Re-operation should be considered, if lesion is surgically accessible, to differentiate immune-
treatment effects from progression. The BMS Medical Monitor should be consulted. Potential for 
clinical benefit should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive benefit from continued treatment with nivolumab. Nivolumab 
treatment should be discontinued permanently upon confirmation of RANO-assessed progression 
but prolonged observation (eg, 3 months) may be required, as suggested in Okada et al.48
4.5.1.7
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent 
in this protocol. Early recognition and management of AEs associated with immuno oncology 
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agents may mitigate severe toxicity. Management Algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in Appendix 1 and in the nivolumab Investigator Brochure.49
4.5.1.8
Treatment of Nivolumab/Placebo-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.03) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab/placebo administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
≤24 hours):
•
Stop the nivolumab/placebo infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
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symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur, 
then no further nivolumab/placebo will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab/placebo infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of nivolumab/placebo. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the Investigator is comfortable that the symptoms will not recur. Nivolumab/placebo will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.5.2
Temozolomide Dosing
4.5.2.1
Temozolomide Dose and Schedule
Subjects will be administered temozolomide (TMZ, Temodar®) daily during RT and as 
maintenance therapy for 6 cycles. TMZ dosing will be performed according to investigator 
judgment; the following guidance is drawn from published literature.
TMZ will be dosed at 75 mg/m2 once per day continuously throughout RT, typically for 42 days 
and with a maximum of 49 days. See Table 4.5.2.3-1 for dose modifications during concomitant 
RT+TMZ dosing. After completion of RT, there will be a 4 week break. Subjects will receive 
6 cycles of temozolomide daily x 5 days every 28 days. The timing of maintenance TMZ cycles 
may be adjusted for clinical convenience, eg, to coincide with nivolumab/placebo dosing.
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Table 4.5.2.1-1:
Dose Levels for Maintenance TMZ Monotherapy
Dose Level
TMZ Dose in mg/m2/day
Notes
-1
100 mg/m2/day
Reduction for prior toxicity
0
150 mg/m2/day
Dose during first maintenance cycle
1
200 mg/m2/day
Dose during subsequent maintenance TMZ in absence of TMZ-
related toxicity
Source: adapted from Temodar® package insert (PI)
In the first maintenance cycle, TMZ is given at a dose of 150 mg/m2, and then increased to 
200 mg/m2 in Cycle 2 as follows: If, during the first cycle, all non-hematologic AEs observed were 
Grade ≤2 (except alopecia, nausea and vomiting) and with platelets ≥100 x 109/L and 
ANC ≥1.5 x109/L, then the temozolomide dose should be escalated to dose level 1, and this dose 
should be used as the starting dose for subsequent cycles. Doses of TMZ are not precise but are 
adjusted based on tolerance; rounding of up to 10% is entirely acceptable.  
If treatment after Cycle 1 has to be delayed because of ongoing non-hematologic AEs of Grade ≥2, 
then no escalation is possible. If the dose was not escalated at Cycle 2, then the dose should not be 
escalated in further cycles based on adverse events (see Table 4.5.2.3-2). If there was a prior dose 
reduction or discontinuation during the concomitant period with RT, then dose -1 should be the 
starting dose for subsequent cycles. Table 4.5.2.1-1 describes dose levels during temozolomide 
maintenance.
As noted in Section 4.5.1.1, if toxicity is related to TMZ only, then only that agent should be 
interrupted. If the toxicity is considered related to either TMZ or nivolumab/placebo; however, 
both may be delayed, based on investigator judgment.
4.5.2.2
Criteria to Start Temozolomide Maintenance Cycles 
Maintenance treatment begins following a 4-week treatment break after RT. TMZ treatment may 
begin if blood count (obtained within the prior 3 days) shows ANC ≥1.5 x 109/L, platelet count 
≥100 x 109/L and any Grade ≥3 non-hematologic AE (except alopecia) must have resolved to 
Grade ≤1). If AEs persist, treatment should be delayed by 1 week for up to 4 consecutive weeks. 
If, after 4 weeks of delay, all AEs have still not resolved to ≤Grade 1: then any further maintenance 
treatment with temozolomide should be discontinued.
4.5.2.3
Dose Modifications or Discontinuation for Temozolomide
TMZ dosing will be performed according to investigator judgment; the following guidance is 
drawn from published literature.
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Table 4.5.2.3-1:
Temozolomide Dose Modification Guidelines During Concomitant 
Radiotherapy and TMZ Dosing
Laboratory Value/Clinical Criteria:
Dose Modification:
Additional Information:
ANC:
≥0.5 and < 1.5 x109/L
Delay TMZ Dosing
Continue when ≥1.5 x109/L
< 0.5 x109/L
Discontinue TMZ
May restart at dose -1 in maintenance
Platelets:
≥10 and < 100 x 109/L
Delay TMZ Dosing
Continue when ≥100 x 109/L
< 10 x 109/L
Discontinue TMZ
May restart at dose -1 in maintenance
Any Non-Hematologic Toxicity (except alopecia, nausea, vomiting)
CTC Grade 2
Delay TMZ dosing
Continue when ≤CTC Grade 1 
(except for alopecia, nausea, vomiting)
CTC Grade 3 or 4
Discontinue TMZ dosing
May restart at dose -1 in maintenance
Source: adapted from Temodar® package insert (PI)
Table 4.5.2.3-2:
Temozolomide Dose Modification Guidelines During Maintenance 
TMZ Dosing
Laboratory Value/
Clinical Criteria:
Dose Modificationa:
Additional Information:
ANC:
< 1.0 x109/L
Reduce TMZ Dosing by 1 
dose level per Table 5.4.2-1
< 0.5 x109/L
Discontinue TMZ dosing
If Dose Level -1 (100 mg/m2) still results in 
unacceptable toxicity
Platelets:
≥10 and < 100 x 109/L
Reduce TMZ Dosing by 1 
dose level per Table 5.4.2-1
< 10 x 109/L
Discontinue TMZ dosing
If Dose Level -1 (100 mg/m2) still results in 
unacceptable toxicity
Any Non-Hematologic Toxicity (except alopecia, nausea, vomiting)
CTC Grade 3
Reduce TMZ Dosing by 1 
dose level per Table 5.4.2-1
CTC Grade 4
Discontinue TMZ dosing
If Dose Level -1 (100 mg/m2) still results in 
unacceptable toxicity or the same Grade 3 non-
hematologic toxicity recurs
a Dose reductions of temozolomide during maintenance should be based on the lowest blood count and worst non-
hematologic toxicity during the prior cycle.
Source: adapted from Temodar package insert (PI)
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4.5.2.4
Supportive Care during Temozolomide
Subjects should be treated to receive prophylaxis against Pneumocystis pneumonia (inhaled 
pentamidine [preferred], dapsone or oral trimethoprim–sulfamethoxazole) during concomitant 
treatment with RT plus TMZ and may be continued during maintenance at investigator discretion. 
Details regarding prophylactic agent use will be collected as concomitant medications.
Antiemetic prophylaxis with metoclopramide or a 5-hydroxytryptamine 3 antagonist is allowed 
prior to treatment with temozolomide.
4.6
Blinding/Unblinding
The blinding strategy selected for the protocol is the single-blinding design, also called 
“site-subject blinded.”50 The subjects, investigator, and site staff will be blinded to the study 
therapy administered. Each investigative site must assign an unblinded pharmacist/designee. 
Designated staff of BMS Research & Development will be unblinded to facilitate drug supply and 
safety monitoring. 
 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if the treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the BMS Medical Monitor, but the investigator always has ultimate authority 
for the decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made. Once the subject is unblinded, the 
decision to discontinue cannot be reversed. 
For this study, the method of unblinding for emergency purposes is through the IVRS. For 
information on how to unblind for emergency, please consult the IVRS manual.
In cases of accidental unblinding, contact the BMS Medical Monitor and ensure every attempt is 
made to preserve the blind.
On 09-Dec-2020, the DMC conducted a pre-planned routine safety review of all available safety 
data and initially recommended that the study continue unchanged. Subsequently, the DMC noted 
that it is not possible for the study to demonstrate an OS benefit for the investigational treatment 
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arm, and after further discussion with the DMC, the decision was made to unblind all study 
subjects, and inform all investigators, ethics committees, and health authorities as required.
4.7
Treatment Compliance
Assessment of study medications will be performed at each study visit. Subjects should be 
instructed to bring all unused study drug to each visit as well as any empty containers. The dates 
and number of capsules dispensed and returned must be recorded on the drug accountability form 
maintained on-site. Unused or partially used study drug are returned to the subject and dosing 
should continue from the in-use container until it has been emptied. Drug accountability will be 
reviewed at each visit to confirm treatment compliance. Sites should discuss discrepancies with 
the patient at each visit.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS or sourced by the investigator) such as partially used 
study drug containers, vials and syringes may be destroyed on site. 
If...
Then...
IP supplied by BMS (including its 
vendors)
Any unused IP supplied by BMS can only be destroyed after being 
inspected and reconciled by the responsible Study Monitor unless IP 
containers must be immediately destroyed as required for safety, or to 
meet local regulations (eg, cytotoxics or biologics).
If IP will be returned, the return will be arranged by the responsible 
Study Monitor.
IP sourced by site, not supplied by BMS 
(or its vendors) (examples include IP 
sourced from the sites stock or commercial 
supply, or a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of all 
containers according to the institutional guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
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It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced by the site, not 
supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for guidance on IP records and documentation. 
4.9
Retained Samples for Bioavailability/Bioequivalence
Not applicable. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedures (CA209548)
Procedure
Screening
Visit
Notes: Windows refer to calendar days
Informed Consent for enrollment
X
Call IVRS to obtain subject number
Inclusion/Exclusion Criteria
X
Centrally-confirmed MGMT-methylated or indeterminate GBM
Medical History
X
Physical Examination, Vital Signs, 
Performance Status
X
Height, weight, BSA; Karnofsky Performance Status (Appendix 3), and full physical exam, BP, HR, 
RR, temperature, within 14 days prior to randomization
Post-operative Tumor Assessment
X
Contrast-enhanced MRIa within 72 hours post-surgery (within 24 hours preferred); see Imaging 
Manual. If not available, must be performed prior to randomization (> 2 weeks post-op preferred). 
See Section 5.4.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization
Concomitant Medication Collection
X
Within 14 days prior to randomization, to include corticosteroid dose
Adverse Events Assessment
X
Serious Adverse Events from time of consent. See Section 6.1.1
Laboratory Tests
X
CBC w/differential; Chemistry panel including: AST, ALT, ALP, T.Bili, BUN or serum urea level, 
albumin, creatinine, phosphorus, Ca, Na, K, Cl, Glucose, within 14 days prior to randomization.
TSH, T3 and T4 (Free or Total), Hep B/C (HBsAG, HCV antibody or HCV RNA), within 28 days 
prior to randomization
Pregnancy Test [WOCBP]
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG ) to be done 
at screening visit and within 24 hours of first dose of study therapy
a Post-operative baseline MRI following consensus recommendations must be obtained prior to randomization. It is strongly recommended that this scan be obtained 
<72 hours or >14 days post-surgery in order to minimize artifact. There is no requirement that MRI performed prior to randomization be on a “qualified machine.”
See Section 5.4.
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nivolumab
Table 5.1-2:
On-Treatment Assessments (CA209548)a
Procedure
Concomitant 
RT + TMZ + 
Nivo/
placebo
TMZ 
Break/
Nivo/
placebo
Maintenance
Notes: Cycle duration is 2 weeks until 8 doses of nivo/placebo are 
complete. Remaining subsequent cycles are 4 weeks in duration. 
Procedures must be done within 72 hours prior to dosing unless 
otherwise specified.
IVRS Randomization call 
X
Confirm eligibility criteria prior to randomization
Targeted Physical Examination, 
Vital Signs, Performance Status
X
X
X
Weight, Karnofsky Performance Status, BP, HR, RR, temperature 
Adverse Events Assessment
Continuously
Record at each visit
Concomitant Medications
Continuously
Record at each visit, including steroid dose
Radiation Therapy
X
Total dose 60 Gy over 6-7 weeks, see Section 3.1.2.2
CBC with Differential
X
X
X 
Weekly during RT, then Day 1 and 22 of maintenance TMZ (repeat 
weekly if TMZ delayed), then prior to each nivo/placebo dose, and as 
clinically indicated.
Chemistry Panela
X
X
X
Chemistry panel every 4 weeks prior to nivolumab/placebo dose: AST, 
ALT, ALP, T.Bili, albumin, BUN or serum urea, creatinine, Ca, Na, K, 
Cl, Glucose, and as clinically indicated.
Thyroid Function Test
X
X
TSH every 8 weeks, T3 and T4 (Free or Total, if TSH abnormal) and as 
clinically indicated
Pregnancy Test [WOCBP only]
X
X
X
Serum or urine pregnancy test every 4 weeks (± 3 days; minimum 
sensitivity 25 IU/L or equivalent units of HCG)
Tumor Assessment
X
Contrast-enhanced MRI 4 weeks (± 7 days) after completing RT, then 
every 8 weeks (± 7 days)b up to 24 months, then every 12 weeks until 
progression, see Imaging Manual and Section 5.4. Following study 
unblinding, tumor assessments will not continue for subjects who have 
discontinued all study treatment.
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Table 5.1-2:
On-Treatment Assessments (CA209548)a
Procedure
Concomitant 
RT + TMZ + 
Nivo/
placebo
TMZ 
Break/
Nivo/
placebo
Maintenance
Notes: Cycle duration is 2 weeks until 8 doses of nivo/placebo are 
complete. Remaining subsequent cycles are 4 weeks in duration. 
Procedures must be done within 72 hours prior to dosing unless 
otherwise specified.
Dispense Nivolumab/Placebo
X
Day 1 within 3 days of randomization up to 7 days prior to RT start, then 
every 2 weeks for 8 doses, then every 4 weeks, see Section 4.5.1
Dispense Temozolomide
X
X
Temozolomide taken daily during RT then 4 week break, then daily x 5 
in 28-day cycles x 6 cycles, see Section 4.5.2
Tumor Sample Submission at time 
of progression or suspected 
progression
At time of PD or suspected PD
If biopsy or surgical resection is performed at progression or suspected 
progression, a tumor sample (block or slides) should be submitted for 
central neuropathologic review 
a If a subject discontinues nivolumab or placebo but continues TMZ, on-treatment assessments should continue. Chemistry panel will be collected every 4 weeks 
prior to TMZ dosing.
b Per RANO, assessment of disease progression during study requires that MRI scan be performed >12 weeks after RT; it is therefore recommended that second 
on-treatment scan be performed at least 84 days after completion of RT
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Table 5.1-3:
Treatment Follow-up and Survival Follow-up (CA209548)
Procedure
Treatment 
Follow-upa
Survival 
Follow-upb
Notes
Targeted Physical Examination
X
Weight, BP, HR, RR, temperature and Karnofsky Performance Status
Adverse Events Assessment
X
X 
Beyond 100 days from the last dose of study treatment subjects will be followed for 
ongoing nivolumab-related adverse events until resolved, return to baseline or 
deemed irreversible or until lost to follow-up, withdrawal of study consent, or 
discontinuation from the study.
Laboratory Tests
X
CBC w/differential, LFTs, BUN, creatinine and TSH at 35 days, repeat labs at 115 
days visit if study drug-related toxicity persists
Pregnancy Test [WOCBP only]
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG)
Review of Concomitant Medications
X
Tumor Assessment
X
Every 8 weeks (± 7 days) for 24 months and then every 12 weeks until progression, 
required only for subjects who did not progress on study treatment (eg, discontinued 
for AEs). Following study unblinding, tumor assessments will not continue for 
subjects who have discontinued study treatment. See Section 5.4.  
Tumor Sample Submission at time of 
progression or suspected progression
At time of PD or suspected 
PD
If biopsy or surgical resection is performed at the time of progression or suspected 
progression, a tumor biopsy sample (block or slides) should be submitted for central 
neuropathologic review; following study unblinding, this is optional.
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Table 5.1-3:
Treatment Follow-up and Survival Follow-up (CA209548)
Procedure
Treatment 
Follow-upa
Survival 
Follow-upb
Notes
Survival Status
X
X
Every 3 months (clinic visit or telephone contact), during Survival phase, include 
documentation of subsequent chemotherapy. Following study unblinding, survival 
status will not be collected.
a Subjects must be followed for at least 100 days after last dose of study drug (whichever was administered the latest). Follow-up visit #1 (FU1) occurs
approximately 35 days (± 7 days) after the last dose or coinciding with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days 
after last dose. Follow-up visit #2 (FU2) occurs approximately 115 days (± 7 days) after last dose. Following study unblinding, Follow-up Visit #1 and Follow-
up Visit #2 will occur for subjects who were treated with nivolumab, and Follow-up Visit #1 will occur for subjects who were treated with placebo and were 
receiving temozolomide at time of unblinding.  
b Survival Follow-up visits to occur every 3 months from Follow-up Visit 2 until study unblinding. BMS may request that survival data be collected on all treated
subjects outside of the 3 month specified window. At the time of this request, each subject will be contacted to determine their survival status unless the subject 
has withdrawn consent for all contact.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within the screening period will be 
permitted (in addition to any parameters that require a confirmatory value). Screening procedures 
that were performed do not need to be repeated if they meet the timing criteria in Table 5.1-1
(eg, within 14 days of randomization, 28 days of randomization). Laboratory parameters and/or 
assessments that are included in Table 5.1-1, Screening Procedural Outline may be repeated in an 
effort to find all possible well-qualified subjects. Consultation with the BMS Medical Monitor 
may be needed to identify whether repeat testing of any particular parameter is clinically relevant.
Any new result will override the previous result (ie, the most current result prior to randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
5.2
Study Materials
•
NCI CTCAE version 4.03
•
Nivolumab Investigator Brochure
•
SMPC and/or USPI for temozolomide
•
Pharmacy Binder
•
Laboratory Manuals for collection and handling of blood samples 
 
 and tissue specimens
•
Site 
manual 
for 
operation 
of 
interactive 
voice 
response 
system, 
including 
enrollment/randomization worksheets
•
Manual for entry of local laboratory data
•
Pregnancy Surveillance Forms
•
Imaging Manual includes specifications for Radiology scan submission
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include height, weight, BSA, Karnofsky Performance Status, BP, 
HR, RR, and temperature and should be performed as noted in Table 5.1-1. Baseline signs and 
symptoms are those that are assessed within 14 days prior to first dose of study drug. Concomitant 
medications including steroid dose within 14 days prior to first dose of study drug through the 
study treatment period will be collected (see Section 5.1).
Baseline local laboratory assessments should be done within 14 days prior to first dose to include: 
CBC w/differential to include ANC, Chemistry panel including AST, ALT, alkaline phosphatase, 
total bilirubin, BUN or serum urea level, albumin, creatinine, phosphorus, Ca, Na, K, Cl, and 
glucose. TSH, T3 and T4 (Free or Total), and Hep B and C testing (HBVs Ag, HCV Ab, or HCV 
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RNA) to be collected within 28 days prior to randomization (see Table 5.1-1). Pregnancy testing 
for WOCBP (done locally) to be done at screening, within 24 hours prior to first dose, and then 
every 4 weeks regardless of dosing schedule, and at each safety follow up visit. Where required 
by local regulations, an HIV test must also be performed. Cycle 1 pre-dose laboratory assessments 
do not need to be collected if the screening assessments were collected within the specified 
timeframe, ie, 14 days or 28 days prior to treatment start.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Table 5.1-3), 
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase, 
either in person or documented telephone calls to assess the subject’s status are acceptable.
On-treatment laboratory assessments include CBC w/differential to include ANC, done weekly 
during RT, then Day 1 and 22 during maintenance TMZ, then prior to each nivolumab/placebo 
cycle. Chemistry panel including AST, ALT, alkaline phosphatase, total bilirubin, albumin, BUN 
or serum urea, creatinine, Ca, Na, K, Cl, glucose will be performed every 4 weeks prior to 
nivolumab/placebo dosing or prior to TMZ dosing if the subject has been determined to be in the 
placebo arm. TSH, T3 and T4 (Free or Total, only if TSH abnormal) will be performed every 8 
weeks for all subjects, or as clinically indicated. Pregnancy test will be performed every 4 weeks. 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.03.
On-study weight, Karnofsky performance status, and vital signs should be assessed every 2 weeks 
during RT followed by every 4 weeks in maintenance and at each on-study visit prior to dosing 
for nivolumab/placebo. Vital signs should also be taken as per institutional standard of care for 
subjects during and after dosing. The start and stop times of the infusions should be documented. 
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse events page.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible.
Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac or pulmonary-related signs (hypoxia, abnormal heart rate or changes from baseline) or 
symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations). Some of the previously referred 
to assessments may not be captured as data in the eCRF. They are intended to be used as safety 
monitoring by the treating physician. Additional testing or assessments may be performed as 
clinically necessary or where required by institutional or local regulations.
5.4
Efficacy Assessments
All subjects will undergo brain Magnetic Resonance Imaging (MRI) at the time points specified 
in Table 5.1-1, Table 5.1-2, and Table 5.1-3. The baseline MRI will be used for stratification of 
randomization. If MRI is not available at study enrollment, a high-quality contrast-enhanced CT 
scan may be used; in this case, a MRI must be performed prior to randomization (> 2 weeks post-op 
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preferred). Additional MRI scan may be obtained if clinically appropriate, eg, for radiotherapy 
planning, but are not required; in this case the last scan prior to randomization that meets the 
diagnostic quality required in the imaging manual provided by the central imaging vendor will be 
considered the baseline MRI. 
On treatment and follow-up assessments may be performed at designated time points in Table 5.1-
2 and Table 5.1-3 (± 7 days). Per RANO, assessment of disease progression during study requires 
that MRI scan be performed >12 weeks after RT; it is, therefore, recommended that second 
on-treatment scan be performed at least 84 days after completion of RT. Investigators may obtain 
more frequent follow-up MRI scans as medically indicated. 
 
 Local radiologic assessment of tumor measurements will be used for clinical 
management and investigator-assessed disease progression (see Section 4.5.1.6 and Section 5.4.2).
Subjects who are unable (due to coexisting medical condition, eg, pacemaker or ICD device) or 
unwilling to have a brain MRI at baseline are excluded from the study. Subjects who become 
unable to undergo MRI imaging after randomization may continue in the study for assessment of 
overall survival as long as there is no safety issue which would require monitoring by MRI. 
Images will be submitted to a central imaging vendor for blinded independent central review 
(BICR) at any time during the study until study unblinding. Prior to scanning first participant, sites 
should be qualified and understand the image acquisition guidelines and submission process as 
outlined in the CA209-548 Imaging Manual provided by the central imaging vendor. Study sites 
will retain local access to the imaging results for safety and efficacy reading purposes. The study 
investigator will review the local MRI results as clinically appropriate to ensure that any 
potentially emergent clinical situations are addressed in a timely fashion. Clinically significant 
radiologic findings or changes from baseline scans will be coded as adverse events or serious 
adverse events according to the criteria described below in Section 6. Additional radiographic 
findings of potential clinical relevance that are not directly associated with the objectives of the 
protocol should be evaluated and handled by the Study Investigator as per standard 
medical/clinical judgment.
Sites will be trained in image acquisition parameters, image submission process, application of 
RANO criteria34 (as outlined in Section 5.4.2) prior to scanning the first study subject. These 
guidelines will be outlined in a separate Site Imaging Manual, following recent consensus 
recommendations.51 All radiologic imaging from this study (including scans performed prior to 
Screening) until study unblinding will be transmitted to a centralized imaging core lab for BICR.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study investigator as per 
standard medical/clinical judgment.
5.4.1
Suspected Progression
In order to distinguish potential treatment effects (or “pseudoprogression”) from progressive 
disease and thus to minimize premature discontinuation of nivolumab or temozolomide, subjects 
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who initially meet radiologic criteria for disease progression, but are tolerating study drug, may 
continue receiving study drug until confirmation of progression with an MRI performed 
approximately 8 weeks later. If possible, MRI perfusion images should also be obtained. If a 
determination cannot be made after an 8-week interval, then treatment may continue until either 
progression is confirmed or regression is observed, consistent with either pseudoprogression or 
immune-treatment effect. Consultation with the BMS Medical Monitor is recommended but not 
required.
Confirmation of progression is mandatory if recurrence occurs within 12 weeks of completion of 
RT. Suspected disease progression within 12 weeks after the end of RT must be confirmed by 
subsequent MRI performed within 8 weeks after the initial radiological assessment of progression. 
Prior to 12 weeks after RT, progression can only be defined using diagnostic imaging if there is 
new enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line) 
or if there is unequivocal evidence of viable tumor on histopathologic sampling.33 Note: in the 
absence of radiographic or histologic confirmation of progression, clinical decline alone is not 
sufficient for definition of progressive disease. 
If the follow-up assessment confirms that progression has occurred, the date of progression will 
be the date at which progression was first determined. If the follow-up assessment does not confirm 
progression, then the original time point response will be assessed as SD.
5.4.2
Assessment of Response
Response will be assessed using RANO34 criteria. Subjects who have undergone visible-total or 
near-total resection and have no lesion measuring ≥1 cm on 2 perpendicular diameters on baseline 
MRI cannot have a complete or partial response and will be followed only for recurrence. These 
subjects will be considered non-evaluable for BOR analysis, but their disease status will be 
assessed (SD or PD) at each tumor assessment, and they will be included in analysis of PFS and 
OS. If no signs of progression are observed, according to MRI, the radiologic assessment will be 
categorized as SD. The appearance of any index or non-index lesion consistent with tumor will be 
categorized as PD.
The assessments that will contribute to evaluation of PD include response assessments recorded 
between the date of randomization and the first to occur of the following:
•
The date of objectively documented progression per RANO criteria
•
The date of subsequent therapy, or
•
The date of pathology results from diagnostic surgical resection
The criteria in Table 5.4.2-1 will be used for assessing progression.
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Table 5.4.2-1:
Criteria for Determining First Progression Depending on Time 
From Initial Chemoradiotherapy 
Response
Criteriaa
Progressive disease
< 12 weeks after
completion of
chemoradiotherapy
Progression can only be defined using diagnostic imaging if there is new enhancement 
outside of the radiation field (beyond the high-dose region or 80% isodose line) or if there 
is unequivocal evidence of viable tumor on histopathologic sampling (eg, solid tumor areas 
[ie, > 70% tumor cell nuclei in areas], high or progressive increase in MIB-1 proliferation 
index compared with prior biopsy, or evidence for histologic progression or increased 
anaplasia in tumor). Note: Given the difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of radiographic or histologic 
confirmation of progression, will not be sufficient for definition of progressive disease in 
the first 12 weeks after completion of concurrent chemoradiotherapy.
Progressive disease
≥ 12 weeks
after
chemoradiotherapy
completion
1. New contrast-enhancing lesion outside of radiation field on decreasing, stable, or 
increasing doses of corticosteroids.
2. Increase by ≥ 25% in the sum of the products of perpendicular diameters between the 
first postradiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 
12 weeks or later on stable or increasing doses of corticosteroids.
3. Clinical deterioration not attributable to concurrent medication or comorbid conditions 
is sufficient to declare progression on current treatment but not for entry onto a clinical 
trial for recurrence.
4. For patients receiving antiangiogenic therapy, significant increase in T2/FLAIR 
nonenhancing lesion may also be considered progressive disease. The increased T2/FLAIR 
must have occurred with the patient on stable or increasing doses of corticosteroids 
compared with baseline scan or best response after initiation of therapy and not be a result 
of comorbid events (eg, effects of radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects).
NOTE: Radiologic interpretation guidelines, definitions and tumor measurement instructions will be provided 
separately in a separate imaging manual. All measurable and nonmeasurable lesions must be assessed using the same 
techniques as at baseline.
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery
* Stable doses of corticosteroids include subjects not on corticosteroids
Table 5.4.2-2:
Assessment of Best Overall Response
Best Overall Response
Criteria
Complete Response (CR)
CR observed in consecutive assessments ≥4 weeks apart per RANO
Partial Response (PR)
PR observed in consecutive assessments ≥4 weeks apart per RANO
Stable Disease (SD)a
SD observed and does not qualify for CR or PR
or Suspected PD followed with histologic results not confirming PD, and no 
CR, PR or SD observed
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Table 5.4.2-2:
Assessment of Best Overall Response
Best Overall Response
Criteria
Not Evaluable (NE)
Insufficient data to determine disease progression or response
Progressive Disease (PD)
No CR, PR, or SD prior to PD
a To qualify for SD there must be a minimum on-treatment period of 10 weeks.
The minimum duration between baseline post-operative scan and first on-study scan in order to 
determine BOR of SD is 4 weeks after completion of RT. If the minimum time is not met when 
SD is otherwise the best time point response, the subject’s best response will depend on the 
subsequent assessments. For example, a subject who has SD at a time point < 4 weeks post-RT 
and PD at a second assessment will have a best response of PD.
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5.6.1
Tumor Samples
 
Tumor tissue (block or slides) 
must be available for submission prior to randomization. If a block is not available, a minimum of 
20 unstained slides of good quality is required. In situations where on-treatment biopsies or 
surgeries are performed, tumor sample should be sent for central pathology reading.
5.6.1.1
Tumor Sample Collection Details
Collection of tumor tissue at diagnostic surgery is required for study eligibility. Additional biopsies 
obtained at any time, eg, if progression is suspected, should also be submitted. 
Biopsy samples from neurosurgical resections should be fixed in 10% Neutral-buffered formalin 
for 24 – 48 hours prior to paraffin embedding. Tumor tissue samples should not be shipped in 
formalin as the temperature and length of fixation cannot be controlled during shipping.
 2 paraffin blocks are requested 
(1 minimum). If only slides are available, they should be unstained, have a recommended tissue 
section thickness of 4 microns and be positively charged. Slides must be shipped refrigerated at 
2-8° C.
An assessment of tissue quality by a pathologist is strongly encouraged at the time of the 
procedure. 
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Sample shipments should include a completed requisition form containing collection date, 
collection method, primary/met, site, fixation conditions, and a copy of the pathology report, if 
available.
Detailed instructions of the obtaining, processing, labeling, handling, storage, and shipment of 
specimens will be provided in a separate Procedure Manual at the time of study initiation.
5.6.1.2
MGMT Status
Randomization to this study is limited to subjects with established MGMT-methylated or 
indeterminate status. Testing will be performed using a centralized RT-PCR assay through study 
CA209498.
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5.8
Other Assessments 
5.8.1
Results of Central Pathology Reading
In situations where on-treatment biopsies or surgeries are performed, tumor sample should be sent 
for central pathology reading. Instructions for shipping biopsy samples/slides can be found in the 
lab manual. Investigators will receive central pathology results.
5.8.3
Results of Central Radiology Assessments
The clinical management of subjects during the study protocol and PFS will be based upon local 
radiologic tumor measurements and the investigator-assessed RANO response criteria described 
in Section 1.2. Radiologic imaging from this study will be also be transmitted to a centralized 
imaging core lab until study unblinding for storage and for analysis by blinded independent central 
review. The site will be informed of quality issues or need for repeat scanning via queries from the 
core lab.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
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temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The definition of immune-mediated AEs can be found in Section 0.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study treatment administration
(including SOC) and the AE.
Not related: There is not a reasonable causal relationship between study treatment
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
In this study the relationship may be assessed to any component of the study treatment: radiation 
therapy, TMZ, and/or nivolumab/placebo.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI)
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Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE. (See Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
−
admission for administration of anticancer therapy in the absence of any other SAEs 
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs, and all AEs (SAEs and non-serious AEs) associated with 
confirmed or suspected SARS-CoV-2 infection, must be collected that occur during the screening 
period and within 100 days following the last dose of nivolumab and for 30 days following the last 
dose of temozolomide. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy). For subjects randomized and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements. 
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information (with the exception of non-serious AEs related to 
SARS-CoV-2 infection) should begin at initiation of study drug. Nonserious AE information 
should also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects. 
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Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of nivolumab treatment, and for 30 days following discontinuation of temozolomide treatment.  
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the subject’s case report form.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (electronic) as appropriate: Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the Sponsor or 
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS Designee 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call Sponsor or designee within 24 hours of 
awareness of the pregnancy.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
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of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant within 6 months (or as 
noted in the locally applicable package insert, summary of product characteristics [SmPC] or 
similar document) of the last dose of TMZ should be reported to Sponsor or designee. In order for 
BMS to collect any pregnancy surveillance information from the female partner, the female partner 
must sign an informed consent form for disclosure of this information. Information on this 
pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
•
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
•
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the subject’s case report form.
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“Treatment effect,” collected in CNS studies only, is a neurologic AE related to nivolumab 
attributable to the immune-reaction at or around the tumor site. Most commonly, these are 
confusion, seizure, weakness, vomiting, aphasia, hydrocephalus, etc (depending on tumor site). 
Use of “tumor flare” as a single aggregate AE term is preferable to reporting each individual 
neurologic finding.  [Note: MRI findings per se are not AEs.]
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
A Data Monitoring Committee will be established to provide oversight of safety and efficacy 
evaluation of the entire study and to provide advice to the sponsor regarding actions the committee 
deems necessary for the continuing protection of subjects. The DMC will be charged with 
assessing such actions in light of an acceptable benefit/risk profile for nivolumab. The DMC will 
act in an advisory capacity to BMS and will monitor subject safety and evaluate the available 
efficacy data for the study. The oncology therapeutic area of BMS has primary responsibility for 
design and conduct of the study. The DMC will meet at least every 6 months or more frequently 
as needed on an ad-hoc basis. Information regarding DMC membership, responsibilities, and 
procedures are detailed in the DMC charter. The DMC will be informed should a safety signal 
emerge and may convene an ad-hoc meeting on its own initiative. The DMC will review all 
available data (safety and efficacy) at each meeting. At the conclusion of each DMC meeting the 
committee, will provide the sponsor with a recommendation to continue, modify or terminate the 
study protocol based upon their review. Ultimately, decisions regarding the study protocol will be 
made by the sponsor in conjunction with feedback from investigators and the DMC. Following 
study unblinding, the DMC will be discontinued, and the sponsor will monitor safety for the 
subjects remaining on treatment.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is a Phase 3, randomized, single blinded, multicenter study of RT + TMZ + nivolumab or 
placebo in adult (≥18 years) subjects with newly diagnosed GBM and MGMT-methylated or 
indeterminate tumors.
The familywise type I error rate for the primary comparisons will be set to 0.05, with 0.01 being 
allocated to the PFS comparison and 0.04 being allocated to the OS comparison. 
The primary objectives of the study are:
•
to compare progression-free survival (PFS) in an all-comers group of subjects with newly 
diagnosed MGMT-methylated or indeterminate GBM subtypes treated with RT plus TMZ 
combined with nivolumab or placebo.
•
to compare overall survival (OS) of subjects with newly diagnosed MGMT methylated or 
indeterminate GBM subtypes without baseline corticosteroids and regardless of baseline 
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corticosteroids (ie, all-comers) treated with RT plus TMZ combined with nivolumab or
placebo. 
These primary objectives on OS will test RT plus TMZ combined with nivolumab or placebo in 
the following hierarchy via a stratified log rank test: 
1) OS in newly diagnosed MGMT-methylated or indeterminate GBM subtype without baseline 
corticosteroids. 
2) If 1 is significant, OS in newly-diagnosed MGMT-methylated or indeterminate GBM subtype 
regardless of baseline steroid use (all comers).
The sample size for this study is based on the following assumptions:
•
PFS and OS follows exponential distribution
•
Median PFS in RT+TMZ arm is 10.0 months
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ for PFS is 0.68, translated to 
median PFS improvement of 4.7 months (10.0 months vs 14.7 months for arm RT + TMZ and 
arm RT + TMZ + nivolumab, respectively)
•
Median OS in RT+TMZ arm is 26.0 months54
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ is 0.7 for the randomized 
population with no baseline corticosteroid, translated to median OS improvement of 11.1 
months (26.0 months vs 37.1 months for arm RT + TMZ and arm RT + TMZ + nivolumab, 
respectively)
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ is 0.75 for the overall 
randomized population, translated to median OS improvement of 8.7 months (26.0 months vs 
34.7 months for arm RT + TMZ and arm RT + TMZ + nivolumab, respectively)
•
Proportion of no baseline corticosteroid population within the entire newly-diagnosed MGMT-
methylated or indeterminate GBM subtypes is 0.70
Approximately 693 subjects will be randomized in a 1:1 ratio, stratified by complete or partial 
resection. Of these 693 subjects, 485 subjects are assumed to be no baseline corticosteroids. 
Accrual is estimated to take approximately 25 months based on an observed monthly accrual in 
CA209548 of approximately 28 subjects per month; in the no baseline corticosteroids population, 
a piecewise accrual of 1, 4, 5, 8, 13, 16, 19, and then 23 subjects per month thereafter is assumed. 
At least 337 OS events (deaths) in the no baseline corticosteroid population are needed to achieve 
88% power using a 2-sided Type 1 error of 4%. This number of events is projected to occur after 
an additional 44 months of follow-up (ie, at 69 months). 
One interim analysis will be conducted on OS in the randomized population with no baseline 
corticosteroid. It will occur approximately 20 months after accrual is finished or when 70% or 236
OS events is reached which is estimated to occur at 45 months after study start, providing a 58% 
probability of stopping under H1. The stopping boundaries at the interim and final analyses will 
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be based on the actual number of OS events at the time of the analysis using Lan-DeMets alpha 
spending function with O’Brien-Fleming boundaries. If the planned interim analyses occur exactly 
at the planned number of events, the projected alpha level will be 0.011 and 0.037. 
See Table 8.1-1. The interim analysis will also be conducted on OS in the overall randomized 
population. The interim analysis will be conducted at the same time as the interim for the no 
baseline corticosteroids population in a hierarchy with stopping boundaries at the interim and final 
analysis based on actual number of OS events at the time of the analysis using Lan-DeMets alpha 
spending function with O’Brien-Fleming boundaries. 
The PFS comparisons will be based on first 558 randomized subjects in all-comers. At least 
404 PFS events are needed to achieve 90% power using a 2-sided Type 1 error of 1%. Accrual is 
estimated to take approximately 23 months and this number of events is projected to occur after 
an additional 12 months of follow-up (ie, at 35 months).
The technique of alpha-recycling will be used to adjust for multiplicity with details provided in 
the SAP.
Power calculations were done using East v 6.3 and R.
Table 8.1-1:
Key Parameters of Sample Size Calculation of PFS and OS
Primary Endpoint
PFS
OS
OS
Power
90%
88%
87%
Alpha
0.01
0.04
0.04
Hypothesized Median Control vs. exp (months)
10 vs 14.7
26 vs 37.1
26 vs. 34.7
Hypothesized Hazard ratio
0.68
0.7
0.75
Expected number of events for comparison 
towards primary objective
404
337
494
Accrual Duration (months)
23
25
25
Sample size
558 
(all-comers)
485 (no baseline 
corticosteroids)
693 
(all-comers)
Expected number of events at IA
N/A
236
346
FPFV to IA (months)
N/A
45
45
FPFV to LPLV (months)
35
69
69
8.2
Populations for Analyses
•
All Enrolled subjects: All subjects who signed an informed consent form and were registered 
into the IVRS
•
All Randomized subjects: All enrolled subjects who were randomized to any treatment arm. 
This is the primary dataset for analyses of efficacy parameters and baseline characteristics
•
All Treated subjects: All randomized subjects who received at least one dose of study drug. 
This is the primary dataset for safety and exposure analyses.
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
The two primary endpoints of the trial will be OS in the randomized population with no 
corticosteroids at baseline as well as in the overall randomized population, and PFS determined by 
BICR, based on RANO criteria (see Section 5.4.2).
8.3.2
Secondary Endpoint(s)
OS rate at 12 months and 24 months estimated from OS Kaplan-Meier curve.
PFS determined by investigator assessment based on RANO criteria.
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized for all randomized subjects by 
treatment group, as randomized, using descriptive statistics.
8.4.2
Efficacy Analyses
OS is defined as time from the date of randomization to the date of death. Subjects who have not 
died by the end of the study will be censored to last known date alive. The analysis of the OS 
endpoint will be based on all randomized subjects in the respective populations of no baseline 
corticosteroids and the overall randomized population. A group sequential testing procedure will 
be applied to OS to control the overall type I error from interim and final analyses. Each analysis 
will be conducted in a hierarchy first testing OS in the population of no baseline corticosteroids 
and then if positive in the overall randomized population. The α spending function is described in 
Section 8.1. 
PFS is defined as the time from randomization to the date of the first documented tumor 
progression or death by any cause. Subjects who did not have disease progression or die will be 
censored at the date of the last tumor assessment. Subjects who did not have any on study tumor 
assessment and did not die will be censored at the last tumor assessment. Subjects who started any 
subsequent anti-cancer therapy without a prior reported progression will be censored at the last 
tumor assessment prior to initiation of the anti-cancer therapy. Subjects who had surgical resection 
after start of study treatment will be censored at the last tumor assessment date prior to initiation 
of surgical resection. PFS will be determined by BICR based on RANO criteria. 
8.4.2.1
Analyses of Primary Endpoint
The distribution of OS in the sub-population of subjects with no baseline corticosteroids and in all 
randomized subjects will be compared in arms RT + TMZ + nivolumab and RT + TMZ at interim 
and final analyses via two-sided, log-rank tests, stratified by complete resection or partial resection 
at baseline. The boundaries for declaring superiority at the interim and final analyses will be based 
on the actual number of OS events at the time of the analysis using Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries. For example, if the interim and final analyses occur 
exactly at the planned number of events, superiority of an arm will be declared if P ≤0.011 at the 
interim analysis or P ≤0.037 at the final analysis. The Kaplan-Meier product limit method will be 
used to estimate the survival curve in each arm including medians and its 95% CI, OS rates at 
various time points. The HR and the corresponding two-sided (1-adjusted α) % CIs will be 
estimated in a Cox proportional hazards model with treatment arm as a single covariate stratified 
by corresponding stratification factor (complete or partial surgical resection at baseline).
The comparison of PFS (by BICR) will be based on a two-sided log-rank test stratified by 
corresponding stratification factor (complete surgical or partial resection at baseline). PFS will be 
compared in the first 558 subjects out of the (total) 714 treated subjects. The Kaplan-Meier product 
limit method will be used to estimate the survival curve in each arm including medians and its 
95% CI, PFS rates at various time points. The HR and the corresponding two-sided 99% CIs will 
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be estimated in a Cox proportional hazards model with treatment arm as a single covariate stratified 
by corresponding stratification factor (complete or partial surgical resection at baseline).
PFS (based on BICR) will be analyzed in overall randomized subjects and all randomized subjects 
without baseline corticosteroids.
The CA209548 DMC convened on 09-Dec-2020 to conduct a pre-planned, routine safety review 
of all data. Although the initial recommendation was that the study should continue unchanged 
and this was communicated to study investigators, subsequently the DMC notified BMS that they 
had deliberated further and unanimously agreed on the following:
•
The OS data clearly shows that there is no plausible scenario for this study to have a positive 
OS result at the final analysis based on either all randomized patients or on patients without 
baseline corticosteroids. This statement is based on the DMC̓s review of the OS results to 
date, with over 80% of the final required number of events reached and related statistical 
considerations including conditional power of < 1% for a statistically significant final result.
•
While the group receiving nivolumab has a higher incidence of toxicities, the DMC members 
believed the increased toxicity was expected and did not warrant stopping the study because 
of safety.
The DMC recommended to unblind the sites and subjects, which was approved by BMS. The study 
was unblinded to investigators on 22-Dec-2020. As a consequence, the timing of the primary OS 
analysis, originally planned for when 337 and 494 events were to be reached respectively for the 
population without corticosteroids at baseline and the overall population, has been updated. To 
prevent any bias due to unblinding of subjects, the primary OS analysis will be conducted using 
the cut-off date (or LPLV) of 22-Dec-2020, which is when the study was unblinded.
The primary OS analysis in all randomized subjects without baseline corticosteroids and the 
primary PFS analysis in all randomized subjects will report a p-value as planned in the alpha 
recycling plan. Overall survival in all randomized subjects will be tabulated descriptively, as 
described in the current SAP. Potential subsets analyses will be presented descriptively. The 
primary analysis of PFS per BICR will be conducted using the cut-off date of 14-Jun-2019 with a 
database lock date of 09-Aug-2019 (the primary PFS analysis assessed by the DMC in 2019). The 
same analysis will also be conducted using the cut-off date of 22-Dec-2020.
Based on CP calculation (< 1%) for OS, there is no plausible scenario for this study to have a 
positive OS result. Therefore, only selected analyses will be included in the primary Clinical Study 
Report, as described in the current SAP.
8.4.2.2
Analyses of Secondary Endpoints
Overall survival rates at 12 and 24 months will be derived from the Kaplan Meier estimate and
corresponding confidence interval will be derived based on Greenwood formula for variance
derivation and on log-log transformation applied on the survivor function.
PFS based on investigator assessment will be analyzed in the first 558 subjects, all randomized 
subjects and all randomized subjects who did not receive corticosteroids at baseline.
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All secondary endpoints will be analyzed at the same time as the OS and PFS primary analyses
using the analysis methods already defined in the SAP.
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8.5
Interim Analyses
This study will include 1 formal interim analysis on OS for superiority. 
A formal interim analysis for superiority of OS will be performed when approximately 236 (70% 
of planned events or 236/337) events is reached in the population of no baseline corticosteroids. 
Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary will be used. 
The stopping boundary will depend on the actual number of OS events at the time of the interim 
analysis. At the time of the interim analyses, the DMC will review OS and other efficacy endpoints 
as defined in the DMC charter.
In addition to the formal planned interim analysis for OS, the DMC will have access to periodic 
interim reports of efficacy and safety to allow a risk/benefit assessment. Details will be included 
in the DMC charter. 
8.6
End of Study Analyses at Study Closure 
Subjects who have continued on study treatment following the study unblinding will be followed 
per protocol through treatment discontinuation and safety follow-up. 
The end of study analyses will be performed for the selected safety and duration of treatment data
using all randomized subjects. 
Data to be reported:
•
Subject disposition
•
Duration of treatment (nivolumab, temozolomide)
•
Death
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•
Adverse events
•
Serious adverse events
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations per national requirements
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) if applicable, also by local health authority, must be sent to BMS. If an amendment 
substantially alters the study design or increases the potential risk to the subject: (1) the consent 
form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable 
opinion; (2) the revised form must be used to obtain consent from subjects currently enrolled in 
the study if they are affected by the amendment; and (3) the new form must be used to obtain 
consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS or designee representatives will review data centrally to identify potential issues to determine 
a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by BMS or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS or designee. 
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9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.2
Records
9.2.1
Records Retention
The investigator (or head of study site in Japan) must retain all study records and source documents 
for the maximum period required by applicable regulations and guidelines, or institution 
procedures, or for the period specified by BMS or designee, whichever is longer. The investigator 
(or head of study site in Japan) must contact BMS or designee prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health Authority.
If...
Then...
Supplied by BMS (or 
its vendors):
Records or logs must comply with applicable regulations and guidelines and should 
include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each subject, including unique subject 
identifiers
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If...
Then...
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
Sourced by site, and 
not supplied by BMS 
or its vendors 
(examples include IP 
sourced from the sites 
stock or commercial 
supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility for documenting traceability and 
study drug integrity in accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject 
identifiers
•
dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 
 
 CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
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Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
BMS or designee at the earliest practicable time prior to submission or presentation and otherwise 
within the time period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete 
Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence for entry into a clinical trial, 
post-ovulation methods) and withdrawal, which are not acceptable methods of 
contraception. Women must continue to have pregnancy tests. Acceptable alternate methods 
of highly or less effective contraception’s must be discussed in the event that the subject 
chooses to forego complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
ACTH
adrenocorticotropic hormone
AE(s)
adverse event(s)
AIDS
Acquired Immunodeficiency Syndrome
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
β-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BICR
Blinded Independent Central Review
BMS
Bristol-Myers Squibb Company
BOR
Best Overall Response
BP
blood pressure
BSA
body surface area
BUN
blood urea nitrogen
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CTA
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
%CV%
geometric mean
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Term
Definition
DILI
drug-induced liver injury
dL
deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTIC
Dacarbazine
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
Eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
ESR
expedited safety report
FDA
Food and Drug Administration
FLAIR
fast fluid-attenuated inversion recovery
FSH
follicle stimulating hormone
GBM
glioblastoma
GCP
Good Clinical Practice
Gy
Gray (radiotherapy dose)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
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Term
Definition
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCV-RNA
hepatitis C virus-ribonucleic acid
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
IB
investigator brochure
ICD
implantable cardioverter defibrillator
ICF
informed consent form
ICH
International Conference on Harmonisation 
Ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
imAEs
immune-mediated adverse events
IND
Investigational New Drug Exemption
I-O
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRC
Independent Radiology Review Committee
IU
international unit
IUDs
intrauterine devices
IV
intravenous
IVRS
interactive voice response system
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Term
Definition
K+
potassium
Kg
kilogram
LPLV
Last patient last visit
mg
milligram
Mg/kg
milligram per kilogram
Mg++
magnesium
MGMT
tumor O-6-methylguanine DNA methyltransferase
mL
milliliter
MMR
measles, mumps, rubella 
MRI
magnetic resonance imaging
μg
microgram
N
number of subjects or observations
N
nivolumab (BMS-936558)
Na+
sodium
N/A
not applicable
NCI
National Cancer Institute
NE
not evaluable
NIMP
non-investigational medicinal products 
O2
oxygen
OS
overall survival
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Term
Definition
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PID
patient identifier 
PO
per os (by mouth route of administration)
PR
partial response
PVC
polyvinyl chloride
QD
once a day 
QOL
quality of life
RANO
Radiologic Assessment in Neuro-Oncology
RR
respiratory rate
RT
radiation therapy
RT-PCR
reverse transcription polymerase
SAE(s)
serious adverse event(s)
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SAP
statistical analysis plan 
SD
stable disease
SmPC
summary of product characteristics
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Term
Definition
SOC
standard of care 
SOP
standard operating procedures
T1/2
geometric elimination half-life
TIL
tumor infiltrating lymphocytes
TMZ
Temozolomide
TSH
thyroid stimulating hormone
μg
microgram
ULN
upper limit of normal
w
week
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 1
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 2
RADIATION THERAPY GUIDELINES
Radiation therapy for GBM contributes importantly to both efficacy and toxicity. Modern 
radiotherapeutic management of GBM was recently summarized: Niyazi M, et al. (2016) 
ESTRO-ACROP guideline “target delineation of glioblastomas”. Radiother Oncol 118:35-42.
A high level of experience is assumed in participating centers. Guidelines are provided in order 
to support appropriate homogeneity in a trial environment without imposing excessive 
constraints on expert practice. Therefore, the following guidelines should be interpreted as 
expectations rather than protocol requirements.
Dose Specification 
A total dose of 60 Gy, in 2 Gy daily fractions on 5 days/week, will be administered in 6 weeks 
(30 fractions). Radiation treatment duration may be extended due to delays or holidays up to 
7 weeks (49 calendar days). 
Radiation treatment will be delivered with a megavoltage machine with photon energy ≥6 MV
utilizing either 3-D Conformal or Intensity-Modulated (IMRT or VMAT) approaches. Electron, 
particle, or implant boost is not permitted.
An initial target volume (see below definitions) will be irradiated to 46 Gy in 23 fractions with 
an additional 14 Gy in 7 fractions to the boost volume for a total of 60 Gy. Alternatively, based 
on institutional practice, a one-phase approach to a dose of 60 Gy, is acceptable. 
Simulation and Treatment Planning
Simulation using treatment planning CT (supine position with immobilization, eg, thermoplastic 
mask) is standard. Fusion with MR images for target and OAR delineation is mandatory. 
Target volumes will be based upon post-operative
contrast-enhanced MRI, although 
pre-operative imaging should be used for correlation, and may be modified based on subsequent 
scans if anatomic shift is evident. The method of dose volume planning and documentation 
should be not be investigational.
The initial gross tumor volume (GTV1) is defined by either the T2 or the FLAIR abnormality, 
including enhancing tumor volume and surgical cavity. The boost volume (GTV2) will be based 
on the T1-enhancing tumor volume plus the surgical cavity. Derived clinical target volumes 
(CTV1-2) are the corresponding GTV plus a margin of approximately 2 cm; smaller margins are 
permitted, based on clinical judgment and anatomic constraints. Planning target volume 
(PTV1-2) margins, typically approximately 0.5 cm, will be determined by institutional practice 
based on technical considerations and reproducibility. Weekly verification is expected.
Doses will be specified such that at least 95% of the planned CTV shall receive 100% of the 
prescribed dose, with acceptable variance of 90% PTV coverage for clinical or technical reasons.
Isodose distributions must be recorded. Details of field modification will be determined by the 
radiation oncologist using currently-accepted practice based on primary tumor extension, natural 
structures and organs at risk (eg, optic chiasm or brainstem), as well as on reproducibility 
considerations, potential overlap regions and the like.
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APPENDIX 3
KARNOFSKY PERFORMANCE SCALES
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort, some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death nor imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
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APPENDIX 4
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below. Local laws and regulations may require use of alternative and/or additional contraception 
methods.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as 
follows:
1) Progestogen only hormonal contraception associated with inhibition of ovulation.
2) Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena®
3) Nonhormonal IUDs, such as ParaGard®
4) Bilateral tubal occlusion
5) Vasectomised partner with documented azoospermia 90 days after procedure
♦Vasectomised partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomised partner 
has received medical assessment of the surgical success.
6) Intrauterine hormone-releasing system (IUS).
7) Complete abstinence
♦Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
(refer to Glossary of Terms)
♦Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).
♦It is not necessary to use any other method of contraception when complete abstinence is 
elected.
♦Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 5.
♦Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
♦The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
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UNACCEPTABLE METHODS OF CONTRACEPTION
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2) Withdrawal (coitus interruptus)
3) Spermicide only
4) Lactation amenorrhea method (LAM)
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APPENDIX 5
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 06, 26-Feb-2021
The CA209548 Data Monitoring Committee (DMC) convened on 09-Dec-2020 to conduct a 
pre-planned, routine safety review of all data. Although the initial recommendation was that the 
study should continue unchanged and this was communicated to study investigators, 
subsequently the DMC notified BMS that they had deliberated further and unanimously agreed 
on the following:
•
The overall survival (OS) data clearly shows that there is no plausible scenario for this study 
to have a positive OS result at the final analysis based on either all randomized patients or on 
patients without baseline corticosteroids. This statement is based on the DMC’s review of the 
OS results to date, with over 80% of the final required number of events reached and related 
statistical considerations including conditional power of < 1% for a statistically significant 
final result.
•
While the group receiving nivolumab has a higher incidence of toxicities, the DMC members 
believed the increased toxicity was expected and did not warrant stopping the study because 
of safety.
The DMC recommended to unblind the sites and patients, which was approved by BMS. The 
study was unblinded to investigators on 22-Dec-2020. As a consequence, the timing of the 
primary OS analysis, originally planned for when 337 and 494 events were to be reached 
respectively for the population without corticosteroids at baseline and the overall population, has 
been updated. To prevent any bias due to unblinding of patients, the primary OS analysis will be 
conducted using the cut-off date (or last patient last visit [LPLV]) of 22-Dec-2020, which is 
when the study was unblinded.
Following unblinding, study subjects who were currently on nivolumab therapy, tolerating the 
treatment, and were considered by the treating physician to derive benefit were permitted to 
continue if they choose. However, study procedures in the treatment and follow-up phases are 
now simplified, since additional post-unblinding data are no longer needed for analyses.
Protocol languages per BMS standards for nivolumab studies and for COVID-19 have also been 
incorporated. 
This protocol amendment incorporates the changes from the approved Administrative Letters 10 
and 11 which are not detailed in the summary of key changes below.
Summary of key changes of Protocol Amendment 06
Section Number & Title
Description of Change
Brief Rationale
Title Page
The study contacts and naming 
conventions have been updated.
The name, address, and 
confidentiality statement of the 
Sponsor have been updated. 
Changes in BMS personnel and team 
assignments.
Changes in the BMS protocol model 
document.
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Summary of key changes of Protocol Amendment 06
Section Number & Title
Description of Change
Brief Rationale
Summary: Study Design
Unblinding information has been 
added.
Follow-up for progression and 
survival after study treatment 
discontinuation has been deleted.
The study was unblinded following 
DMC recommendation, necessitating 
this amendment to update the timing 
of the primary OS analysis and to 
simplify study procedures following 
unblinding.
3.1: Study Design and Duration
Post-treatment follow-up 
instructions revised to remove 
contrast MRI.
BICR submission will stop with 
unblinding, clarification added.
Following study unblinding, the 
collection of imaging data for 
analysis purposes is not relevant; 
BICR and post-treatment imaging 
data is no longer needed.
Summary: Study Schematic Figure 
3.1-1: Study Design Schematic
Schematic figure updated to: safety 
only following unblinding
Clarification added below figure 
indicating that following
unblinding, subjects may continue 
on treatment.
Aligned with changes concerning 
study unblinding.
Summary: Study Assessments
3.1.3: Follow-up Phases
Follow up procedures have been 
further clarified.
Instructions for assessments after 
treatment discontinuation for 
reasons other than disease 
progression have been removed.
Aligned with simplified procedures 
following study unblinding; 
3.1.4: Overall Study Duration
Updates due to unblinding, 
including the timing of study 
closure, have been made.
The study was unblinded following 
DMC recommendation; the OS 
primary analysis will include data 
through the date of study unblinding. 
Additional OS data are not required, 
so the study will close following all 
subjects’ treatment discontinuation 
and safety follow-up.
3.3.1: Inclusion Criteria
Male contraception requirements 
revised for Inclusion Criterion 3e. 
Updated per BMS standard for all 
studies with nivolumab.
3.5: Discontinuation of Subjects 
following any Treatment with 
Study Drug
Post-treatment follow-up for 
progression and survival has been 
removed.
Aligned with changes concerning 
study unblinding.
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Summary of key changes of Protocol Amendment 06
Section Number & Title
Description of Change
Brief Rationale
3.6: Post Study Drug Follow-up
Post-treatment follow-up for 
survival has been removed.
Aligned with changes concerning 
study unblinding.
4.5.1: Nivolumab/Placebo Dosing
Unblinding clarification added.
Due to study unblinding, the 
provisions for dosing and dose 
modification no longer apply for the 
placebo treatment arm.
4.5.1.3: Dose Delay Criteria for 
Nivolumab/Placebo
4.5.1.4: Criteria to Resume Dosing 
for Nivolumab/Placebo
Added SARS-CoV-2 infection 
criteria
Updated per BMS standard for 
COVID-19 protocol language.
4.5.1.5: Treatment Discontinuation 
Criteria for Nivolumab/Placebo
Decision by treating physician and 
subject to discontinue treatment 
following unblinding has been 
added to criteria for 
discontinuation.
Aligned with changes concerning 
study unblinding.
4.6: Blinding/Unblinding
Statement regarding unblinding 
has been added.
The study was unblinded following 
DMC recommendation, necessitating 
this amendment to update the timing 
of the primary OS analysis and to 
simplify study procedures following 
unblinding.
Table 5.1-2: On-treatment 
Assessments
Table 5.1-3: Treatment Follow-up 
and Survival Follow-up
Footnote ‘a’ added to chemistry 
panel row.
Footnote ‘a’ updated to clarify 
chemistry panel collection in 
relation to TMZ dosing.
 
 
notes 
clarified to include instructions 
following unblinding.
Footnote ‘a’ updated to add 
instructions following unblinding.
Footnote ‘b’ updated to clarify that 
survival follow-up visits do not 
occur following unblinding.
Aligned with simplified procedures 
following study unblinding; 
subsequent response, survival, 
 
 are no 
longer needed.
5.3: Safety Assessments
Clarification for subjects on TMZ 
treatment following placebo 
discontinuation has been added.
Instruction to evaluate for cardiac 
or pulmonary toxicity has been 
added.
Aligned with changes concerning 
study unblinding.
Updated per BMS standard for all 
studies with nivolumab.
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Summary of key changes of Protocol Amendment 06
Section Number & Title
Description of Change
Brief Rationale
5.4: Efficacy Assessments
5.8.3: Results of Central Radiology 
Assessments
Clarification has been added to 
discontinue BICR submission, 
 
 following unblinding.
Aligned with simplified procedures 
following study unblinding; 
subsequent response data
 
are no 
longer needed.
6.1.1: Serious Adverse Event 
Collection and Reporting
6.2.1: Nonserious Adverse Event 
Collection and Reporting
6.4: Pregnancy
Clarification has been added 
concerning SAEs and non-serious 
AEs related to SARS-CoV-2.
Clarification for collection of 
nonserious AEs for a minimum of 
100 days following discontinuation 
of nivolumab and 30 days
following discontinuation of TMZ 
has been added.
Clarification that a pregnancy 
occurring in the female partner of a 
male subject within 3 months of 
his last dose of TMZ must be 
reported to the Sponsor has been 
added.
Updated per BMS standard for 
COVID-19 protocol language.
Aligned with simplified procedures 
following study unblinding; 
continued AE collection is not 
needed for subjects discontinuing the 
placebo treatment arm. Subjects in 
the placebo treatment arm who 
discontinue TMZ treatment require 
30 days of adverse event collection 
following the last TMZ dose. 
Updated pregnancy reporting per 
BMS standard for all nivolumab 
studies. 
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Summary of key changes of Protocol Amendment 06
Section Number & Title
Description of Change
Brief Rationale
Summary: Primary Endpoints
8.1: Sample Size Determination
8.4.2.1: Analyses of Primary 
Endpoint
8.5: Interim Analyses
Statement describing the impact of 
DMC unblinding decision has been 
added. 
Statistical description of the 
primary OS analysis has been 
updated.
PFS interim analysis updated per 
Administrative Letter 10.
The study was unblinded following 
DMC recommendation; the OS 
primary analysis will include data 
through the date of study unblinding, 
and is no longer event driven.
The PFS interim analysis was 
removed.
Summary: Secondary Endpoints
8.4.2.2: Analyses of Secondary 
Endpoints
Clarification for the timing of 
secondary endpoint analysis added.
Aligned with updated timing for the 
OS primary analysis. 
8.6: End of Study Analyses at 
Study Closure
Section added to describe what 
analyses will occur at study closure 
once all post unblinding data have 
been collected.
Subjects may remain on study 
treatment post unblinding and will be 
followed through the safety follow-
up phase. Limited reporting will be 
completed as described in the 
analysis plan.
Overall Rationale for Revised Protocol 05, 08-Nov-2018
Per Revised Protocol 05, progression free survival (PFS) has been changed from a secondary to a 
primary objective of the study. In support of this change, blinded independent central review 
(BICR) has been added and may occur at any time during the study. Overall survival (OS) rate at 
12 and 24 months and PFS based on investigator assessment by RANO criteria have been added 
as secondary objectives. The statistical section has been revised to support changes in the study 
objectives. The study will now include 1 formal interim analysis for PFS and 1 formal interim 
analysis for OS for superiority.
Updates per BMS standards for nivolumab studies and changes per Administrative Letter 06, as 
described in the document history on the preceding page, have also been incorporated.
Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Synopsis, Objectives, Research 
Hypothesis, and Study Schema
•
Sections 1.3.1 and 1.3.2  
Primary and Secondary 
Objectives
Change of PFS to a primary 
rather than a secondary objective.
Addition of OS rate at 12 and 24 
month as a secondary objective.
PFS has been changed to a primary 
objective of the study and is 
supported by the addition of BICR. 
PFS as surrogate survival marker 
enables an earlier assessment of 
treatment effects. 
Survival rates at 12 and 24 months 
are widely used endpoints in 
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Section 3.1 Study Design and 
Duration and Figure 3.1-1 
Study Design Schematic 
neuro-oncology to better describe 
long-term survival or a “plateau”.
•
Synopsis Objectives
•
Section 1.3.2 and 1.3.3 
Secondary 
 
Objectives 
PFS based on investigator 
assessment by RANO criteria 
added as a secondary objective.
As a secondary endpoint, PFS will 
also be estimated by investigator 
assessment based on RANO criteria 
to compare it with PFS determined 
by BICR. 
•
Synopsis, Study Assessments
•
5.4 Efficacy Assessments
Language added to specify that 
study images will be submitted to 
a central imaging vendor for 
blinded independent central 
review (BICR) at any time during 
the study.
The addition of BICR supports the 
change of PFS to a primary objective 
of the study. BICR performed by 
blinded radiologists at a central 
facility provides the most objective 
evaluation of the PFS endpoint. 
•
Synopsis, Statistical 
Considerations
•
Section 8: Statistical 
Considerations
The statistical section has been 
revised to support changes in the 
study objectives. Of note, the 
study will now include 1 formal 
interim analysis for PFS and 
1 formal interim analyses for OS
for superiority.
Aligned with changes in study 
objectives.
•
Section 3.1.4 Overall Study 
Duration
Text changes that reflect changes 
in the study objectives and 
interim analyses. 
Aligned with changes in study 
objectives and updated statistical 
considerations.
•
Section 3.3.1, Inclusion 
Criteria, 4. Physical and 
Laboratory Test Findings e) 
Updated to:
Serum creatinine ≤1.5 x ULN 
unless (changed from or) 
creatinine clearance (CrCl) ≥50 
mL/min) (measured or calculated 
[added] using the Cockcroft-
Gault formula)
Aligned with BMS standard for 
studies of nivolumab in subjects with 
glioblastoma.
•
Section 3.3.2 Exclusion Criteria 
2) Medical History 
•
Section 3.4.1 Prohibited and/or 
Restricted Treatments 
Treatment with any 
live/attenuated vaccine (eg 
varicella, zoster, yellow fever, 
rotavirus, oral polio and measles, 
mumps, rubella (MMR)) has been 
added as an exclusion criterion 
and is prohibited during treatment 
and until 100 days post last dose.
Updated to BMS standard for all 
studies with nivolumab.
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Section 3.4.2.1
Imaging 
Restriction and Precautions
Standard language for imaging 
added to this section
Updates per BMS standard.
•
Section 4.5.1.5 Treatment 
Discontinuation Criteria for 
Nivolumab/Placebo
Updated to:
Grade 3 drug-related uveitis, 
pneumonitis, bronchospasm, 
neurologic toxicity, [added], 
myocarditis [added], 
hypersensitivity reaction, or 
infusion reaction of any duration 
requires discontinuation
Updated to BMS standard for all 
studies with nivolumab.
•
Section 5.6.1. Tumors Samples
Subsections revised to align with 
standard BMS practice.
Update per BMS technology 
standard.
•
Appendix 1: Hepatic Adverse 
Event Management Algorithm
Deletion of footnote stating I-O 
therapy may be delayed rather 
than discontinued if AST/ALT ≤ 
8 x ULN or T.bili ≤ 5 x ULN 
Updated per BMS standard for all 
studies with nivolumab.
Throughout the protocol
Minor editorial corrections and clarifications with no impact on protocol 
content.
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SAP_001.pdf: 
Official Title of Study: 
A Randomized Phase 3 Single Blind Study of Temozolomide plus Radiation Therapy combined with 
Nivolumab or Placebo in Newly Diagnosed Adult Subjects with MGMT-Methylated (tumor O6-
methylguanine DNA methyltransferase) Glioblastoma 
 
PROTOCOL(S) CA209-548 
 
NCT Number: NCT02667587  
Document Date (Date in which document was last revised): March 29, 2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A RANDOMIZED PHASE 3 SINGLE BLIND STUDY OF TEMOZOLOMIDE PLUS 
RADIATION THERAPY COMBINED WITH NIVOLUMAB OR PLACEBO IN NEWLY 
DIAGNOSED ADULT SUBJECTS WITH MGMT-METHYLATED (TUMOR O6-
METHYLGUANINE DNA METHYLTRANSFERASE) GLIOBLASTOMA
PROTOCOL(S) CA209548
VERSION # 6.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ........................................................................................10
2.1
Study Design ..........................................................................................................10
2.1.1
Screening Phase .....................................................................................................12
2.2
Treatment Assignment............................................................................................13
2.3
Blinding and Unblinding.........................................................................................13
2.4
Protocol Amendments.............................................................................................14
2.5
Data Monitoring Committee ...................................................................................16
3
OBJECTIVES ........................................................................................................17
3.1
Primary...................................................................................................................17
3.2
Secondary...............................................................................................................17
4
ENDPOINTS..........................................................................................................18
4.1
Primary Endpoint(s) ...............................................................................................18
4.2
Secondary Endpoint(s)............................................................................................19
5
SAMPLE SIZE AND POWER...............................................................................26
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................28
6.1
Study Periods..........................................................................................................28
6.1.1
Baseline Period ......................................................................................................28
6.1.2
Post Baseline Period...............................................................................................29
6.2
Treatment Regimens...............................................................................................29
6.3
Populations for Analyses ........................................................................................29
7
STATISTICAL ANALYSES..................................................................................30
7.1
General Methods ....................................................................................................30
7.2
Study Conduct........................................................................................................30
7.2.1
Accrual...................................................................................................................30
7.2.2
Relevant Protocol Deviations..................................................................................30
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7.3
Study Population ....................................................................................................31
7.3.1
Subject Disposition.................................................................................................31
7.3.2
Demographics and Baseline Characteristics...........................................................31
7.3.3
Prior Therapy.........................................................................................................32
7.3.4
Baseline Examinations............................................................................................32
7.3.5
Discrepancies Between IVRS and CRF Stratification Factors.................................32
7.4
Extent of Exposure .................................................................................................32
7.4.1
Administration of Study Therapy.............................................................................33
7.4.2
Modifications of Study Therapy ..............................................................................34
7.4.2.1
Nivolumab Dose Delays..........................................................................................34
7.4.2.2
Nivolumab Infusion Interruptions and Rate Changes ..............................................34
7.4.2.3
Temozolomide Dose Modifications .........................................................................35
7.4.2.4
Missing Radiotherapy.............................................................................................35
7.4.2.5
Dose Reductions/Escalation....................................................................................35
7.4.3
Concomitant Medications.......................................................................................35
7.5
Efficacy..................................................................................................................35
7.5.1
Overall Survival .....................................................................................................35
7.5.1.1
Primary Analysis ....................................................................................................35
7.5.1.2
OS Sensitivity Analyses...........................................................................................36
7.5.1.3
Consistency of Treatment Effect on OS in Subsets...................................................37
7.5.1.4
Subject Follow-Up..................................................................................................37
7.5.1.5
Subsequent Therapy................................................................................................38
7.5.2
Progression Free Survival ......................................................................................38
7.5.2.1
Primary Analysis ....................................................................................................38
7.5.2.2
Sensitivity Analysis .................................................................................................39
7.5.3
Other Efficacy Analyses..........................................................................................41
7.5.3.1
Analyses of BOR, DOR, TTR...................................................................................41
7.5.3.2
Analyses of Tumor Burden......................................................................................41
7.5.3.3
Analysis of Immune-Related Tumor Effects.............................................................41
7.5.3.4
Analysis of Subjects Treated beyond Progression ...................................................41
7.5.4
Protection of Type I Error ......................................................................................42
7.5.5
Interim Analysis......................................................................................................44
7.6
Safety.....................................................................................................................45
7.6.1
Deaths ....................................................................................................................45
7.6.2
Serious Adverse Events...........................................................................................46
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................46
7.6.4
Adverse Events Leading to Dose Delay of Study Therapy........................................46
7.6.5
Adverse Events .......................................................................................................46
7.6.7
Immune-Mediated Adverse Events ..........................................................................46
7.6.8
Immune Modulating Medication .............................................................................46
7.6.9
Multiple Events.......................................................................................................46
7.6.10
Clinical Laboratory Evaluations.............................................................................46
7.6.10.1
Hematology ............................................................................................................46
7.6.10.2
Serum Chemistry ....................................................................................................46
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7.6.12
Vital Signs and Pulse Oximetry...............................................................................46
7.7
Pregnancy...............................................................................................................46
7.13
End of Study Analyses at Study Closure.................................................................52
8
CONVENTIONS....................................................................................................52
9
CONTENT OF REPORTS .....................................................................................54
10
DOCUMENT HISTORY........................................................................................54
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LIST OF TABLES
Table 2.1-1:
Study Design Schematic.........................................................................11
Table 2.1.1-1:
Screening and Randomization ................................................................12
Table 2.4-1:
Protocol Revision History.......................................................................14
Table 5-1:
Key Parameters of Sample Size Calculation of PFS and OS....................28
Table 10-1:
Document History ..................................................................................54
LIST OF FIGURES
Figure 4.1-1:
Graphic Display of PFS Primary Definition............................................19
Figure 7.5.2.2-1:
Graphic Display of PFS Accounting for Assessment after 
Subsequent Therapy ...............................................................................40
Figure 7.5.4-1:
Graphical Representation of the Testing Strategy....................................42
Figure 7.5.4-2:
Rejection of PFS in the First 558 Subjects from All Randomized 
Population ..............................................................................................43
Figure 7.5.4-3:
Rejection of OS in All Randomized Population without Baseline 
Corticosteriods .......................................................................................44
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Research Hypothesis:  
•
Addition of nivolumab to standard radiotherapy (RT) plus temozolomide (TMZ) will increase 
overall survival (OS) in subjects with newly-diagnosed GBM of MGMT-methylated or 
indeterminate subtypes without baseline corticosteroids and regardless of baseline 
corticosteroids.
•
Addition of nivolumab to standard radiotherapy (RT) plus temozolomide (TMZ) will increase 
progression free survival (PFS) in subjects with newly-diagnosed GBM of MGMT-methylated 
or indeterminate subtypes regardless of baseline corticosteroids.
Schedule of Analyses:
In this study, following are the planned formal efficacy analyses:
•
For superiority of PFS in the first 558 subjects from all randomized subjects who were 
randomized to RT plus TMZ combined with nivolumab vs. subjects who were randomized to 
RT plus TMZ combined with placebo. One interim analysis will occur when 70% or 283 PFS 
events is reached, or when each of the 558 subjects reaches 12 months follow-up whichever 
comes first. The final PFS analysis is planned to be performed when at least 404 events in the 
first 558 subjects from all randomized population have been observed.
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•
For superiority of OS in all randomized subjects without baseline corticosteriods who were 
randomized to RT plus TMZ combined with nivolumab vs. subjects who were randomized to 
RT plus TMZ combined with placebo. One interim analysis will occur approximately 20 
months after accrual is finished or when 70% or 236 OS events is reached which is estimated 
to occur at 45 months after study start. The final OS analysis is planned to be performed when 
at least 337 events in the sub-population of randomized subjects with no baseline 
corticosteroids have been observed. 
The interim and final analyses for OS in all randomized subjects regardless of baseline 
corticosteroid are planned at the same time as the analyses in all randomized population with no 
baseline corticosteroid. An independent Data Monitoring Committee (DMC) will monitor the 
formal PFS and OS interim analyses and have access to periodic interim safety and efficacy reports 
to allow for a benefit/risk assessment. Details are specified in the DMC charter4.
If PFS or OS data crosses the pre-specified boundary at the time of planned interim analyses, the 
DMC will inform the sponsor, as described in the DMC charter4. If PFS data crosses the pre-
specified stopping boundary the study will continue up to the final analysis.
If the pre-specified stopping boundary is not crossed at any of the formal interim analyses, the 
study will continue up to the final analysis.
Changes to the Planned Analyses:
•
For this study, tumor scan measurements are reviewed by blinded independent radiologic 
review (BICR) in a batch read mode, i.e., independent reviews commence after all exams for 
each time point have been received. It is challenging to obtain data in real time. Due to delayed 
BICR data, the number of PFS events passed the pre-specified events required for interim 
analysis and it was close to the number of pre-specified PFS events required for final analysis. 
As a result, interim analysis for PFS will not be conducted.
•
The Data Monitoring Committee (DMC) reviewed all available data on 09-Dec-2020 and 
agreed that there is no plausible scenario for this study to have a positive OS result at the final 
analysis based on either all randomized patients or on patients without baseline corticosteroids. 
This statement is based on the DMC̓s review of the OS results to date, with over 80% of the 
final required number of events reached and related statistical considerations including 
conditional power (CP) of < 1% for a statistically significant final result. Therefore, the DMC 
recommended to unblind the sites and patients, which was approved by the sponsor. The study 
was officially unblinded on 22-Dec-2020.  
As a consequence, the timing of the primary OS analysis, originally planned when 337 and 
494 events were to be reached respectively for the population without corticosteroid at baseline 
and the overall population, has been updated. It is no longer event-driven. 
To prevent any bias due to unblinding of patients, the primary OS analysis and the safety 
analysis will be conducted using the cut-off date of 22-Dec-2020, which is when the study was 
unblinded. The primary analysis of PFS per BICR will be conducted using the cut-off date of 
14-Jun-2019 with a database lock date of 09-Aug-2019 (the primary PFS analysis assessed by 
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the DMC in 2019). The same analysis will also be conducted using the cut-off date of 22-Dec-
2020.
•
The efficacy analyses will be performed for the primary and secondary endpoints. All the 
secondary endpoints will be analyzed at the same time as the primary endpoints using the 
analysis methods already defined in the current SAP.
The primary OS analysis in all randomized subjects without baseline corticosteroids and the 
primary PFS analysis in all randomized subjects will report a p-value as planned in the alpha 
recycling plan. Overall survival in all randomized subjects will be tabulated descriptively, as 
described in the Section 7.5.4. Potential subsets analyses will be presented descriptively.
•
Based on CP calculation (<1%) for OS, there is no plausible scenario for this study to have a 
positive OS result. Therefore only selected analyses will be included in the primary CSR: 
Subject Disposition
Demographics and Baseline Characteristics
Prior Therapy
Medical History
Baseline Examinations
Extent of Exposure
o
Administration of Study Therapy
o
Modifications of Study Therapy
o
Nivolumab Dose Delays
o
Nivolumab Infusion Interruptions and Rate Changes
o
Temozolomide Dose Modifications
o
Missing Radiotherapy
o
Dose Reductions/Escalation
o
Concomitant Medications
Efficacy
o
Overall Survival
o
Consistency of Treatment Effect on OS in Subsets and PFS in subsets
o
Subject Follow-Up
o
Progression Free Survival + subsets
Safety
o
Deaths
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o
Serious Adverse Events
o
Adverse Events Leading to Discontinuation of Study Therapy
o
Adverse Events Leading to Dose Delay of Study Therapy
o
Adverse Events
o
Select Adverse Events
o
Immune-Mediated Adverse Events
o
Immune Modulating Medication
o
Multiple Events
o
Clinical Laboratory Evaluations
o
Hematology
o
Serum Chemistry
o
Vital Signs and Pulse Oximetry
o
Pregnancy
o
Biomarkers
o
Distribution of PD-L1 Expression
•
End of study analyses at study closure will be performed for subject disposition, duration of 
treatment and selected safety outputs. 
2
STUDY DESCRIPTION
2.1
Study Design
This is a randomized phase 3 single blind study of temozolomide plus radiation therapy combined
with nivolumab or placebo in newly diagnosed adult subjects with MGMT-methylated 
glioblastoma.
This study will enroll subjects with newly-diagnosed GBM, following surgical resection of the 
tumor. Tumor tissue will be evaluated for MGMT methylation by a central laboratory assay 
through the CA209498 study. After enrolling in the CA209498 study, the subjects may enroll in 
the CA209548 study and begin the screening process while they wait for the MGMT results. The 
screening number assigned in the CA209498 IVRS will be the same subject number entered by 
the site to screen the subject into the CA209548 IVRS. Those with a MGMT status of methylated 
or indeterminate may be eligible to randomize in the CA209548 study. In order to randomize 
693 eligible subjects, a total of approximately 780 subjects will be evaluated. For details, see 
Section 2.1.1. 
Subjects with a central laboratory result of MGMT-methylated or indeterminate may continue in 
the screening phase, in which eligibility for randomization will be documented and baseline 
demographic and disease information submitted; for details, see Section 2.1.1. A 
contrast-enhanced MRI should have been obtained within 72 hours post-surgery (within 24 hours 
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preferred) as part of the initial screening for the CA209498 study. If not obtained at that time, then 
a MRI must be performed prior to randomization (> 14 days post-op preferred).  
When ready to begin study treatment, subjects will proceed to the treatment phase of the study. 
The treatment phase will consist of an induction phase (chemoradiation therapy) followed by 4 
weeks break and maintenance temozolomide therapy; for details, see Table 2.1-1. All subjects who 
enter the treatment phase, ie, all randomized subjects, will be followed for safety and tolerability, 
tumor progression and survival. The first on-study contrast-enhanced MRI should be performed 4 
weeks (± 7 days) after completing radiation therapy, then subsequent scans should be every 
8 weeks (± 7 days) up to 24 months post randomization, then every 12 weeks until progression 
regardless of treatment schedule or dose delays. Tumor progression will be assessed using RANO
criteria. 
 
For the purposes of this protocol, each 
cycle duration is 2 weeks until 8 doses of nivolumab/placebo are complete. The remaining 
subsequent cycles are 4 weeks in duration.
After cessation of all study treatment for any reason, all randomized subjects will enter a follow-up 
phase. In the short-term, visits are defined for reporting of treatment-related adverse events. 
Following study unblinding, subjects who discontinue all treatment will not be followed for 
progression per RANO criteria, or for survival. 
Baseline and all subsequent scans will be submitted to an independent radiology review committee 
(IRC) for archiving, once the subject is randomized and until study unblinding on 22Dec2020. . 
A Data Monitoring Committee (DMC) will meet regularly during the study to ensure that subject 
safety is carefully monitored.
The study design schematic is presented in Table 2.1-1.
Table 2.1-1:
Study Design Schematic
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*Following unblinding subjects may continue on nivolumab and/or temozolomide (if applicable) treatment, following 
all protocol procedures.
2.1.1
Screening Phase
Subjects will provide consent for enrollment and tumor submission in the peri-operative period 
through the CA209498 study so that MGMT status can be determined. Consent for enrollment in 
the CA209548 study will occur while waiting for the MGMT results to be obtained and 
randomization and study treatment will occur once MGMT status of methylated or indeterminate 
is known and eligibility is established (Table 2.1.1-1).
Table 2.1.1-1:
Screening and Randomization
A centralized tumor tissue assay for MGMT is required as part of the CA209498 MGMT testing. 
Subjects will consent to the MGMT testing and the CA209548 study simultaneously. Following 
informed consent for both studies, subjects will be enrolled via a call to an IVRS system for the 
CA209498 MGMT testing, in order to obtain a subject number. Immediately after the subject 
number is obtained from the CA209498 IVRS, the site will then screen the subject into the 
CA209548 IVRS. The original subject number from CA209498 must be entered into the eCRF. 
When possible, subjects should not be on corticosteroids at Screening i.e. should be off 
corticosteroids at least 5 days prior to start of dosing. It is expected that corticosteroid therapy will 
be tapered to the maximum extent possible during this phase. Subjects who cannot tolerate tapering 
of steroids to < 20 mg prednisone or < 3 mg dexamethasone per day (or equivalent) are not eligible 
for randomization.
RT should begin within 42 days of surgical resection but may be delayed if clinically required. 
Typically, the time from screening procedure to treatment should not exceed 28 days, but may be 
longer if clinically indicated. If repeat resection to improve tumor control is performed for newly-
diagnosed GBM prior to any other therapy (eg, upon referral to research site), the 42-day interval 
should restart at the time of this second surgery and a new post-operative MRI must be performed. 
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2.2
Treatment Assignment
After informed consent has been obtained for both the CA209498 and CA209548 studies, the 
subject must first be enrolled into the CA209498 study by calling an interactive voice response 
system (IVRS) to obtain the subject number. The subject identification number in the CA209498 
study will become the study number for the CA209548 study. Every subject that signs the informed 
consent form must be assigned a subject number in the IVRS. The investigator or designee will 
register the subject for enrollment by following the enrollment procedures established by BMS. 
The following information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth of subject
•
Gender (at birth) of subject
•
Patient ID from the CA209498 study
Once enrolled in the IVRS, enrolled subjects who meet all eligibility criteria, and are clinically 
ready to begin treatment, will be randomized through the IVRS. Central lab confirmation of 
MGMT-methylated or indeterminate status must be received prior to the IVRS randomization call. 
The following information is required for randomization: 
•
Subject number
•
Date of birth of subject
•
Extent of tumor resection: Complete or Partial
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to receive radiotherapy 
plus temozolomide combined with nivolumab or placebo. MGMT methylation status will be 
transferred from the testing laboratory to the IVRS database.
The exact procedures for using the IVRS are detailed in the IVRS manual.
2.3
Blinding and Unblinding
The blinding strategy selected for the protocol is the single-blinding design, also called “site-
subject blinded”.5 The subjects, investigator and site staff will be blinded to the study therapy 
administered. Access to treatment codes will be restricted from all participants, and site and BMS 
personnel prior to final database lock, with exceptions as specified below. Each investigative site 
must assign an unblinded pharmacist/designee. Designated staff of BMS Research & Development 
will be unblinded to facilitate drug supply and safety monitoring.
 
 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
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broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if the treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the BMS Medical Monitor, but the investigator always has ultimate authority 
for the decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made. Once the subject is unblinded, the 
decision to discontinue cannot be reversed. 
For this study, the method of unblinding for emergency purposes is through the IVRS. For 
information on how to unblind for emergency, please consult the IVRS manual.
In cases of accidental unblinding, contact the BMS Medical Monitor and ensure every attempt is 
made to preserve the blind.
The DMC convened a pre-planned, periodic, routine review of all available data on 09-Dec-2020. 
The initial recommendation was that the study should continue unchanged, however subsequently
the DMC notified BMS that they had deliberated further and unanimously agreed that based on 
the review of the OS results to date the study may not demonstrate an OS benefit for the 
investigational treatment arm, and after further discussion with the DMC the decision was made 
to unblind all study patients, and inform all investigators, ethics committees, and health authorities 
as required. This statement is based on the DMC̓s review of the OS results to date, with over 
80% of the final required number of events reached and related statistical considerations including 
conditional power (CP) of < 1% for a statistically significant final result.
2.4
Protocol Amendments
The SAP is based on the protocol v.06 of 26-Feb-2021 which incorporates the following 
amendments:
Table 2.4-1:
Protocol Revision History
Document
Date of Issue
Summary of change
Original 
Protocol
16-Dec-2015
Not applicable
Amendment 05
22-Apr-2016
The main purpose of the first global amendment is to provide additional 
clarification on several items in response to questions arising from 
investigators and IRB/IEC/HAs:
•
Add any ≥2 creatinine drug-related abnormality.
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Table 2.4-1:
Protocol Revision History
Document
Date of Issue
Summary of change
•
Delete provision regarding delay in subjects with baseline Grade 1 
ALT, AST or total bilirubin toxicity to be allowed to continue 
dosing to Grade ≥3 toxicity, thus having all subjects delay for ≥
Grade 2 drug-related toxicity.
•
Modify criteria to specify that subjects with Grade 2 AST/ALT, or 
total bilirubin elevations may resume dosing when lab values return 
to baseline and management with corticosteroids is complete.
•
Modify criteria to specify subjects must discontinue for any Grade 
3 non-skin, drug-related adverse event lasting > 7 days or which 
recurs with some exceptions.
•
Modify criteria for drug-related liver function test abnormality to 
discontinue for AST or ALT > 5 x ULN, Total bilirubin > 3 x ULN 
or concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x 
ULN.
•
Add a definition for single blind.
Additional modifications are as described below:
•
Revise resection cutoffs
•
Clarify time windows and technical descriptions around the 
infusion, examinations, and administration schedule
•
Remove exclusion criteria 2d for subjects with interstitial lung 
disease
•
Add exclusion criteria 2k to exclude subjects with prior 
hypersensitivity to dacarbazine (DTIC)
•
Add a Radiotherapy Guideline Appendix
•
Move Highly Effective Methods of Contraception to an Appendix
•
Incorporate other minor changes to correct and/or clarify protocol 
requirements
Revised 
Protocol 01
22-Apr-2016
Incorporates Amendment 05
Amendment 09
26-Oct-2016
This amendment updates the nivolumab clinical information in GBM and 
safety management algorithms as a result of most recent version of the 
Investigator Brochure (version 15). The amendment also clarifies several 
items as well as corrects minor errors.
•
Renal, Pulmonary, Hepatic, and Skin safety management 
algorithms revised based on IBv.15
•
Time windows and technical descriptions around assessments and 
administration schedule have been added or expanded to allow for 
flexibility at the site level while not affecting the conduct or the 
analysis of the data.
Revised 
Protocol 02
26-Oct-2016
Incorporates Amendment 09
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Table 2.4-1:
Protocol Revision History
Document
Date of Issue
Summary of change
Administrative 
Letter 04
08-May-2017
Change in Study Director
Amendment 11
03-Jun-2017
Changed to a Phase 3 trial with Primary Objective of OS
Revised 
Protocol 03
03-Jun-2017
Incorporates Amendment 11
Amendment 12
17-Jun-2017
Corrects an error in the Dose Delay Criteria and aligns the Dose Delay 
Criteria and Dose Discontinuation Criteria with the nivolumab program 
standards.
Revised 
Protocol 04
17-Jun-2017
Incorporates Amendment 12
Revised 
Protocol 05
8-Nov-2018
Major Changes
• Progression Free Survival (PFS) is now a primary objective of the study, 
changed from secondary. In support of this change, blinded independent 
central review (BICR) has been added and may occur at any time during 
the study.
• Overall survival (OS) rates at 12 and 24 months and PFS based on 
investigator assessment by RANO criteria are added as a secondary 
objective.
• The statistical section has been revised to support changes in the study 
objectives. The study will now include 1 formal interim analysis for PFS 
and 1 formal interim analysis for OS for superiority.
Revised 
Protocol 06
26-Feb-2021
•
The study was officially unblinded on 22-Dec-2020 per DMC 
recommendation based on the DMC review conducted on 9-Dec-2020 
and BMS approval.
•
The timing of the primary OS analysis has been updated. To prevent 
any bias due to unblinding of subjects, the primary OS analysis will be 
conducted using the unblinding date of 22-Dec-2020.
•
Study procedures for subjects remaining on treatment and in follow-up 
have been simplified. 
•
Following study unblinding, subjects who discontinue study drug will 
only be followed for safety as required. 
•
Protocol language per BMS standards for nivolumab studies and for 
COVID-19 has been incorporated.
•
Incorporates approved Administrative Letters 10 and 11.
2.5
Data Monitoring Committee
A Data Monitoring Committee will be established to provide oversight of safety and efficacy 
evaluation of the entire study and to provide advice to the sponsor regarding actions the committee 
deems necessary for the continuing protection of subjects. The DMC will be charged with 
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assessing such actions in light of an acceptable benefit/risk profile for nivolumab. The DMC will 
act in an advisory capacity to BMS and will monitor subject safety and evaluate the available 
efficacy data for the study. The oncology therapeutic area of BMS has primary responsibility for 
design and conduct of the study. The DMC will meet at least every 6 months or more frequently 
as needed on an ad-hoc basis. Information regarding DMC membership, responsibilities, and 
procedures are detailed in the DMC charter. The DMC will be informed should a safety signal 
emerge and may convene an ad-hoc meeting on its own initiative. The DMC will review all 
available data (safety and efficacy) at each meeting. At the conclusion of each DMC meeting the 
committee, will provide the sponsor with a recommendation to continue, modify or terminate the 
study protocol based upon their review. Ultimately, decisions regarding the study protocol will be 
made by the sponsor in conjunction with feedback from investigators and the DMC.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
3
OBJECTIVES
3.1
Primary
•
To compare PFS of subjects with newly-diagnosed MGMT-methylated or indeterminate GBM 
subtypes treated with RT plus TMZ combined with nivolumab or placebo. PFS will be 
determined by blinded independent central review (BICR) based on RANO criteria.
•
To compare OS of subjects with newly-diagnosed MGMT-methylated or indeterminate GBM 
subtypes without baseline corticosteroids and regardless of baseline corticosteroids (ie, all 
comers) treated with RT plus TMZ combined with nivolumab or placebo.
3.2
Secondary
•
To compare OS of subjects with newly-diagnosed MGMT-methylated or indeterminate GBM 
subtypes without baseline corticosteroids and regardless of baseline corticosteroids (ie, all 
comers) treated with RT plus TMZ combined with nivolumab or placebo at 12 and 24 months.
•
To compare PFS based on investigator’s assessment by RANO criteria of subjects with newly-
diagnosed MGMT methylated or indeterminate GBM subtypes treated with RT plus TMZ 
combined with nivolumab or placebo. 
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4
ENDPOINTS
4.1
Primary Endpoint(s)
The primary endpoints of the trial will be assessed by OS and PFS.
OS is defined as time from the date of randomization to the date of death. Subjects who did not 
die by the end of the study will be censored to last known date alive. OS will be assessed in the 
randomized population with no corticosteroids at baseline and in the all randomized population. 
PFS is defined as the time from randomization to the date of the first documented tumor 
progression or death due to any cause. Subjects who did not have disease progression or die will 
be censored at the date of the last tumor assessment. Subjects who did not have any on study tumor 
assessment and did not die will be censored at the last tumor assessment. Subjects who started any 
subsequent anti-cancer therapy without a prior reported progression will be censored at the last 
tumor assessment prior to initiation of the anti-cancer therapy. Subjects who had surgical resection 
after start of study treatment will be censored at the last tumor assessment date prior to initiation 
of surgical resection. PFS will be determined by BICR, based on RANO criteria. PFS will be 
assessed in the first 558 subjects from all randomized population. The progression free survival 
rate at time T is defined as the probability that a subject has not progressed and is alive at time T
following randomization.
Censoring rules for the primary analysis of PFS are presented in Figure 4.1-1. Alternate censoring 
rules for sensitivity analyses are specified in Section 7.5.2.2.
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Figure 4.1-1:
Graphic Display of PFS Primary Definition
4.2
Secondary Endpoint(s)
•
OS rate at 12 months and 24 months derived Kaplan-Meier curve of OS
•
PFS assessed by investigator based on RANO criteria
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5
SAMPLE SIZE AND POWER
This is a Phase 3, randomized, single blinded, multicenter study of RT+TMZ+nivolumab or 
placebo in adult (≥18 years) subjects with newly diagnosed GBM and MGMT-methylated or 
indeterminate tumors.
The familywise type I error rate for the primary comparisons will be set to 0.05, with 0.01 being 
allocated to the PFS comparison and 0.04 being allocated to the OS comparison. 
The primary objectives on OS will test RT plus TMZ combined with nivolumab or placebo in the 
following hierarchy via a stratified log rank test: 
1. OS in newly diagnosed MGMT-methylated or indeterminate GBM subtype without 
baseline corticosteroids. 
2. If 1 is significant, OS in newly-diagnosed MGMT-methylated or indeterminate GBM 
subtype regardless of baseline steroid use (all comers).
The sample size for this study is based on the following assumptions:
•
PFS and OS follows exponential distribution
•
Median PFS in RT+TMZ arm is 10.0 months
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ for PFS is 0.68, translated to 
median PFS improvement of 4.7 months (10.0 months vs 14.7 months for arm RT + TMZ and 
arm RT + TMZ + nivolumab, respectively)
•
Median OS in RT+TMZ arm is 26.0 months3
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ is 0.7 for the randomized 
population with no baseline corticosteroid, translated to median OS improvement of 11.1 
months (26.0 months vs 37.1 months for arm RT + TMZ and arm RT + TMZ + nivolumab, 
respectively)
•
Hazard ratio (HR) of arm RT + TMZ + nivolumab vs RT + TMZ is 0.75 for all randomized 
population, translated to median OS improvement of 8.7 months (26.0 months vs 34.7 months 
for arm RT + TMZ and arm RT + TMZ + nivolumab, respectively)
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•
Proportion of no baseline corticosteroid population within the entire newly-diagnosed MGMT-
methylated or indeterminate GBM subtypes is 0.70
Approximately 693 subjects will be randomized in a 1:1 ratio, stratified by complete or partial 
resection. Of these 693 subjects, 485 subjects are assumed to be no baseline corticosteroids. 
Accrual is estimated to take approximately 25 months based on an observed monthly accrual in 
CA209548 of approximately 28 subjects per month; in the no baseline corticosteroids population, 
a piecewise accrual of 1, 4, 5, 8, 13, 16, 19, and then 23 subjects per month thereafter is assumed. 
At least 337 OS events (deaths) in the no baseline corticosteroid population are needed to achieve 
88% power using a 2-sided Type 1 error of 4%. This number of events is projected to occur after 
an additional 44 months of follow-up (ie, at 69 months). 
One interim analysis will be conducted on OS in the randomized population with no baseline 
corticosteroid. It will occur approximately 20 months after accrual is finished or when 70% or 236 
OS events is reached which is estimated to occur at 45 months after study start, providing a 58% 
probability of stopping under H1. The stopping boundaries at the interim and final analyses will 
be based on the actual number of OS events at the time of the analysis using Lan-DeMets alpha 
spending function with O’Brien-Fleming boundaries. If the planned interim analyses occur exactly 
at the planned number of events, the projected alpha level will be 0.011 and 0.037. See Table 5-1. 
The interim analysis will also be conducted on OS in the overall randomized population. The 
interim analysis will be conducted at the same time as the interim for the no baseline corticosteroids 
population in a hierarchy with stopping boundaries at the interim and final analysis based on actual 
number of OS events at the time of the analysis using Lan-DeMets alpha spending function with 
Pocock boundaries12. 
The PFS comparisons will be based on first 558 randomized subjects in all-comers. At least 404 
PFS events are needed to achieve 90% power using a 2-sided Type 1 error of 1%. Accrual is 
estimated to take approximately 23 months and this number of events is projected to occur after 
an additional 12 months of follow-up (ie, at 35 months).
One interim analysis on PFS is planned and it will occur when 70% or 283 PFS events is reached, 
providing a 54% probability of stopping under H1, or when each of the 558 subjects reaches 12 
months follow-up whichever comes first. The stopping boundaries at the interim and final analyses 
will be based on the actual number of PFS events at the time of the analysis using Lan-DeMets 
alpha spending function with O’Brien-Fleming boundaries. If the planned interim analyses occur 
exactly at the planned number of events, the projected alpha level will be 0.002 and 0.009.
Due to delayed BICR data, the number of PFS events passed the pre-specified events required for 
interim analysis and it was close to the number of pre-specified PFS events required for final 
analysis. As a result, interim analysis for PFS will not be conducted and alpha of 0.01 will be fully 
allocated to the final analysis for PFS.
Power calculations were done using East v 6.3 and R.
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Table 5-1:
Key Parameters of Sample Size Calculation of PFS and OS
Primary Endpoint  
PFS
OS
OS
Power
90%
88%
87%
Alpha
0.01
0.04
0.04
Hypothesized Median Control vs. exp 
(months) 
10 vs 14.7
26 vs 37.1
26 vs. 34.7
Hypothesized Hazard ratio
0.68
0.7
0.75
Expected number of events for 
comparison towards primary objective
404
337
494
Accrual Duration (months)
23
25
25
Sample size 
558 (all-comers)
485 (no baseline 
corticosteroids)
693 (all-comers)
Expected number of events at IA
236  
346
FPFV to IA (months)
45
45
FPFV to LPLV (months)
35
69
69
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment (or date of randomization in case of no treatment).
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply:
• Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment
• Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations with a date on or prior to the day of first dose of study treatment
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected at the same date (and time if collected), the assessment with the latest 
database entry date (and time if collected) will considered as baseline. 
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6.1.2
Post Baseline Period
On-treatment AEs will be defined as AEs with an onset date-time on or after the date-time of the 
first dose of study treatment (or with an onset date on or after the day of first dose of study 
treatment if time is not collected or is missing). An AE will be counted as on-treatment if the event 
occurred within 30 days (or 100 days depending on analysis, see Core Safety SAP6) of the last dose 
of study treatment. 30 day and 100 day cut-off is only for subjects off-treatment and no ‘subtracting 
rule’ will be applied to AEs that occurred pre-treatment.
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations taken after the day (and time, if collected and not missing) of first dose of study 
treatment. An evaluation will be counted as on-treatment if it occurred within 30 days (or 100 days 
depending on analysis) of the last dose of study.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IVRS system
• Arm RT+TMZ: Radiotherapy + Temozolomide
• Arm RT+TMZ+N: Radiotherapy + Temozolomide + Nivolumab
The treatment group “as treated” will be the same as the arm as randomized by the IVRS. 
However, if a subject received the incorrect drug for the entire period of treatment, the subject’s 
treatment group will be defined as the incorrect drug the subject actually received.
6.3
Populations for Analyses
•
All Enrolled subjects: All subjects who signed an informed consent form and were registered 
into the IVRS.
•
All Randomized subjects: All enrolled subjects who were randomized to any treatment arm. 
This is the primary dataset for analyses of efficacy parameters and baseline characteristics.
•
All Treated subjects: All randomized subjects who received at least one dose of study drug. 
This is the primary dataset for safety and exposure analyses.
•
All Randomized subjects with no baseline corticosteroids: Randomized subjects who did not 
take corticosteroids for at least 5 days prior to start of dosing (or randomization for subjects 
not treated).
•
Response evaluable subjects: Randomized subjects with measurable lesions at baseline 
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7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, the titles in the following subsections describe tabulations of discrete 
variables, by the frequency and proportion of subjects falling into each category, grouped by 
treatment (with total). Percentages given in these tables will be rounded and, therefore, may not 
always sum to 100%. Continuous variables will be summarized by treatment group (with total) 
using the mean, standard deviation, median, minimum and maximum values. If a missing category
is not being presented in the data display, only those subjects with non-missing values for the 
parameter being assessed are included in the percentage calculation.
Time to event distributions (i.e. progression free survival, overall survival, time to response and 
duration of response) will be estimated using Kaplan Meier techniques. When appropriate, the 
median along with the corresponding log-log transformed 95% CI will be estimated. Rates at fixed 
timepoints (e.g. OS at 24 months) will be derived from the Kaplan Meier estimate along with their 
corresponding log-log transformed 95% confidence intervals7. Confidence intervals for binomial 
proportions will be derived using the Clopper-Pearson method8.
Unless otherwise specified, the stratified log-rank test will be performed to test the comparison 
between time to event distributions (OS and PFS). Stratification factor (complete resection or 
partial resection at baseline) will be as entered into the IVRS.
Unless otherwise specified, the stratified hazard ratio between 2 groups along with CI will be 
obtained by fitting a stratified Cox model with the group variable as unique covariate. Stratification 
factor (complete resection or partial resection at baseline) will be as entered into the IVRS.
P-values other than those provided for the PFS and OS primary analysis are for descriptive purpose 
only and not adjusted for multiplicity.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site, and per month for all 
enrolled and randomized subjects. By subject listing of randomization date, first dosing date, 
country, investigational site will be provided.
7.2.2
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations and 
summarized by treatment group for all randomized subjects. Non-programmable relevant 
eligibility and on-treatment protocol deviations, as well as significant (both programmable and 
non-programmable) eligibility and on-treatment protocol deviations will be reported through 
ClinSIGHT listings.
At Entrance:
•
Subjects receiving prior treatment for GBM other than Surgery
•
Subjects with un-methylated MGMT status (using central lab)
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•
Subjects with KPS < 70
•
Subjects on > 20 mg prednisone or > 3 mg dexamethasone at the time of randomization. 
•
Subjects with start of treatment more than 52 days after surgery
•
Subjects without baseline MRI scan
On-study:
•
Subjects receiving anti-cancer therapy other than study therapy while on study therapy
•
Subjects treated different than as randomized
Listings will also be provided.
7.3
Study Population
Unless otherwise specified, the following analyses will be presented by treatment group as 
“randomized” for all randomized subjects.
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. 
Number of subjects randomized but not treated along with the reason will be tabulated by treatment 
group as randomized.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
status CRF page. 
A subject listing for all treated subjects will be provided showing the subject’s randomization date, 
first and last dosing date, off treatment date and reason for going off-treatment. A subject listing 
for all enrolled subjects will also be provided, showing the subject’s race, gender, age, consent 
date and reason for not being randomized (for those who were not randomized).
7.3.2
Demographics and Baseline Characteristics
The following baseline characteristics will be summarized by treatment group. All baseline 
presentations will identify subjects with missing measurements. Listings will also be provided.
•
Age at the time of informed consent (descriptive statistics)
•
Age category I (<65, ≥65)
•
Age category II (<65, ≥65- <75, ≥ 75)
•
Gender (male, female)
•
Race (white, black, asian, other)
•
Region (US/Canada, Europe, Rest of the World)
•
Disease diagnosis (Glioblastoma, Gliosarcoma)
•
RPA Class ( III, IV, V, Other)
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•
Type of Surgery (Complete Resection, Partial Resection, Other)
•
Baseline Karnofsky performance status (100%, 90%, 80%, ...)
•
Weight , BSA (descriptive statistics)
•
Gene Promoter Methylation (Methylated, Unmethylated, Indeterminate, Not reported) 
•
Smoking Status (Current/Former, Never, Unknown, Not Reported)
•
Baseline Corticosteroid Use (Based on average corticosteroid use 5 days prior to start of dosing 
(randomization date for subjects not treated)
•
Time from Initial Disease Diagnosis to randomization (in weeks) (Median, Range)
•
All lesions (Investigator Tumor Assessments at Baseline): sites of disease, number of disease 
sites per subject.
•
Measurable lesions (Investigator Tumor Assessments at Baseline): Presence of measurable 
lesions, site of measurable lesion, sum of products of perpendicular diameters of measurable 
lesion.
•
Pre-treatment events: summarized by worst CTC grade presented by SOC/PT
•
Medical History
General medical history will only be listed by subject. 
7.3.3
Prior Therapy
The following will be summarized by treatment group.
•
Prior systemic cancer therapy (yes/no)
•
Prior agent received (generic name)
•
Prior surgery related to cancer (yes/no)
Prior systemic cancer therapy agents and medication will be reported using the generic name.
A summary table by ATC class and generic name and a by-subject listing will also be provided 
for prior/current non study medication.
7.3.4
Baseline Examinations
Subjects with abnormal baseline physical exam results will be tabulated by examination criteria 
(eg neck, cardiovascular, lungs, etc), by treatment group, and by-subject listing will be produced 
for all measurements.
7.3.5
Discrepancies Between IVRS and CRF Stratification Factors
Summary tables (cross-tabulations) by treatment group for stratification factor will be provided to 
show any discrepancies between what was reported through IVRS vs. CRF data (baseline).
•
Extent of tumor resection: Complete or Partial
7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed by treatment group 
“as treated” in all treated subjects, unless otherwise specified.
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7.4.1
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics) by treatment group:
•
Time from randomization and to first dose of study therapy (0 to 3 days, > 3 to 7, > 7 to 14, > 
14 to 21, > 21 to 28, > 28) 
Nivolumab
Dose (mg) is defined as total Dose administered (mg) and is collected on the CRF.
Cumulative Dose (mg) is sum of all the doses (mg) administered to a subject.
Duration of Treatment (in months): (Last dose date - Start dose date + 1)/30.4327
Relative dose intensity (%): Sum of all relative dose intensity for all cycles/N where N is the 
number of cycles of nivolumab administered.
For each cycle i:
Cycle duration (i)(wk)= (dose date(i+1)-dose date (i))/7, when ith cycle is not the last.
Cycle duration (i)(wk)= 2, for the last cycle of the induction phase.
Cycle duration (i)(wk)= 4, for the last cycle of the maintenance phase
Dose Intensity for cycle i (mg/wk)=Dose (i)/Cycle duration (i)
Relative Dose intensity for cycle i (%)=(Dose Intensity for cycle i (mg/wk)/ 120(mg/wk))*100
The following parameters will be summarized (descriptive statistics) for subjects treated with 
nivolumab:
•
Number of doses received
•
Cumulative dose
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥ 110%.
Duration of nivolumab treatment will be presented using a Kaplan-Meier curve. The last dose date 
will be the event date for those subjects who are off study therapy. Median duration of treatment
and associated 95% CI will be provided. Subjects who are still on study therapy will be censored 
on their last dose date.
Temozolomide
Duration of Treatment (in weeks): (Dose end date - Dose start date + 1)/7
Dose (mg/m2): total dose administered (in mg)/BSA at baseline (m2). Dose administered in mg 
at each dosing date is collected on the CRF
Cumulative dose (in mg/m2): sum of all the doses (mg/m2) administered to a subject
The following parameters will be summarized (descriptive statistics) for subjects treated with 
temozolomide:
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•
Duration of Treatment (in weeks)
•
Cumulative dose (in mg/m2)
Radiotherapy
Duration of radiotherapy (in weeks): (Dose end date - Dose start date + 1)/7
Cumulative dose (in Gy): sum of all the doses (Gy) administered to a subject as per CRF.
The following parameters will be summarized for subjects treated with radiotherapy:
•
Duration of radiotherapy (in weeks)
•
Cumulative dose (in Gy)
•
Number of subject that received less than 90% of planned dose
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
and dose changes) and a listing of batch numbers will be also provided.
Analysis on extent of exposure will be restricted to the following populations, unless otherwise 
noted:
•
All treated subjects
•
All treated subjects without baseline corticosteroid
•
All treated subjects in the first 558 subjects from all randomized population 
7.4.2
Modifications of Study Therapy
7.4.2.1
Nivolumab Dose Delays
The following parameters will be summarized for subjects treated with nivolumab.
•
Number of subjects with at least one dose delayed, number of dose delayed per subject, 
Length of Delay and Reason for Dose Delay
7.4.2.2
Nivolumab Infusion Interruptions and Rate Changes
Each nivolumab infusion can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages
The following parameters will be summarized for subjects treated with nivolumab:
•
Number of subjects with at least one dose infusion interruption, number of infusion 
interruptions per subject and the reason for interruption.
•
Number of subjects with at least one IV infusion rate reduction, number of IV infusion 
rate reduction per subject and the reason for reduction
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7.4.2.3
Temozolomide Dose Modifications
The following parameters will be summarized for subjects treated with temozolomide:
•
Number of subjects with at least one dose modification and reasons for dose modification.
7.4.2.4
Missing Radiotherapy
The number of subjects with at least one dose of radiotherapy missed and the reasons for missing 
dose will be tabulated for subjects treated with radiotherapy.
7.4.2.5
Dose Reductions/Escalation
There will be no dose escalations or reductions of nivolumab allowed. 
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables by treatment group will be provided: 
•
Concomitant medications (subjects with any concomitant medication, subjects by 
medication class and generic term).
A by-subject listing will accompany the table.
Incidence of on-treatment corticosteroid use by average dose (in dexamethasone equivalents) 
received over time and by time periods will be presented for: all corticosteroids, corticosteroids 
used for disease, corticosteroids used for adverse events. The median average dose with the 1st 
and 3rd quartiles will also be presented by the time periods.
7.5
Efficacy
Efficacy analyses will be conducted in the first 558 subjects from all randomized subjects (PFS 
analysis only), all randomized subjects with no baseline corticosteroids, all randomized subjects
regardless of corticosteroid use, and 
 unless specified otherwise. 
Analysis will be performed by treatment group as ͆randomized͇.
7.5.1
Overall Survival 
7.5.1.1
Primary Analysis
OS will be analyzed in all randomized subjects without baseline corticosteroids and all randomized 
subjects regardless of baseline corticosteroids.
OS curves for each of the randomized arms will be estimated using the Kaplan-Meier (KM) 
product-limit method and graphically displayed. Median OS and the corresponding two-sided 95% 
confidence intervals (CI) will be constructed based on the log-log transformed CI for survival 
function S(t). The distribution of OS will be compared between the two randomized arms via a 
two-sided stratified (complete or partial surgical resection at baseline) log-rank test at significance 
level α adjusted for the interim. In addition, a stratified Cox proportional hazards regression model 
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will be used to estimate hazard ratio (HR) between the two randomized arms along with the 100(1-
α)% CI adjusted for the interim.
Survival rates at 12, 18 and 24 months will be estimated using KM estimates on the OS curve for 
each randomized arm. Minimum follow-up must be longer than the time point to generate the rate. 
Associated two-sided 95% CI will also be calculated using Greenwood̓s formula.
The status of subjects who are censored in the OS Kaplan-Meier analysis will be tabulated for each 
treatment group using following categories:
•
On-study (on treatment and not progressed, on-treatment progressed, in follow-up) 
•
Off-study: (lost to follow-up, withdraw consent, other).
To examine the assumption of proportional hazards in the Cox regression model, in addition to 
treatment, a time-dependent variable defined by treatment by time interaction will be added into 
the model. A two-sided Wald Chi-Square p-value of less than 0.1 will indicate a potential 
nonconstant treatment effect over time. 
 
7.5.1.2
OS Sensitivity Analyses
The following sensitivity analyses will be performed in all randomized subjects without baseline 
corticosteroids and all randomized subjects regardless of baseline corticosteroids. The same 
significance level as the corresponding primary analysis will be used (unless otherwise specified): 
1. OS will be compared between treatment groups using a two-sided un-stratified log-rank 
test.
2. OS will be compared between the treatment groups using the strata as determined at 
baseline (CRF source). This analysis will be performed only if stratification variable at 
IVRS and at baseline disagree for at least 10% of subjects in the analysis population.
3. OS will be compared between the treatment groups using a two-sided stratified log-rank 
test in all treated subject using arm as randomized. This analysis will be performed only if 
the proportion of randomized but never treated subjects exceeds 5% in the analysis 
population.
4. OS will be compared between the treatment groups using a two-sided stratified log-rank 
test in the subpopulation of subjects with MGMT methylated GBM subtype using arm as 
randomized. This analysis will be performed only if the proportion of subjects with 
indeterminate GBM subtype exceeds 10% in the analysis population.
5. A multivariate Cox regression model will be used to estimate the treatment effect after 
including the following covariates measured at baseline: Backward selection method will 
be used to eliminate non-significant covariates at level 0.15. 
a.
Age (continuous covariate)
b. Steroid Use (Yes, No), except for the analysis on OS in all randomized subjects 
without baseline corticosteroids
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c.
Performance Status (Karnofsky scale) (≤80, >80)
d. Prior Surgery (complete resection, partial resection, other), based on CRF source
The level of the covariate normally associated with the worst prognosis will be coded as 
the reference level i.e. “Yes” for steroid use, “≤80” for Karnofsky Performance Status, and 
“partial resection” for prior surgery. The hazard ratio associated with treatment and with 
each of the baseline covariates will be presented along with its two-sided 95% CI.
7.5.1.3
Consistency of Treatment Effect on OS in Subsets
To assess consistency of treatment effects in different subsets, a “forest” plot of the OS hazard 
ratio (and 95% CI) will be produced for the following variables, but not limited to:
−
Baseline measurable lesion (yes vs. no) (source: CRF)
−
Region (US/Canada vs. Europe vs. Rest of World)
−
Age categorization (< 65, ≥65 - < 75, ≥75, ≥ 65)
−
Age categorization (< 50, ≥50 - <65)
−
Gender (male vs. female)
−
Race (white, black, asian, other)
−
Disease diagnosis (Glioblastoma, Gliosarcoma)
−
RPA class (III, IV, V, other)
−
Smoking Status (Current/Former, Never, Unknown)
−
Type of Surgery (Complete Resection, Partial Resection, Other)
−
Baseline Performance Status (Karnofsky scale) (≤ 80, > 80)
−
Baseline corticosteroid use (Yes, No), except for the analysis on OS in all randomized 
subjects without baseline corticosteroids
If a subgroup category has less than 10 subjects in a treatment group, then HR will not be reported 
for that subgroup.
7.5.1.4
Subject Follow-Up
The minimum follow-up will be reported. The minimum follow-up is defined as the time interval 
between the last patient’s randomization date and the clinical cutoff date.
The extent of follow-up is defined as the time between randomization date and last known date 
alive (for subjects who are alive) or death date (for subjects who died). It will be summarized 
descriptively (median, min, max) for all randomized subjects. 
The currentness of follow-up, defined as the time between last OS contact (i.e., last known date 
alive or death date) and data cut-off date, will be summarized by treatment group. Subjects who 
died and subjects with a Last Known Date Alive (LKDA) on or after data cut-off date will have a 
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value of ‘0’ for currentness of follow-up. The currentness of follow-up will be categorized into the 
following categories: 0 days, 1-30 days, 31-60 days, 61-90 days, 91-120 days, 120-150 days, 151 
or more days.
7.5.1.5
Subsequent Therapy
Subsequent therapy will be summarized by treatment group for all randomized subjects with no 
baseline corticosteroids, all randomized subjects regardless of baseline corticosteroids use, 
 
.
•
Subsequent Therapy
−
Systemic anti-cancer therapy by drug name
−
Surgery (restricted to tumor resection)
−
Subsequent Radiotherapy
In addition, a by-subject listing of follow-up therapy will be produced for subjects who had any 
subsequent therapy.
7.5.2
Progression Free Survival 
PFS determined by BICR based on RANO criteria is the primary endpoint and the primary analysis 
will be based on the first 558 subjects from all randomized population. PFS based on investigator’s 
assessment by RANO criteria is the secondary endpoint and will be analyzed similarly.
The analysis will also be performed on all randomized subjects without baseline corticosteroids,
and all randomized subjects regardless of baseline corticosteroids, unless otherwise specified.
7.5.2.1
Primary Analysis
PFS curves for each randomized arm will be estimated using the Kaplan-Meier (KM) product-
limit method and graphically displayed. Median PFS and the corresponding two-sided 95% 
confidence interval (CI) will be constructed based on the log-log transformed CI for survival 
function S(t). The distribution of PFS will be compared between the two randomized arms via a 
two-sided stratified (complete or partial surgical resection at baseline) log-rank test at significance 
level of 0.01 In addition, a stratified Cox proportional hazards regression model will be used to 
estimate hazard ratio (HR) between the two randomized arms along with the 99% CI. 
PFS rates at 6, 9, 12, 18, and 24 months will be estimated using KM estimates on the PFS curve 
for each treatment group. Minimum follow-up must be longer than the time point to generate the 
rate. The associated two-sided 95% CI will also be calculated using Greenwood̓s formula. The 
source of progression (death vs. progression) will be summarized by treatment group.
The status of subjects who are censored in the PFS KM analysis will be tabulated for each 
treatment group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdrawn consent, never treated)
•
Received subsequent anti-cancer therapy
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•
No baseline tumor assessment
•
No on-study tumor assessments
7.5.2.2
Sensitivity Analysis
The following sensitivity analyses will be performed in the first 558 subjects from all randomized 
subjects, all randomized subjects without baseline corticosteroids and all randomized subjects 
regardless of baseline corticosteroids. The same significance level as the corresponding primary 
analysis will be used (unless otherwise specified): 
1. PFS will be compared between treatment groups using a two-sided un-stratified log-rank 
test.
2. PFS will be compared between the treatment groups using the strata as determined at 
baseline (CRF source). This analysis will be performed only if stratification variable at 
IVRS and at baseline disagree for at least 10% of subjects in the analysis population.
3. PFS will be compared between the treatment groups using a two-sided stratified log-rank 
test in all treated subject using arm as randomized. This analysis will be performed only if 
the proportion of randomized but never treated subjects exceeds 5% in the analysis 
population. 
4. PFS will be compared between the treatment groups using a two-sided stratified log-rank 
test in the subpopulation of subjects with MGMT methylated GBM subtype using arm as 
randomized. This analysis will be performed only if the proportion of subjects with 
indeterminate GBM subtype exceeds 10% in the analysis population.
5. A multivariate Cox regression model will be used to estimate the treatment effect after 
including the following covariates measured at baseline: Backward selection method will 
be used to eliminate non-significant covariates at level 0.15. 
a.
Age (continuous covariate)
b. Steroid Use (Yes, No), except for the analysis on OS in all randomized subjects 
without baseline corticosteroids
c.
Performance Status (Karnofsky scale) (≤80, >80)
d. Prior Surgery (complete resection, partial resection, other), based on CRF source
The level of the covariate normally associated with the worst prognosis will be coded as 
the reference level i.e. “Yes” for steroid use, “≤80” for Karnofsky Performance Status, and 
“partial resection” for prior surgery. The hazard ratio associated with treatment and with 
each of the baseline covariates will be presented along with its two-sided 95% CI.
6. Sensitivity analyses of PFS will also be performed using the following modification:
•
PFS accounting for assessment after subsequent therapy will be defined same as the 
primary definition except that events (progression or death) and tumor assessments that 
occurred on or after subsequent anticancer therapy or diagnostic surgical resection will 
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be taken into account (see censoring scheme for sensitivity analysis in Figure 7.5.2.2-
1). 
Figure 7.5.2.2-1:
Graphic Display of PFS Accounting for Assessment after Subsequent 
Therapy
•
PFS not considering clinical progression as an event will be defined same as the 
primary definition except not considering clinical progression as progression event.
•
PFS not counting clinical progression as event will be defined same as the primary 
definition except that 
o
clinical progression is not considered as progression event
o
events (progression or death) and tumor assessments that occurred on or after 
subsequent anticancer therapy or diagnostic surgical resection will be taken into 
account
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7.5.3
Other Efficacy Analyses 
7.5.3.1
Analyses of BOR, DOR, TTR
Best overall response (BOR) will be tabulated for each treatment group in all response evaluable 
subjects with no baseline corticosteroids and all response evaluable subjects regardless of baseline 
corticosteroids.
Duration of response (DOR) will be summarized for subjects who achieve confirmed PR or CR 
using the Kaplan-Meier (KM) product-limit method for each treatment group. Median DOR, 
corresponding two-sided 95% confidence interval constructed based on the log-log transformed 
CI for survival function, and range will also be calculated. In addition, the percentage of responders 
still in response at different time points (3, 6, 9 and 12 months) will be presented based on the KM 
plot.
Time to response (TTR) will be summarized for subjects who achieve confirmed PR or CR using 
descriptive statistics.
7.5.3.2
Analyses of Tumor Burden
The magnitude of reduction in tumor burden in response evaluable subjects will be summarized 
descriptively.
If enough tissue sample available, following subject-level graphics will also be provided by 
treatment group as randomized: 
•
For all responders, time courses of the following events of interest will be graphically 
displayed: tumor response, progression, last dose received, and death.
•
For response evaluable subjects, a waterfall plot showing the best reduction in measurable
lesion based will be produced. 
•
For response-evaluable subjects, a plot of individual subjects’ percent change in measurable 
lesion tumor burden from baseline.
7.5.3.3
Analysis of Immune-Related Tumor Effects
A summary of surgeries for treatment of tumors (subjects with surgery, reasons for surgery) and 
results of histopathological examination will be presented for all treated subjects by treatments 
groups as treated.
7.5.3.4
Analysis of Subjects Treated beyond Progression
The following analysis may be conducted for subjects treated with RT plus TMZ combined with 
nivolumab who are progressed:
•
Summary of demographic and baseline characteristics by two groups (treated beyond initial
progression or not treated beyond initial progression)
•
Plot of individual subjects’ percent change in measurable lesion tumor burden from baseline.
•
Time courses of the following events of interest will be graphically displayed in relation to OS: 
tumor response, progression, last dose received, on-treatment/subsequent surgery
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•
Summary of overall duration of treatment, number of doses received beyond initial 
progression, duration of treatment beyond initial progression.
•
By-subject listing will include: overall duration of treatment, number of doses received beyond 
initial progression, duration of treatment beyond initial progression, OS
7.5.4
Protection of Type I Error
The main goals of the study include:
•
to compare PFS in the first 558 subjects from all randomized subjects and to prove 
superiority of radiotherapy+TMZ+nivolumab arm over radiotherapy+TMZ+placebo.  
•
to compare OS in all randomized subjects without baseline corticosteroids and to prove 
superiority of radiotherapy+TMZ+nivolumab arm over radiotherapy+TMZ+placebo. OS 
in all randomized subjects will also be tested for superiority.
PFS will be tested at 1% type I error. OS will be tested at 4% type I error. 
To strongly preserve the familywise type I error rate, Bonferroni-based graphical approach by 
Maurer and Bretz (2013)7 will be employed: see Figure 7.5.4-1, for the graphical display of the 
multiple testing procedure. In this graph defining the test procedure, hypotheses together with their 
local significance levels are represented by weighted vertices and the propagation rule is 
represented by weighted directed edges.  Algorithm 1 in Maurer and Bretz (2013) provides the 
rules for updating the local significance levels and the transition weights after rejecting an 
individual hypothesis. The resulting sequentially rejective testing procedure controls family-wise 
Type I error rate of 5% in the strong sense, and is uniquely determined by the graph in Figure 
7.5.4-1.
Figure 7.5.4-1:
Graphical Representation of the Testing Strategy 
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OS = Overall survival, PFS = Progression-free survival, No BL= all randomzied subjects without baseline 
corticosteroids, AC = all-comers (i.e, all randomized subjects)
* first 558 subjects from all randomized population
In Figure 7.5.4-1, each vertex (circle) corresponds to a hypothesis to be tested. The numbers next 
to the vertices are the initially allocated (endpoint-specific) alpha levels. (Note that it is 0 for OS 
in all randomized subjects - meaning that they cannot be tested until alpha is passed to them from 
the OS in all randomized subjects without baseline corticosteroids). The weight (in rectangular 
frame) associated with a directed edge (line) between any two vertices indicates the fraction of the 
(local) significance level at the initial vertex that is added to the significance level at the terminal 
vertex, if the hypothesis at the tail is rejected.
At the time of the PFS analysis, PFS in the first 558 subjects from all randomized population will 
be tested, at alpha of 0.01.
If the hypothesis cannot be rejected, then the study continues to proceed to the OS analysis. If, 
however, the hypothesis can be rejected, graph will be updated as per Algorithm 1 of Maurer and 
Bretz (2013), the algorithm ensures that in case PFS in the first 558 subjects from all randomized 
population is rejected, its entire alpha level (i.e., 0.01) is passed to OS in all randomized subjects 
without baseline corticosteroids. A simple hypothetical example is illustrated in Figure 7.5.4-2 and 
Figure 7.5.4-3.
Figure 7.5.4-2:
Rejection of PFS in the First 558 Subjects from All Randomized 
Population
* first 558 subjects from all randomized population
** Nominal significance levels for based on O’Brien-Fleming with 70% observed information fraction
Further, if OS in all randomized subjects with no baseline corticosteroid is rejected, its significance 
level is passed to the OS in all randomizes subjects (see Figure 7.5.4-3). 
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Figure 7.5.4-3:
Rejection of OS in All Randomized Population without Baseline 
Corticosteriods
** Nominal significance levels for based on O’Brien-Fleming with 70% observed information fraction
*** Nominal significance levels based on Pocock with 70% observed information fraction 
Each time a hypothesis is rejected and the graph is updated, the alpha levels for IA and FA will be 
recalculated for each remaining OS endpoint using Lan-DeMets alpha spending function (O’Brien-
Fleming boundaries will be used for OS in all randomized subjects without baseline 
corticosteriods, and Pocock boundaries will be used for  OS in all randomized subjects). At the 
time of the final OS analysis, all events in the database at the time of the lock will be used. 
Secondary endpoints are not included in a hierarchy of testing and, thus, these comparisons are not 
adjusted for multiplicity across endpoints. Analyses of the secondary OS and PFS endpoints 
(including p-values) will be performed for descriptive purpose only.
7.5.5
Interim Analysis 
An independent statistician external to BMS will perform the analysis. In addition to the formal 
planned interim analyses for PFS and OS, the DMC will meet at least every 6 months or more 
frequently as needed on an ad-hoc basis. Details are included in the DMC charter.
PFS
The population for PFS analysis is the first 558 randomized subjects. A formal interim analysis for 
superiority of PFS will be performed when approximately 283 (70% of planned events or 283/404) 
events is reached, or when the 558 subjects reach 12 months minimum follow-up, whichever 
comes first, where an event is either progression or death. The stopping boundaries at the interim 
and final analyses will be based on the actual number of PFS events at the time of the analysis 
using Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. If the planned 
interim analyses occur exactly at the planned number of events, the projected alpha level will be 
0.002 and 0.009.
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Due to delayed BICR data, the number of PFS events passed the pre-specified events required for 
interim analysis and it was close to the number of pre-specified PFS events required for final 
analysis. As a result, interim analysis for PFS will not be conducted and alpha of 0.01 will be fully 
allocated to the final analysis for PFS.
OS
A formal interim analysis for superiority of OS is planned when 70% or 236 OS events is reached 
in the population of no baseline corticosteroids, which is estimated to occur at 45 months after 
study start. The stopping boundaries at the interim and final analyses will be based on the actual 
number of OS events at the time of the analysis using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries to reject the null hypothesis of no treatment difference, controlling
for a two-sided overall alpha of 4%. If the planned interim analyses occur exactly at the planned 
number of events, the projected alpha level will be 0.011 and 0.037.
OS in the all randomized subjects can be tested at the same time as the interim analysis of OS in 
the all randomized subjects without baseline corticosteriods and afterwards, provided analysis of
OS in all randomized subjects without baseline corticosteroids is significant. The stopping 
boundaries at the interim and final analyses for all randomized subjects will be based on actual 
number of OS events at the time of the analysis using Lan-DeMets alpha spending function with 
Pocock boundaries. 
The DMC will review the safety and efficacy data from the interim analyses and will recommend 
if the study should continue with or without changes or should be stopped. More details of the 
interim analyses are discussed in the Data Monitoring Committee Charter.
The chair of the DMC and the sponsor can call an unscheduled review of the safety data. 
Implications of OS Interim Analysis
At the time of the formal interim analysis for superiority of OS, the DMC may recommend 
continuing or stopping the trial. If the trial continues beyond the interim look, the nominal critical
point for the final OS analysis will be determined using the recalculated information fraction at 
the time of the interim analysis, as described above. The final OS hazard ratio and corresponding 
confidence interval will be reported whereby the confidence interval will be adjusted accordingly 
(i.e. using the recalculated nominal α level at the final analysis). 
If the trial is stopped for superiority of OS at the interim, all the statistical analyses conducted at 
the time of interim analysis would be considered final. 
7.6
Safety
For all safety related analyses, refer to the Core Safety SAP6. Safety will be summarized for: all 
treated subjects by treatment group as treated. 
7.6.1
Deaths
See Core Safety SAP6. 
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7.6.2
Serious Adverse Events
See Core Safety SAP6. 
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP6. 
7.6.4
Adverse Events Leading to Dose Delay of Study Therapy
See Core Safety SAP6. 
7.6.5
Adverse Events
See Core Safety SAP6. 
7.6.7
Immune-Mediated Adverse Events
See Core Safety SAP6.
7.6.8
Immune Modulating Medication
See Core Safety SAP6.
7.6.9
Multiple Events
See Core Safety SAP6. 
7.6.10
Clinical Laboratory Evaluations
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test.
7.6.10.1
Hematology
See Core Safety SAP6. 
7.6.10.2
Serum Chemistry
See Core Safety SAP6.
7.6.12
Vital Signs and Pulse Oximetry
See Core Safety SAP6. 
7.7
Pregnancy
See Core Safety SAP6. 
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7.13
End of Study Analyses at Study Closure
Subjects who have continued on study treatment following the study unblinding will be followed 
per protocol through treatment discontinuation and safety follow-up.
The end of study analyses will be performed for the selected safety data and duration of treatment 
using all randomized subjects. 
Data to be reported:
•
Subject disposition
•
Duration of treatment (Nivolumab, Temozolomide)
•
Death
•
Adverse events
•
Serious adverse events
8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
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For missing and partial adverse event onset dates, imputation will be performed using the Adverse 
Event Domain Requirements Specification9. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in 4.3.3 of BMS Non-Study 
Medication Domain Requirements Specification10.
For death dates, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day. The imputed date will be compared to the last known date alive day 
and the maximum will be considered as the death date.
•
If the month or the year is missing, the death date will be imputed as the last known 
date alive day
•
If the date is completely missing but the reason for death is present the death date will 
be imputed as the last known date alive  day
For date of progression, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day*.
•
If the day and month are missing or a date is completely missing, it will be considered 
as missing.
*In cases where the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
For other partial/missing dates, the following conventions may be used:
•
If only the day of the month is missing, the 15th of the month will be used to replace 
the missing day.
•
If both the day and the month are missing, “July 1” will be used to replace the missing 
information.
•
If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g. time from first diagnosis to first dosing date, duration of response, and time to 
response) will be calculated as follows:
                       Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
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9
CONTENT OF REPORTS
10
DOCUMENT HISTORY
Table 10-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version dated 05-Jan-2017
2.0
Section 2 Study Description: Multiple changes we made in section 2 
Study description in accordance with the amendments of the protocol, 
the history of protocol amendments is added on section 2.4.
Section 2.1 Study Design: “The treatment phase will consist of an 
induction phase (chemoradiation therapy) followed by 4 weeks break 
and maintenance temozolomide therapy” is added to define induction 
and maintenance phase for exposure analysis.
Section 3 Objectives: The section is modified in accordance with the 
protocol update.
Section 4.1 Primary Endpoint(s): two-co-primary endpoints were set 
in accordance with the protocol update.
Section 4.2 Secondary Endpoint(s): Endpoints are modified to 3 
secondary endpoints in accordance with the protocol update; sentence 
“Subjects who die without a reported progression will be considered to 
have progressed on the date of death” is removed; “PFS will be 
determined by investigator reported response based on radiographic 
and clinical findings in accordance with RANO criteria” text in italic 
is added for clarity; censoring rules in Figure 4.1-1: Graphic Display 
of PFS Primary Definition were corrected for cases when subjects 
have PD/death and on-study scans (event and censoring had been 
mixed up) and when subsequent therapy started before an event 
(possibility to censor by randomization date is added).
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Author(s)
Description
Section 5 SAMPLE SIZE AND POWER: Sample size justification is 
updated in accordance with the protocol; a clarifying statement “The 
co-primary objectives of the study will be tested hierarchically, 
therefore, the first endpoint in the hierarchy, i.e. OS in subjects wthout 
baseline corticosteroids will be primarily used to investigate the 
hypothesis of superiority of RT+TMZ+nivolumab treatment compared 
to RT+TMZ+placebo” is added; statement about secondary endpoint 
of PFS is removed as no longer relevant for the sample size.
Section 6.1.1 Baseline Period: “Evaluations on the same date and time 
of the first dose of study treatment will be considered  as baseline 
evaluations.” is removed since it is not precise and the precise rules 
are defined in the next paragraph.
Section 6.3 Populations for Analyses: New populations are defined: 
, All Randomized subjects with no baseline 
corticosteroids, Response evaluable subjects, 
 
.
Section 7.1 General Methods: “P-values other than those provided for 
the OS primary analysis and PFS are for descriptive purpose only”
Section 7.2.2 Relevant Protocol Deviations: Deviation “Subjects with 
methylated MGMT status” is corrected to “Subjects with un-
methylated MGMT status”.
Section 7.3.1 Subject Disposition: description of listings is updated to 
be compliant with the CRF and support the tables.
Section 7.3.2 Demographics and Baseline Characteristics: “Age at the 
time of informed consent” is clarified; BSA is added for analysis; 
“Time from Initial Disease Diagnosis to start of treatment
randomization”; “Target” lesions are changed to “Measurable, 
“longest diameter” is changed to “products of perpendicular 
diameters” in accordance with RANO
Section 7.3.4 Baseline Examinations: “and by-subject listing will be 
produced for all measurements” is added
Section 7.4.1 Administration of Study Therapy: definition of the last 
cycle length is corrected; terms “Dose Intensity”, “Relative Dose 
intensity” and the definitions are made compliant; populations for 
exposure analysis is restricted to subjects treated with a particular 
drug; definition of TMZ Dose (mg/m2) is corrected to be defined via 
BSA instead of weight; TMZ Cumulative planned dose for induction 
phase is defined; the following analyses for TMZ maintenance phase 
is removed: Cycles of treatment, Number of subjects completing 6 
cycles; Duration of Treatment is added to analyses for TMZ 
maintenance phase; structure of the section is improved.
Section 7.4.2 Modifications of Study Therapy: populations for 
exposure analysis is restricted to subjects treated with a particular 
drug.
Section 7.4.2.3 Radiotherapy and Temozolomide is split to 7.4.2.3 
Temozolomide Dose Modifications and 7.4.2.4 Missing Radiotherapy 
for compliance of the analyses with the CRF
Section 7.4.3 Concomitant Medications: “Incidence of on-treatment 
corticosteroid use by average dose (in dexamethasone equivalents) 
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Description
received over time and by time periods will be presented for: all 
corticosteroids, corticosteroids used for disease, corticosteroids used 
for adverse events. The median average dose with the 1st and 3rd 
quartiles will also be presented by the time periods.” is added
Section 7.5 Efficacy: “Efficacy analyses will be conducted in all 
randomized subjects with no baseline corticosteroids, all randomized 
subjects regardless of corticosteroid use, 
 
. Analysis will be performed 
by treatment group as “randomized”.” is added.
Section 7.5.1.1 Primary Analysis: “OS will be analyzed in all 
randomized subjects without baseline corticosteroids, all randomized 
subjects regardless of baseline corticosteroids,
 
.” is 
added for compliance of the analysis with the updated study design; 
graphical display of OS curves is added to the analysis; wording is 
improved.
Section 7.5.1.2 OS sensitivity Analyses: added that the analysis is to 
be conducted “for each of the co-primary endpoints”; wording is 
improved and is made applicable for each of the co-primary endpoints; 
clarified that Steroid Use will not be included in multivariate Cox 
regression model for the analysis of OS in subjects with no baseline 
corticosteroids; the levels of the covariate normally associated with the 
worst prognosis are detailed;
Section 7.5.1.3 Consistency of Treatment Effect on OS in Subsets: 
“The analysis will be performed for both co-primary endpoints” is 
added; Disease diagnosis, Type of Surgery, Baseline corticosteroid use 
are added to subsets for the analysis; Baseline Pathology, Prior 
Corticosteroid use are excluded from subsets for the analysis; subsets 
for Race and smoking status are corrected
Section 7.5.1.4 Subject Follow-Up: minimum follow-up analysis is 
added
Section 7.5.1.5 Subsequent Therapy: populations for the analysis are 
specified: “for all randomized subjects with no baseline 
corticosteroids, all randomized subjects regardless of baseline 
corticosteroids use,
 
; clarification “Surgeries with 
the following reasons for surgery will not be considered subsequent 
therapy: Excisional biopsy, Incisional biopsy, Fine Needle Aspiration, 
Fluid Aspiration, Other” is added; clarified that Subsequent
Radiotherapy is to be summarized; wording is improved.
Section 7.5.5 Interim Analysis is moved at the end of the Section 7.5 
Efficacy
Section 7.5.2.1 Primary Analysis: population is defined: “PFS will be 
analyzed in all randomized subjects without baseline corticosteroids 
and in all randomized subjects regardless of baseline corticosteroids.”; 
wording is improved; PFS rates timepoints are completed for 
compliance with the protocol; censoring status is completed with No 
baseline tumor assessment, No on-study tumor assessments categories
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Author(s)
Description
Section 7.5.2.2 Sensitivity Analysis: populations for the analysis are 
defined: “all randomized subjects without baseline corticosteroids and 
in all randomized subjects regardless of baseline corticosteroids”; 
wording is improved; Table 7.5.3.2-1: Censoring Scheme 1 for 
Sensitivity Analysis of PFS is replaced with Figure 7.5.2.2-1: Graphic 
Display of PFS accounting for assessment after subsequent therapy for 
clarity; “Subjects with no baseline or on-study tumor assessment and 
no death will be censored on the date of randomization.” is removed 
from definition of PFS not considering clinical progression as not 
applicable
Section 7.5.3 Other Efficacy Analyses is split to Subsections 7.5.3.1 
Analyses of BOR, DOR, TTR, 7.5.3.2 Analyses of Tumor Burden, 
7.5.3.3 Analysis of Immune-Related Tumor Effects, 7.5.3.4 Analysis 
of Subjects Treated beyond Progression; analysis of integrated data 
from -548 and -498 (-143) studies is removed.
Section 7.5.3.1 Analyses of BOR, DOR, TTR: populations for analysis 
are defined: “all response evaluable subjects with no baseline 
corticosteroids and all response evaluable subjects regardless of 
baseline corticosteroids”; Time to response (TTR) analysis is added; 
wording for DOR analysis is improved.
Section 7.5.3.2 Analyses of Tumor Burden: population for analysis is 
defined: “in response evaluable subjects”; “target” lesions are changed 
to “measurable” in accordance to RANO criteria.
Sections 7.5.3.3 Analysis of Immune-Related Tumor Effects, 7.5.3.4 
Analysis of Subjects Treated beyond Progression are added
Section 7.5.4 Hierarchy for Efficacy Endpoints is added
Section 7.5.5 Interim Analysis is changed to describe interim analyses 
for two co-primary endpoints in accordance with the updated protocol; 
Hierarchy of efficacy testing is added for clarity; details about control 
of type I error for second co-primary endpoint are added as well as 
projected nominal alpha levels are estimated.
Section 7.6.7 Immune-Mediated Adverse Events: the analysis is to be 
conducted according to the Core Safety SAP, there for “See Core 
Safety SAP” replaced the repeat text
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Author(s)
Description
 
Multiple editorial changes
3.0
Section 1: Research hypothesis and schedule of analyses are modified 
in accordance with the protocol update.
Section 2: Table 2.1-1 Study design schematic is modified in 
accordance with the protocol update.
Section 3: Objectives are modified in accordance with the protocol 
update.
Section 4: Primary and secondary endpoints are modified in 
accordance with the protocol update.
Section 5: Sample size considerations are modified in accordance with 
the protocol update.
Section 7.4: Analysis on TMZ by phase is removed. 
Section 7.5.2: Statistical analysis on PFS is modified in accordance 
with the protocol update. 
Section 7.5.3.4: Statistical analysis on treatment beyond progression is 
updated.
Section 7.5.4: Details on alpha recycling is added.
Section 7.5.5: Interim analysis is modified in accordance with the 
protocol update. 
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Table 10-1:
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Version Number
Author(s)
Description
Multiple editorial changes
4.0
Section 1, Section 5 and Section 7.5.5 are updated on the change of 
removing interim analysis for PFS
Section 2.5 is added.
Section 4.3.7, Section 4.3.8 and Section 4.3.9 are updated on the 
analysis time window to be consistent with I-O core SAP. 
Section 7.5.3.2 is updated.
Multiple editorial changes
5.0
Section 5: Replacing "O’Brien-Fleming" with "Pocock" in order to 
keep consistency with stopping boundary specified in sections 7.5.4 
and 7.5.5 for all randomized population
Section 7.5.4: Minor editorial changes on page 42 to add clarity
Section 7.5.5: Minor editorial changes on page 43 to add clarity
6.0
Section 1: Changes to the Planned Analyses section is updated to 
reflect the unblinding on 22-Dec-2020 per DMC recommendation. 
The timing of the OS primary analysis has been modified by the 
unblinding decision. It is not anymore, an event driven analysis.
Only selected analyses will be performed for the primary CSR analysis 
and the end of study analysis at study closure. 
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