Conditions: Brain Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 560
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate patients with glioblastoma that is MGMT-unmethylated (the MGMT gene is not altered by a chemical change). Patients will receive Nivolumab every two weeks in addition to radiation therapy, and then every four weeks. They will be compared to patients receiving standard therapy with temozolomide in addition to radiation therapy.

Detailed description:

Arms:
arm 1: Nivolumab IV infusion + Radiotherapy dose as specified arm 2: Temozolomide + Radiotherapy dose as specified

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

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA209498
IND Number:
119,590
Ex-US
Non-IND
EUDRACT Number
2015-003739-37
Date:
07-Oct-2015
Revised Date:
15-Nov-2017
Clinical Protocol CA209498
A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination 
with Radiation Therapy in Newly Diagnosed Adult Subjects with Unmethylated MGMT (tumor 
O-6-methylguanine DNA methyltransferase) Glioblastoma
CheckMate498: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 498
Revised Protocol Number: 05
Medical Monitor
Yanfang Liu, MD, PhD
 
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) 
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Revised Protocol No.: 05
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that may be added to this document is also confidential and proprietary to BMS and must 
be kept in 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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No.: 05
Date: 15-Nov-2017
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 05
15-Nov-2017
Incorporates Administrative Letters 04 and 05. In addition, the following 
major changes have been implemented in this Revised Protocol:
1.
Removal of the interim analysis for superiority of the primary 
endpoint of OS
2.
Addition of a secondary endpoint that evaluates, in newly diagnosed, 
unmethylated O-6-methylguanine DNA methyltransferase 
glioblastoma, any relationship between OS or PFS and tumor 
mutational burden in the radiation therapy (RT) + nivolumab arm 
compared to the RT + TMZ control arm
Administrative 
Letter 06
30-May-2017
Updated Study Director Credentials
Administrative 
Letter 05
08-May-2017
Updated Study Director and Medical Monitor
Administrative 
Letter 04
13-Jan-2017
Updated Study Director and removed incorrectly included 
pharmacokinetic and immunogenicity collections at the follow-up visits.
Revised 
Protocol 04
09-Nov-2016
Incorporates Amendment 08
Amendment 08
09-Nov-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.
•
Safety data from protocol CA209-143 added to the nivolumab 
clinical information in GBM.
•
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 03
04-May-2016
Incorporates Amendment 06 and Administrative Letter 01
Amendment 06
04-May-2016
Major changes implemented in this Amendment include
3.
Eligibility criteria
a.
Add exclusion for Gliadel® wafer
b.
Permit baseline MRI to be performed up to 72 hours post-
operatively. If only CT is available, an MRI must be 
obtained prior to randomization.
c.
Modified language for women of child-bearing potential 
4.
Modify cutoff values used to define complete vs partial resection for 
purposes of randomization
 
 
 
 
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Document
Date of Issue
Summary of Change
6.
Update language throughout to conform with the Health Authority 
requests
 
 
 
 
 
 
 
 
Administrative 
Letter 02
25-May-2016
 
 
Administrative 
Letter 01
26-Apr-2016
 
 
 
 
 
 
 
.
Revised 
Protocol 02
24-Feb-2016
Incorporates Amendment 04
Amendment 04
24-Feb-2016
Corrected the temozolomide dose modification guidance during 
maintenance temozolomide dosing; modified nivolumab dose delay and 
discontinuation criteria 
Revised 
Protocol 01
12-Jan-2016
Incorporates Amendment 03
Amendment 03
12-Jan-2016
 
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Document
Date of Issue
Summary of Change
Original 
Protocol
07-Oct-2015
Not applicable
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SYNOPSIS
Clinical Protocol CA209498
Protocol Title: A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination with 
Radiation Therapy in Newly Diagnosed Adult Subjects with Unmethylated MGMT (tumor O-6-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 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 at Dose 9 until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever comes first, or Temozolomide 75 mg/m2 orally daily during 
radiation therapy followed by 4 week break then 6 (28-day) cycles temozolomide dosed 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: Treatment with radiation therapy plus nivolumab (RT + nivolumab) will improve overall 
survival (OS) compared with radiation therapy plus temozolomide (RT + TMZ) in subjects with newly diagnosed 
unmethylated MGMT glioblastoma (GBM).
Objectives:
Primary Objective:
To compare OS of nivolumab plus radiation therapy (RT + nivolumab) versus RT + TMZ in subjects with newly-
diagnosed GBM and unmethylated MGMT tumors after surgical resection.
Secondary Objectives:
To compare investigator-assessed progression-free survival (PFS) of RT + nivolumab versus RT + TMZ
To estimate OS rate at 24 months (OS[24]) of RT + nivolumab versus RT + TMZ (final analysis only)
To evaluate, in newly diagnosed, unmethylated MGMT GBM, any relationship between OS or PFS and tumor 
mutational burden (TMB) in the RT + nivolumab arm compared to the RT + TMZ control arm
Study Design: 
This study will enroll subjects with newly-diagnosed GBM, following surgical resection of the tumor. After informed 
consent is obtained, subjects will enter the screening phase. Tumor tissue will be evaluated for MGMT methylation 
by a central laboratory assay. 
 
 The screening number assigned in the 
CA209498 interactive voice response system (IVRS) will be the same subject number entered by the site to screen the 
subject into the CA209548 IVRS. Those with an MGMT status of methylated or indeterminate may be eligible to 
randomize in the CA209548 study. In order to randomize approximately 550 eligible subjects, a total of approximately 
1200 subjects are expected to have tumor screening, of which approximately 600 subjects are anticipated to have 
unmethylated MGMT tumors. 
Subjects with a central laboratory result of unmethylated MGMT may continue in the screening phase, in which 
eligibility for randomization will be documented and baseline demographic and disease information submitted. During 
the screening phase a contrast-enhanced MRI should be obtained within 72 hours post-surgery (within 24 hours 
preferred). 
When ready to begin study treatment, subjects will proceed to the treatment phase of the study. 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 4 weeks after completing radiation therapy, then every 
8 weeks (± 7 days) until progression regardless of treatment schedule. Tumor progression will be assessed using 
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Radiologic Assessment in Neuro-Oncology criteria (RANO). Additional assessments will be performed for cognitive 
function, neurologic function, biomarkers, and patient-reported quality of life outcomes. 
After cessation of 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. All subjects in whom disease 
progression had not been detected at the time study treatment is stopped will be followed closely for progression with 
contrast enhanced MRI every 8 weeks (± 7 days). After progression, subsequent treatment will be reported. All
randomized subjects MUST be followed for survival (primary endpoint).
A Data Monitoring Committee (DMC) will meet regularly during the study to ensure that subject safety is carefully 
monitored.
Study Population: Subjects must meet all eligibility criteria specified in Sections 3.3.1and 3.3.2 of the protocol, 
including the following:
Key Inclusion criteria:
•
Males and Females age ≥18 years old;
•
Newly diagnosed histologically confirmed supratentorial GBM (Grade 4 malignant glioma by World Health 
Organization including gliosarcoma)
o
No treatment for GBM other than surgery;
o
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
o
No major ongoing safety issues following surgery
o
Able to taper steroids (preferably discontinued). Dose at randomization must be ≤20 mg prednisone daily or 
≤3 mg dexamethasone daily (or equivalent)
•
Centrally confirmed tumor unmethylated MGMT
•
Karnofsky performance status of ≥70
•
Clinically appropriate for concomitant RT + TMZ based on investigator judgement
Key Exclusion Criteria:
•
Prior treatment for GBM (other than surgical resection)
•
Recurrent GBM
•
Biopsy only of GBM at surgery, defined as < 20% resection of enhancing tumor
Histologically Confirmed GBM
Newly-
diagnosed 
GBM
Unmethylated
MGMT 
confirmed by 
Central Lab
Nivolumab 240 mg Q2W x 8 
doses
and
Radiation Therapy
2 GY 5x week x 6 weeks
Treatment Arm RT +TMZ (n=275)
TMZ 75 mg/m2 7 days/week 
x 6 weeks
and
Radiation Therapy
2 GY 5x week x 6 weeks
Treatment Arm RT +Nivolumab (n=275)
Nivolumab 480 mg Q4W
TMZ 150 to 200 mg/m2
D1-5 of 28-day cycles
x 6 cycles
(Following 4-week 
treatment break)
Post-treatment 
follow-up for 
safety, OS, and 
progression.
Primary 
Endpoint: 
OS
Secondary 
Endpoints:
PFS, OS (24), and 
PFS and OS in 
TMB
Screening and Randomization
Treatment
Follow-up
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•
Ongoing requirement for supraphysiologic steroid defined as >20 mg prednisone daily or >3 mg dexamethasone 
daily (or equivalent), due to intracranial mass effect
•
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)
•
Known IDH mutated tumor (if available; test not required)
•
Concomitant use of Gliadel® wafer
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-936558
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Temozolomide
20 mg, 100 mg, 140 mg
IP
Subjects randomized to nivolumab should begin treatment within 7 days of randomization and continue at a dose of 
240 mg given as a 30-minute IV infusion on Day 1 of each treatment cycle every 2 weeks for 8 doses. The nivolumab 
dose will then change to 480 mg as a 30-minute IV infusion every 4 weeks with dose 9. 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. 
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 hrs 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) until disease progression.
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). Survival status 
will be assessed every 3 months (± 14 days) after follow up visits are completed, and may be completed via telephone 
or in person visits.
Statistical Considerations:
Sample Size: Approximately 550 subjects will be randomized to the two arms (RT + nivolumab vs RT + TMZ) in a 
1:1 ratio, stratified by complete or partial resection at baseline. 
This study requires at least 390 events (ie, death) to provide 90% power to detect a hazard ratio (HR) of 0.72 with an 
overall type 1 error of 0.05 (two-sided). This translates to an observed HR of 0.82 (median OS of 13.0 vs 15.8 months) 
or less resulting in a statistically significant improvement. 
The secondary endpoint of only PFS will be tested hierarchically.
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Endpoints: The primary endpoint is OS. OS is defined as the time between the date of randomization and the date of 
death due to any cause. A subject who has not died will be censored at the last known alive date. OS will be followed 
continuously while subjects are on study drug and every 3 months (± 14 days) via in-person or phone contact during 
survival follow-up phase of the study.
The secondary endpoint of 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 die without a reported progression will be considered to have 
progressed on the date of death. Subjects who did not have disease progression or die will be censored at the date of 
last tumor assessment. Subjects who did not have any on study tumor assessment and did not die will be censored at 
the randomization date. 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 subsequent anti-cancer therapy. Subjects who 
had surgical resection post start of study treatment will be censored at the last tumor assessment date prior to initiation 
of surgical resection. PFS will be determined by investigator reported response based on RANO criteria 
The secondary endpoint of survival rate at 24 months, is defined as Kaplan-Meier survival probability at 24 months. 
An additional secondary endpoint is OS and PFS assessed in the TMB-high population, as assessed in the TMB assay 
where the numerical cut-off for high versus low will be specified in the statistical analysis plan. Definition for OS and 
PFS for this endpoint will be the same as defined earlier.
Analyses:
The analyses of primary endpoint of OS and secondary endpoints of PFS and OS[24] will be based on all randomized 
subjects. If superiority in OS is demonstrated, a hierarchical hypothesis testing approach for the secondary endpoint
of PFS will be used to preserve a study-wise type I error rate at 0.05. OS[24] will be estimated using Kaplan Meier 
method. OS and PFS will also be estimated for the TMB-high population.
OS and PFS distribution in all randomized subjects will be compared between treatment groups using a two-sided 
stratified log-rank test. The hazard ratio (HR) and corresponding two-sided 95% confidence intervals (CIs) will be 
estimated in a Cox proportional hazard model using treatment as a single covariate stratified by complete or partial 
resection at baseline.
OS and PFS curves will be estimated using the Kaplan- Meier product-limit method. Median OS and PFS along with 
the corresponding two-sided 95% CIs using the log-log transformation will be computed. 
OS [24] and the corresponding 95% CIs using the log-log transformation will be computed after all subjects have 
follow-up of at least 24 months. OS and PFS in the TMB-high population will be estimated using the Kaplan-Meier 
method.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 05 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05............................ 
 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory 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 ......................................................... 
3.4.3 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 Dosing ................................................................................... 
4.5.1.1 Nivolumab Dose and Schedule ....................................................... 
4.5.1.2 Dose Modifications for Nivolumab ................................................. 
4.5.1.3 Dose Delay Criteria for Nivolumab ................................................ 
4.5.1.4 Criteria to Resume Dosing for Nivolumab ..................................... 
4.5.1.5 Treatment Discontinuation Criteria for Nivolumab ....................... 
4.5.1.6 Continuing Nivolumab with Suspected Progression....................... 
4.5.1.7 Management Algorithms for Immuno-Oncology Agents ................ 
4.5.1.8 Treatment of Nivolumab-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 of Study Drug ................................................................................ 
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 ................................................................................................. 
 
 
 
 
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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 ................................................... 
 
 
 
 
 
 
8.5 Interim Analyses ............................................................................................... 
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 .................................................................................. 
 
 
 
 
 
 
 
 
 
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1.2
Research Hypothesis 
Treatment with radiation therapy plus nivolumab will improve OS compared with radiation 
therapy plus temozolomide in subjects with newly-diagnosed unmethylated MGMT GBM.
1.3
Objectives(s)
1.3.1
Primary Objective
To compare OS of nivolumab plus radiation therapy (RT + nivolumab) versus temozolomide plus
radiation therapy (RT + TMZ) in subjects with newly-diagnosed GBM and unmethylated MGMT 
tumors after surgical resection.
1.3.2
Secondary Objectives
•
To compare investigator-assessed PFS of RT + nivolumab versus RT + TMZ
•
To estimate the OS rate at 24 months (OS[24]) of RT + nivolumab versus RT + TMZ (final 
analysis only)
•
To evaluate, in newly diagnosed, unmethylated MGMT GBM, any relationship between OS 
or PFS and TMB in the RT + nivolumab arm compared to the RT + TMZ control.
 
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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 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
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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), 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, 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 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 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.
Investigators must:
1) 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
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study
3) 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
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4) 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
5) 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
6) 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 glioblastoma (GBM), following surgical 
resection of the tumor. After informed consent is obtained, subjects will enter the screening phase. 
Tumor tissue will be evaluated for MGMT methylation by a central laboratory assay. 
 
 
 
 
 
 
 
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Post-operative baseline MRI following consensus recommendations,52 must be obtained prior to 
randomization. It is strongly recommended that this scan be obtained < 72 hrs or > 14 days 
post-surgery in order to minimize artifact. There is no requirement that this baseline scan be 
performed on a “qualified” machine (a qualified MRI is one that meets the Imaging Manual 
specifications and has been validated with the required phantom scan). If a post-operative MRI is 
not available, a high-quality, contrast-enhanced CT scan may be performed initially, but in this 
case a contrast-enhanced MRI must be performed prior to randomization (> 2 weeks post-op 
preferred).
Subjects with a central laboratory result of unmethylated MGMT 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. A 
contrast-enhanced MRI should be performed 4 weeks (± 7 days) after completing radiation 
therapy, then every 8 weeks (± 7 days) until progression regardless of treatment schedule or dose 
delays. Tumor progression will be assessed using RANO criteria described in Section 5.4.2. 
Additional assessments will be performed for cognitive function, neurologic function, biomarkers
and patient-reported quality of life outcomes.
After cessation of 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 AEs. All subjects in 
whom disease progression had not been detected at the time study treatment is stopped will be 
followed closely for progression with contrast enhanced MRI every 8 weeks (± 7 days) until 
progression. After progression, subjects MUST be followed for survival (primary endpoint); 
subsequent treatments will be reported. For details on the follow-up phase, see section 3.1.3.
Baseline and all subsequent scans will be submitted to a blinded independent radiology review 
committee (BIRC) for archiving, once the subject is randomized and throughout the study period.
A Data Monitoring Committee (DMC) will meet regularly during the study 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
3.1.1
Screening Phase
Subjects will provide consent for enrollment and tumor submission in the peri-operative period, 
so that MGMT status can be determined.  Consent for randomization and study treatment may be 
deferred until MGMT unmethylated status and eligibility is established (or be obtained 
concurrently). However, consent for tumor submission only may be obtained pre-operatively based 
on a clinical/radiographic diagnosis of GBM. The clinical circumstances should be considered 
with respect to the timing of consent.
Histologically Confirmed GBM
Newly-
diagnosed 
GBM
Unmethylated
MGMT 
confirmed by 
Central Lab
Nivolumab 240 mg Q2W x 8 
doses
and
Radiation Therapy
2 GY 5x week x 6 weeks
Treatment Arm RT +TMZ (n=275)
TMZ 75 mg/m2 7 days/week 
x 6 weeks
and
Radiation Therapy
2 GY 5x week x 6 weeks
Treatment Arm RT +Nivolumab (n=275)
Nivolumab 480 mg Q4W
TMZ 150 to 200 mg/m2
D1-5 of 28-day cycles
x 6 cycles
(Following 4-week 
treatment break)
Post-treatment 
follow-up for 
safety, OS, and 
progression.
Primary 
Endpoint: 
OS
Secondary 
Endpoints:
PFS, OS (24), and 
PFS and OS in 
TMB
Screening and Randomization
Treatment
Follow-up
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Figure 3.1.1-1:
Screening and Randomization
Following informed consent, subjects with histologic diagnosis of GBM and no evident exclusions 
will be enrolled via a call to an IVRS system, in order to obtain a subject number, after which 
tumor tissue will be submitted to the central laboratory. For details, see Table 5.1-1.
A centralized tumor tissue assay for MGMT is required for randomization. Therefore, the tumor 
sample should be submitted as soon as possible.
Eligibility will be established and baseline information submitted for subjects with a central 
laboratory result of unmethylated MGMT. A subject cannot be randomized until the result of the 
central laboratory MGMT is entered into the IVRS. Subjects without a confirmed result of
unmethylated MGMT will be considered screen failures and will not be eligible for randomization. 
If the assay result is methylated or indeterminate MGMT, they may be enrolled onto another BMS 
study (if available) based on the same MGMT assay.
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.
Schema: Screening and Randomization
MGMT 
Unmethylated 
reported
Confirmed 
Diagnosis 
of GBM
Informed 
Consent
Submit tissue 
to Central Lab
Call IVRS for 
Enrollment
Eligibility Confirmed 
Ready for Treatment
MGMT 
Unmethylated 
confirmation
Call IVRS for 
Randomization
* Enrolled subjects may continue screening assessments regardless 
of MGMT results at a local laboratory; randomization requires 
confirmation of MGMT unmethylated status at Central Lab
Complete 
Screening *
Time from surgery to start RT = 42 days
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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 plus nivolumab 
(RT + nivolumab) or radiotherapy plus temozolomide (RT + TMZ).
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 on T1 images of the post tumor 
surgical region following surgical resection. A partial resection is defined as ≥10 mm of residual
contrast-enhancing tumor tissue on T1 images following surgical resection. Resections with a 
residual of between > 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 diagnostic surgery to initiation of RT should not exceed 42 days,
including a maximum of 7 days from randomization to initiation of RT; however, treatment may 
be delayed if clinically required. Subjects in the RT + nivolumab arm should begin nivolumab 
within 7 days after randomization, and may be given at any time prior to RT start, as clinically 
appropriate. Subjects randomized to the RT + TMZ arm will
begin combination 
chemoradiotherapy on the same day, within 7 days after randomization, as clinically appropriate.
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.53
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 AEs related to RT, see section 6.
Note: Suspected progression occurring within or during 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.
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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 AEs, for maximum clinical benefit (investigator decision), for subject 
request, for completion of TMZ maintenance therapy (6 cycles), disease progression, or another 
reason.
Subjects will be evaluated for AEs 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. All AEs must be documented for a minimum 
of 100 days after discontinuation, but drug-related toxicities should continue to be followed until 
they resolve, return to baseline or are deemed irreversible.
 
 
 
 
3.1.4
Overall Study Duration
The start of the trial is defined as first visit for first subject screened. End of trial is defined as last 
visit or scheduled procedure shown in Time and Events schedule for the last subject. Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
Enrollment and randomization of 550 subjects is expected to require approximately 10 months. 
Final analysis is planned after at least 390 deaths have been reported. Depending on assumptions, 
this analysis is anticipated to occur at approximately 33 months after first subject is randomized, 
respectively; see Statistical Considerations, section 8 for details.
Data may be collected up to 12 months after the pivotal analysis has occurred, after which the 
study may be closed. At discretion of the Sponsor, survival data may continue to be collected for 
up to 5 years.
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.
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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)54
i)
No treatment for GBM other than surgery;
ii) Post-operative baseline MRI following consensus recommendations,52 must be 
obtained prior to randomization. It is strongly recommended that this scan be obtained 
<72 hrs or >14 days post-surgery in order to minimize artifact;
b) Substantial recovery from surgical resection 
i)
No major ongoing safety issues following surgery;
ii) Able to taper steroids (preferably discontinued). Dose at randomization must be 
 ≤20 mg prednisone or ≤3 mg dexamethasone daily (or equivalent);
c) Centrally confirmed (ie, third-party vendor) unmethylated MGMT;
d) Karnofsky performance status of ≥70 (Appendix 3)
e) Clinically appropriate for concomitant temozolomide plus radiation therapy based on 
institutional guidelines.
f)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has 
not been treated) is permitted. If re-enrolled, the subject must be re-consented.
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) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of study treatment with nivolumab 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)
WOCBP randomized to receive temozolomide should use an adequate method to avoid 
pregnancy for 6 weeks (30 days plus the time required for temozolomide to undergo 
five half-lives) after last dose of temozolomide. 
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e) 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 nivolumab and for 
7 months after the last dose of study treatment (90 days [duration of sperm turnover] plus 
the time required for the investigational drug to undergo approximately five half-lives).
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 
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 upper limit of normal (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 Exceptions
a) Prior treatment for GBM (other than surgical resection)
b) Recurrent GBM 
c) MGMT methylated, or indeterminate GBM
d) Biopsy-only of GBM at surgery, defined as <20% resection of enhancing tumor
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e) Ongoing requirement for supraphysiologic steroid, defined as > 20 mg prednisone or 
> 3 mg dexamethasone daily (or equivalent), due to intracranial mass effect
f)
Central nervous system (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)
i)
Known IDH-mutated tumor (if available; test not required)
j)
Concomitant use of Gliadel® wafer;
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
b) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 
antibody or any other antibody or drug specifically targeting T-cell co-stimulation or 
immune checkpoint pathways
c) 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
d) Subjects with a co-existing 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
e) (Not applicable per Protocol Amendment 06)
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, vascular access device no restriction
i)
Subjects unable (eg, due to pacemaker or ICD device) or unwilling to have a 
contrast-enhanced MRI of the head
j)
History of allergy or hypersensitivity to study drug components
k) Unable to swallow oral medication or any gastrointestinal disease or surgical procedure 
that may impact the absorption of study drug
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l)
Subjects with prior hypersensitivity to dacarbazine (DTIC)
m) 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
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection, and/or detectable virus
b) 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.
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
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
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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 screening phase, and discontinued if possible prior to randomization. 
Supportive care for all disease-related or treatment-related AEs should be maximized for all 
subjects on this study. See Section 4.5.2.4 for prophylaxis of Pneumocystis pneumonia.
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 AE):
•
Immunosuppressive agents 
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.4.3)  
3.4.2
Other Restrictions and Precautions
Subjects with a coexisiting condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone or equivalent) or other immunosuppressive medications (including 
within 14 days of randomization) are excluded. Subjects continuing to require supraphysiologic 
steroids (prednisone > 20 mg daily or > 3 mg dexamethasone per day or equivalent) for increased 
intracranial pressure may not be randomized. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active 
autoimmune disease.
Study-related MRI imaging of the brain will be performed using contrast materials. Subjects with 
severe renal insufficiency, who should not receive contrast materials (eg, estimated glomerular 
filtration rate (eGFR) < 30 mL/min/1.73m2) are excluded. 
Certain surgically-implanted devices (pacemaker, deep brain stimulator, metallic implants, etc.) 
are incompatible with MRI imaging. The local imaging facility and investigator should determine 
the appropriate precautions or guidelines that should be instituted for subjects with tattoos, body 
piercings or other body art. For other locally performed imaging, it is the local imaging facility’s 
responsibility to determine, based on subject attributes (eg, allergy history, diabetic history and 
renal status, other contraindications), the appropriate imaging modality and contrast regimen for 
each subject. The ultimate decision to perform MRI in an individual subject in this study rests with 
the site radiologist, the investigator, and the standard set by the local Ethics Committee.
In accordance with TMZ labeling, valproic acid should not be used concomitant with TMZ; at 
investigator discretion, alternative anticonvulsants should be used.
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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 TMZ or nivolumab, see Sections 4.5.1.5
and 4.5.2.3
•
Maximum clinical benefit, as determined by investigator
•
Any clinical 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
•
Subject’s request to stop study treatment (other than for an AE)
•
Completion of 6 cycles of maintenance TMZ (for exception see Table 4.5-1)
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
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 antineoplastic therapy other than as randomized
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This is a survival study, therefore subjects discontinuing study treatment will remain on study for 
documentation of progression and death.
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 the pregnancy and if allowed by local regulations, a discussion between the 
investigator and the Sponsor or 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 (CRF) page.
3.6
Post Study Drug Follow up
In this study, OS is the primary endpoint of the study. Post treatment follow-up is thus of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Table 5.1-3 until death or the conclusion of the study.
Subjects who discontinue study drug will continue to be followed.
BMS may request that survival data be collected on all treated/randomized subjects outside of the 
3 month (± 14 days) 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 
contact.
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.
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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, 
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 CA209498
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
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 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 (SmPC).
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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. Although not a medicinal product, Radiation 
Therapy is also considered part of study treatment.
In this protocol, investigational products are:
•
BMS-936558 (nivolumab)
•
Temozolomide
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 BMS-936558 
(nivolumab).51
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4.3.1
Nivolumab (BMS-936558)
For details regarding drug storage, preparation, administration, and use time please refer to the 
BMS-936558 (nivolumab) Investigator Brochure and/or pharmacy reference sheets.
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, the subject must be enrolled into the study by calling 
an IVRS to obtain the subject number. 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
CA209498 is a randomized study. Central lab confirmation of MGMT un-methylated status must 
be received prior to the IVRS randomization call. Once enrolled in IVRS, enrolled subjects who
meet all eligibility criteria, and are clinically ready to begin treatment, will be randomized through 
the IVRS. 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 + 
nivolumab (RT+ nivolumab) or radiotherapy + temozolomide (RT + TMZ). 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 Sections 3.1. For the RT + nivolumab arm, the first dose 
of nivolumab is to be administered within 7 days of randomization. For the RT + TMZ arm, the 
first dose of temozolomide is to be administered at the beginning of radiotherapy. Treatment details 
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are described separately for each arm below; treatment modifications (eg, dose delay, reduction, 
or discontinuation) will be based on specific laboratory and AE criteria, as described in Sections 
4.5.1 and 4.5.2.
Table 4.5-1:
Selection and Timing of Dose
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Arm RT +
Nivolumab
(BMS-936558)
240 mg, then
480 mg after 8 doses
Every 2 weeks, for 
8 doses, then
Every 4 weeks after 
8 doses 
30 minute 
intravenous 
(IV)
Until progression, 
unacceptable 
toxicity, or 
discontinuation from 
treatment
Arm RT + TMZ
(Temozolomide)
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
4.5.1
Nivolumab Dosing
4.5.1.1
Nivolumab Dose and Schedule
Subjects randomized to nivolumab should begin treatment within 7 days of randomization, but RT 
should begin within 42 days after definitive resection, but 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. 
Subjects randomized to the RT + nivolumab arm will begin nivolumab at a dose of 240 mg, given 
as a 30-minute IV infusion on Day 1 of each treatment cycle Q2W for 8 doses. The nivolumab 
dose will then change to 480 mg as a 30-minute IV infusion Q4W with dose 9 (starting week 17, 
in the absence of delays). Nivolumab injection can be infused undiluted or diluted so as not to 
exceed a total infusion volume of 120 mL. Nivolumab infusion must be promptly followed by a 
saline flush to clear the line.
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.
There will be no dose escalations or reductions of nivolumab allowed. 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 will be considered a delay. For Q4W dosing cycles, subjects may be dosed within 
a ± 3 day window. Premedications are not recommended for the first dose of nivolumab.
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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. Dosing visits are not skipped, only delayed. Nivolumab should be 
delayed (see Section 4.5.1.3) for toxicities considered at least possibly-related to nivolumab.
Nivolumab interruption refers to stopping the infusion, eg, for an infusion reaction (see 
Section 4.5.1.8).
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.
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy reference sheet. Care must be taken to assure sterility of 
the prepared solution because the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
4.5.1.2
Dose Modifications for Nivolumab
Dose modification is not allowed for nivolumab; for dose delay, see 4.5.1.3.
4.5.1.3
Dose Delay Criteria for Nivolumab
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 AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities
•
Grade 3 skin drug-related AE
•
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 ALT/AST or total bilirubin will require dose discontinuation (see 
Section 4.5.1.5)
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
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).
4.5.1.4
Criteria to Resume Dosing for Nivolumab
Subjects may resume treatment with study drug when the drug-related AE(s) resolve 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
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•
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 (or designee).
•
Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor
(or designee). Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
4.5.1.5
Treatment Discontinuation Criteria for Nivolumab
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 AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurological toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurological toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation
−
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
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•
Any Grade 4 drug-related AE 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 AEs, 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 (or designee). 
•
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 AEs 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 (or designee). 
−
Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS 
medical monitor (or designee) 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.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
4.5.1.6
Continuing Nivolumab 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). Subjects on the RT + 
nivolumab arm may, at investigator discretion, 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 applies to both treatment arms.] 
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 initial (suspected) progression only if they meet the 
following criteria:
•
Subject is tolerating nivolumab
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•
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.40
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 
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
The above algorithms are found in Appendix 1 and in the nivolumab Investigator Brochure.
4.5.1.8
Treatment of Nivolumab-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.
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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 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 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 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 BMS-
936558 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 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. 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 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.
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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 on RT + TMZ will be administered temozolomide (TMZ, Temodar®) daily during RT 
and as maintenance therapy for 6 cycles. TMZ dosing will be performed according to institutional 
standard; the following guidance is drawn from published literature. 
Temozolomide (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. 
Table 4.5.2.1-1:
Dose Levels for TMZ Maintenance 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 Cycle 1
1
200 mg/m2/day
Dose during C2-6 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 AEs (see Table 4.5.2.3-2). If there was a prior dose reduction 
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 monotherapy.
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. 
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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
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
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Table 4.5.2.3-2:
Temozolomide Dose Modification Guidelines During Maintenance 
TMZ Dosing
Laboratory Value/Clinical Criteria:
Dose Modificationa
Additional Information:
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 on the lowest blood count and worst 
non-hematologic toxicity during the prior cycle.
Source: adapted from Temodar® package insert (PI)
4.5.2.4
Supportive Care during Temozolomide
Subjects should be treated 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
Not applicable.
4.7
Treatment Compliance
Assessment of study medications will be performed at each study visit. For subjects receiving 
temozolomide, the subject 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. Subjects will be instructed to record dosing in a dosing diary which will be reviewed at 
each visit, in combination with drug accountability to confirm treatment compliance. Sites should 
discuss discrepancies between the diary and the drug log to reconcile actual dosing with the patient 
at each visit.
4.8
Destruction of Study Drug
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. 
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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.
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 (CA209498)
Procedure
Screening
Visit 1
Notes
Informed Consent for Enrollment
X
Call IVRS to obtain subject number; see Section 3.1.1
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization
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
Tumor Sample Submission
X
Surgical biopsy (block or slides) Submission: See Laboratory Manual. Central Laboratory 
MGMT result must be available prior to randomization.
Baseline 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, LDH, Glucose, within 14 days 
prior to randomization. 
TSH, T3 and T4 (Free or Total), Hep B/C (HBVsAG, HCV antibody or HCV RNA), within
28 days prior to randomization
Urinalysis
X
Dipstick, obtain within 14 days prior to randomization
Pregnancy Test [WOCBP only]
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
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a Post-operative baseline MRI following consensus recommendations must be obtained prior to randomization. It is strongly recommended that this scan be 
obtained <72 hrs 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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Table 5.1-2:
On-Treatment Assessments (CA209498)
Procedure
RT + TMZ
TMZ
Maintenance
RT + 
Nivolumab
Notes: Windows refer to calendar days. Procedures must be
done within 72h prior to dosing unless otherwise specified.
IVRS Randomization call 
Day 1
Day 1
Confirm eligibility criteria prior to randomization. 
Targeted Physical Examination, Vital 
Signs
Q2 wks
Day 1 of each 
cycle 
Q2 wks x 8 
doses, then 
Q4 wks
Weight. BP, HR, RR, temperature, and Karnofsky Performance 
Status
Adverse Events Assessment
Continuously
Record at each visit
Review of Concomitant Medications
X
X
X
Record at each visit, including steroid dose
Radiation Therapy
See Note
See Note
Total dose 60 Gy over 6-7 weeks, see Section 3.1.2.2
CBC with Differential
Weekly
Day1&22
of each cycle
Within 3 days 
prior to each 
dose
Weekly if delayed and as clinically indicated
Chemistry panel
Q4 wks
Day 1
each cycle
Within 3 days 
prior to each 
dose
Chemistry panel: AST, ALT, ALP, T.Bili, albumin, BUN or 
serum urea, creatinine, Ca, Na, K, Cl, LDH, Glucose
Additional tests, as clinically indicated, will also be submitted
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]
Every 4 weeks
Serum or urine pregnancy test every 4 weeks (±3 days; minimum 
sensitivity 25 IU/L or equivalent units of HCG).
 
Tumor Assessment
X (See Note)
Contrast-enhanced MRI 4 weeks (± 7 days) after completing RT, 
then every 8 weeks (± 7 days)a until progression. 
See Section 5.4.1 
 
 
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Table 5.1-2:
On-Treatment Assessments (CA209498)
Procedure
RT + TMZ
TMZ
Maintenance
RT + 
Nivolumab
Notes: Windows refer to calendar days. Procedures must be
done within 72h prior to dosing unless otherwise specified.
 
 
 
Health Care Resource Utilization
X (See Note)
Obtained prior to dosing Day 1 Week 1 and then with each MRI, 
(± 7 days) see Section 5.8.4
Dispense Nivolumab 
X
(see note)
Day 1 within 7 days of randomization, then every 2 weeks for 8 
doses, then every 4 weeks
Dispense Temozolomide
D1, D15, 
D29 & D43
(if needed)
D1 each cycle
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 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 
Assess Temozolomide Compliance
X
X
Review medication diary
a 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 (CA209-498)
Procedure
Treatment 
Follow-upa
Survival 
Follow-upb
Notes
TIMING
35 and 115 days
(±7 Days) after 
last dose
Q 3 Months
(± 14 Days)
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 drug-related adverse events until resolved, return to baseline or 
deemed irreversible or until lost to follow-up or withdrawal of study consent
Laboratory Tests
X
CBC w/differential, LFTs, BUN, creatinine and TSH at 35 days, repeat labs at 
115 day 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
Q8 weeks (± 7 days) until PD
Required for subjects who did not progress on study treatment, eg, discontinued 
for AEs. 
NANO scale
X
X
Completed by study physician with each MRI (± 7 days)
Cogstate
X
Cogstate Assessments should occur at Months 6, 12, 18, and 24 (± 15 days) and 
then continue every 12 months (± 15 days) as long as MRIs are performed. See 
Section 5.7.1.
Biomarker Sample
X
Serum and whole blood at time of progression; See Section 5.6.
Tumor Sample at time of progression
X
X
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.
EORTC QLQ-C30 and BN20
X
EQ-5D
X
X
May be obtained through telephone call or clinic visit
Survival Status
X
Every 3 months (± 14 days) (clinic visit or telephone contact), during Survival 
phase, include documentation of subsequent chemotherapy.
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a Subjects must be followed for at least 100 days after last dose of study treatment. 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 the last dose
b Survival Follow-up visits to occur every 3 months (± 14 days) from Follow-up Visit 2. 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 will be permitted 
(in addition to any parameters that require a confirmatory value). 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 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
 
•
Site manual for operation of IVRS, including enrollment/randomization worksheets
•
Manual for entry of local laboratory data
•
Pregnancy Surveillance Forms
•
Imaging Manual includes specifications for Radiology scan submission manual
•
Dosing Diary for temozolomide
 
 
 
 
 
 
 
 
 
 
 
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5.4
Efficacy Assessments
All subjects will undergo brain 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 preferred). Additional MRI 
scan may be obtained if clinically appropriate, eg for radiotherapy planning, but is not required; in 
this case the last scan prior to randomization will be considered the baseline MRI. 
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Subjects who are unable (due to existent medical condition, ie, 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 
OS as long as there is no safety issue which would require monitoring by MRI. 
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 AEs 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.
 
 
 
 
 
 
 
 
 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled 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 
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 
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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.39 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.
 
 
 
 
 
 
 
 
 
 
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X
X
X
X
  
 
 
 
5.6.1
Tumor Samples
Tumor specimens will be obtained from consenting subjects prior to treatment to characterize 
immune cell populations and expression of selected tumor markers. Tumor tissue (block or slides) 
must be available for submission prior to randomization. If a block is not available, a minimum of 
twenty (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. If clinically 
appropriate, additional biopsies obtained at any time, eg, if progression is suspected, may also be 
collected. 
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.
In order to provide adequate tissue for MGMT testing and exploratory analyses, two paraffin 
blocks are requested (1 minimum). If only slides are available, they should be unstained, have a
recommended tissue section thickness is 4 microns and must be positively charged. Slides should 
be shipped refrigerated at 2-8° C.
An assessment of tissue quality by a pathologist is strongly encouraged at the time of the 
procedure. The tumor tissue that is obtained will be divided in the following priority order: 1) into 
formalin for fixation and paraffin-embedding, 2) into RNALater for RNA/DNA extraction.
Sample shipments should include a completed requisition form containing collection date, 
collection method, primary/met, site, fixation conditions, and a copy of Pathology report, if
available.
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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 unmethylated MGMT status. 
Testing will be performed using a centralized RT-PCR assay. Details regarding MGMT testing are 
provided in Section 5.6.1.1.
 
 
 
 
 
5.6.1.4
Characterization of T cell repertoire
As described above, DNA sequencing may be performed on pre-and post-treatment tumor tissue 
to assess the composition of the T cell repertoire. DNA will be isolated from either the FFPE tumor 
block or from RNAlater or equivalent preparations.
5.6.1.5
Gene expression profiling
Tumor tissue collected in RNAlater or equivalent fixative will be examined for mRNA gene 
expression by Affymetrix gene array technology and/or quantitative real-time polymerase chain 
reaction (qPCR) to detect expression of selected immune related genes.
5.6.1.6
Tumor genotyping, mutational analysis, and tumor antigen profiling
DNA and RNA from tumor samples will be analyzed using whole-exome and transcriptome 
sequencing to determine the number of mutations found within a given sample relative to a normal 
host tissue, such as adjacent non-transformed cells or PBMC. Mutations that are detected will be 
analyzed for their ability to bind the MHC I and MHC II proteins using prediction algorithms, such 
as NetMHC. Evaluating the ability of tumor mutations to bind MHC molecules will provide 
evidence that these mutations are serving as antigens that are recognized by the immune system 
and are potential rejection antigens.
 
 
 
 
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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 secondary outcomes (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 for storage and for analysis by blinded independent central review 
as determined by the Sponsor. The site will be informed of quality issues or need for repeat 
scanning via queries from the core lab.
5.8.4
Healthcare Resource Utilization
Healthcare resource utilization data associated with hospitalizations and non-protocol specified 
medical visits related to either study therapy or disease will be collected for all randomized 
subjects. The healthcare resource utilization will be collected prior to dosing on day 1 week 1 and 
then at a convenient clinical visit near the time of the MRI scan. 
 
 
 
 
 
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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.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is a Phase 3, randomized, open label, multicenter study of RT + nivolumab versus RT + TMZ 
in adult (≥18 years) subjects with newly diagnosed GBM subjects with unmethylated MGMT 
tumors.
Primary objective of the study is to compare the OS of RT+ nivolumab versus RT+TMZ in subjects 
with newly diagnosed GBM subjects with unmethylated MGMT tumors after surgery.
The sample size for this study is based on the following assumptions:
1) OS follows exponential distribution
2) Median OS in RT + TMZ arm is 13.0 months (Weller 200934)
3) Hazard ratio (HR) of arm RT + nivolumab vs RT + TMZ is 0.72, translated to median OS 
improvement of 5.0 months (13.0 months vs 18.0 months for arm RT + TMZ and arm RT +
nivolumab, respectively)
At least 390 events (ie, death) provides 90% power to detect a hazard ration (HR) of 0.72 with an 
overall type 1 error of 0.05 (two-sided). This translates to an observed HR of 0.82 (median OS of 
13.0 vs 15.8 months) or less resulting in a statistically significant improvement.
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Approximately 550 subjects will be randomized to the two arms (RT +nivolumab vs RT + TMZ) 
in a 1:1 ratio stratified by complete or partial resection at baseline. Accrual will take approximately 
10 months. The total duration of the study from start of randomization to final analysis of OS is 
expected to be approximately 33 months (10 months of accrual + 23 months of follow-up, Table 
8.1-1).
Power calculations were done using East v 6.3.
Table 8.1-1:
Key parameters of Sample Size Calculation of OS
Assumptions
Analysis
Goal/Timing 
(from first 
subject 
randomized)
Significant 
Nominal
p-value
Probability for 
declaring 
superiority 
Under HA/H0
α = 0.05
Power = 90%
Control arm (RT+TMZ)
median OS = 13.0 months;
Treatment arm 
( RT + Nivolumab)
Median OS = 18.0 months
HR = 0.72
Final 
Superiority
390
OS events/
33 months
Superiority 
Observed nominal 
p-value
≤ 0.05
90%/5%
The PFS, overall survival at 24 months (OS[24]), and OS and PFS in TMB-high patients are 
secondary endpoints. OS[24] is included as secondary endpoint to evaluate the improvement in 
long term survival. Only PFS will be tested using a hierarchical testing procedure. (Section 8.4.2). 
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.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint is OS. OS is defined as the time between the date of randomization and the 
date of death due to any cause. A subject who has not died will be censored at the last known alive 
date. OS will be followed continuously while subjects are on study drug and every 3 months (± 14 
days) via in-person or phone contact during survival follow-up phase of the study.
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8.3.2
Secondary Endpoint(s)
The first secondary objective (comparing PFS between arm RT + nivolumab and RT + TMZ) will 
be measured by the endpoint of PFS. 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 die without a 
reported progression will be considered to have progressed on the date of death. Subjects who did 
not have disease progression or die will be censored at the date of last tumor assessment. Subjects 
who did not have any on study tumor assessment and did not die will be censored at the 
randomization date. 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 
subsequent anti-cancer therapy. Subjects who had surgical resection post start of study treatment
will be censored at the last tumor assessment date prior to initiation of surgical resection. PFS will 
be determined by investigator reported response based on RANO criteria (Section 5.4.3). 
The secondary objective (estimate the overall survival rate at 24 months (OS[24]) of RT + 
nivolumab) will be Kaplan-Meier probability of survival at 24 months. 
The secondary objective is OS and PFS assessed in the TMB-high population, as assessed in the 
TMB assay where the numerical cut-off for high versus low will be specified in the statistical 
analysis plan (SAP). Definition for OS and PFS for this endpoint will be the same as defined 
earlier.
 
 
 
 
 
 
 
 
 
 
 
 
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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
The analyses of primary (OS) and secondary (PFS, OS[24]) endpoints will be based on all 
randomized subjects. Safety summaries will be based on all treated subjects. If superiority in OS 
is demonstrated, a hierarchical hypothesis testing approach for the secondary endpoint of PFS will 
be used to preserve a familywise type I error rate at 0.05. 
The formal statistical testing for PFS will take place only if OS is statistically significant.
Secondary endpoints of OS[24] and OS and PFS in the TMB-high population will be estimated 
using the Kaplan Meier method.
8.4.2.1
Analyses of Primary Endpoint
The distribution of OS in all randomized subjects will be compared in arms RT + nivolumab and 
RT + TMZ at the final analysis via a two-sided, log-rank test, stratified by complete resection or 
partial resection at baseline. The Kaplan-Meir product limit method will be used to estimate the 
survival curve in each arm including medians and its 95% CI, OS rates at pre-specified time points.
The HR and the corresponding two-sided 95% 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).
8.4.2.2
Analyses of Secondary Endpoints
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). The details of the testing 
procedure will be specified in the SAP. OS[24] will be estimated when all censored subjects have 
had follow-up of at least 24 months. OS and PFS in the TMB-high population will be estimated 
using the Kaplan-Meier method. Additional details for the analysis of OS[24] endpoint will be 
included in SAP.
 
 
 
 
 
 
 
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8.5
Interim Analyses
Not applicable.
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) and 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), 
AE 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, whichever is longer. The investigator (or head of 
study site in Japan) must contact BMS prior to destroying any records associated with the study.
BMS will notify the investigator (or head of 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, IRB). Notice of such 
transfer will be given in writing to BMS.
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
•
amount transferred to another area/site for dispensing or 
storage
•
nonstudy disposition (eg, lost, wasted) 
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If...
Then...
•
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. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. 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 BMS 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 
paper or 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 BMS. 
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 BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. 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. 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 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
ADA
anti-drug antibodies
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
BMS
Bristol-Myers Squibb
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
CL
clearance
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
CTLA 4
Cytotoxic T lymphocyte associated antigen 4
%CV%
geometric mean
DILI
drug-induced liver injury
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Term
Definition
dL
deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTIC
Dacarbazine
EANO
European Association of Neuro-Oncology
EC
ethics committee 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EQ-VAS
EuroQol visual analog scale
EORTC
European Organization for Research and Treatment of Cancer
ESR
expedited safety report
FDA
Food and Drug Administration
FFPE
Formalin-Fixed, Paraffin-Embedded
FLAIR
fast fluid-attenuated inversion recovery
FSH
follicle stimulating hormone
GBM
glioblastoma
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
Gy
gray (radiotherapy dose)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
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Term
Definition
HCV-RNA
hepatitis C virus-ribonucleic acid
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus
HR
heart rate
HrQoL
health-related quality of life
HRT
hormone replacement therapy
IB
investigator brochure
ICD
Implantable Cardioverter Defibrillator
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICOS
increased activation markers
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
immunohistochemistry
imAEs
immune-mediated adverse events
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
I-O
immuno-oncology
IP
investigational product
iRANO
Immune Radiologic Assessment in Neuro-Oncology
IRB
Institutional Review Board
IRC
Independent Radiology Review Committee
IU
International Unit
IUDs
Intrauterine devices
IV
intravenous
IVRS
Interactive voice response system
ITIM
Immunoreceptor tyrosine inhibitory motif 
ITSM
Immunoreceptor tyrosine-based switch motif
K+
potassium
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Term
Definition
kg
kilogram
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test
mAbs
monoclonal antibodies
mg
milligram
Mg/kg
Milligram per kilogram
Mg++
magnesium
MGMT
tumor O-6-methylguanine DNA methyltransferase
mL
milliliter
MRI
Magnetic Resonance Imaging
MST
Medical safety team
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
N
nivolumab (BMS-936558)
Na+
sodium
NANO
Neurologic Assessment in Neuro-Oncology
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
Not evaluable
NIMP
non-investigational medicinal products 
NSCLC
non-small cell lung carcinoma
O2
Oxygen
OS
overall survival
PBMC
Peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamics
PD
progressive disease
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Term
Definition
PD-1
Programmed cell death protein 1
PD-L 1
Programmed cell death ligand 1
PFS
Progression-free survival
PID
Patient identifier 
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population pharmacokinetics
PR
partial response
PVC
polyvinyl chloride
QD
once a day
QLQ-C30
European Organization for Research and Treatment of Care General 
Cancer Module
QLQ-BN20
European Organization for Research and Treatment of Cancer - Brain 
Cancer Module
QOL
Quality of life
QxW
Every x weeks
RANO
Radiologic Assessment in Neuro-Oncology
RCC
Renal cell carcinoma
RNA
ribonucleic acid
RR
respiratory rate 
RT
radiation therapy
RT-PCR
reverse transcription polymerase
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD
stable disease
SmPC
summary of product characteristics
SNP
single nucleotide polymorphism
SOC
standard of care 
SOP
Standard Operating Procedures
T1/2
Geometric elimination half-life
TCR
T cell receptor
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Term
Definition
TIL
tumor infiltrating lymphocytes
TMB
tumor mutational burden
TMZ
Temozolomide
TSH
thyroid stimulating hormone
μg
microgram
ULN
upper limit of normal
VAS
visual analogue scale
Vss
volume of distribution at steady state 
w
week
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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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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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan for 
 
A RANDOMIZED PHASE 3 OPEN LABEL STUDY OF NIVOLUMAB VS. 
TEMOZOLOMIDE IN COMBINATION WITH RADIATION THERAPY IN NEWLY 
DIAGNOSED ADULT SUBJECTS WITH UNMETHYLATED MGMT (TUMOR 06- 
METHYLGUANINE DNA METHYLTRANSFERASE) GLIOBLASTOMA 
NCT02617589 
 
08-February-2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A RANDOMIZED PHASE 3 OPEN LABEL STUDY OF NIVOLUMAB VS. 
TEMOZOLOMIDE IN COMBINATION WITH RADIATION THERAPY IN NEWLY 
DIAGNOSED ADULT SUBJECTS WITH UNMETHYLATED MGMT (TUMOR 06-
METHYLGUANINE DNA METHYLTRANSFERASE) GLIOBLASTOMA
PROTOCOL(S) CA209498
VERSION # 3.0
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Statistical Analysis Plan
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2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................6
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................8
2.1.1
Screening Phase .......................................................................................................9
2.2
Treatment Assignment............................................................................................10
2.3
Blinding and Unblinding.........................................................................................11
2.4
Protocol Amendments.............................................................................................11
2.5
Data monitoring Committee....................................................................................13
3
OBJECTIVES ........................................................................................................13
3.1
Primary...................................................................................................................13
3.2
Secondary...............................................................................................................13
4
ENDPOINTS..........................................................................................................14
4.1
Primary...................................................................................................................14
4.2
Secondary...............................................................................................................14
4.2.1
Progression Free Survival ......................................................................................14
4.2.2
Overall Survival at 24 months.................................................................................15
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3
5
SAMPLE SIZE AND POWER...............................................................................22
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................23
6.1
Study Periods..........................................................................................................23
6.2
Treatment Regimens...............................................................................................24
6.3
Populations for Analyses ........................................................................................24
7
STATISTICAL ANALYSES..................................................................................25
7.1
General Methods ....................................................................................................25
7.1.1
Adverse Events, Serious Adverse Events, Multiple events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................25
7.1.1.1
Select Adverse Events .............................................................................................26
7.1.1.2
Other Events of Special Interest..............................................................................27
7.1.1.3
Immune-Mediated Adverse Events ..........................................................................27
7.1.2
Laboratory Tests.....................................................................................................27
7.1.3
Immunogenicity data ..............................................................................................28
7.2
Study Conduct........................................................................................................28
7.2.1
Accrual...................................................................................................................28
7.2.2
Relevant Protocol Deviations..................................................................................28
7.3
Study Population ....................................................................................................29
7.3.1
Subject Disposition.................................................................................................29
7.3.2
Demographics and Baseline Characteristics...........................................................29
7.3.3
Medical History......................................................................................................30
7.3.4
Prior Therapy.........................................................................................................30
7.3.5
Baseline Examinations............................................................................................31
7.4
Extent of Exposure .................................................................................................31
7.4.1
Administration of Study Therapy.............................................................................32
7.4.2
Modifications of Study Therapy ..............................................................................33
7.4.2.1
Nivolumab Dose delays ..........................................................................................33
7.4.2.2
Nivolumab Infusion Interruptions and Rate Changes ..............................................33
7.4.2.3
Temozolomide Dose Modifications .........................................................................34
7.4.2.4
Missing Radiotherapy.............................................................................................34
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7.4.2.5
Dose Reductions/Escalation....................................................................................34
7.5
Efficacy..................................................................................................................36
7.5.1
Overall Survival .....................................................................................................36
7.5.1.1
Primary Analysis ....................................................................................................36
7.5.1.2
OS sensitivity Analyses ...........................................................................................37
7.5.1.3
Consistency of Treatment Effect on OS in Subsets...................................................37
7.5.1.4
Subject Follow-Up..................................................................................................38
7.5.2
Interim Analysis......................................................................................................38
7.5.3
Progression Free Survival ......................................................................................38
7.5.3.1
Primary Analysis ....................................................................................................38
7.5.3.2
Sensitivity Analysis .................................................................................................39
7.5.4
Overall Survival Rate at 24 Months ........................................................................40
7.5.5
Relationship between OS or PFS and TMB.............................................................40
7.5.6
Other Efficacy Analyses..........................................................................................40
7.5.6.1
Analysis of Objective Response Rate.......................................................................40
7.5.6.2
Time to Tumor Response and Duration of Response ...............................................40
7.5.6.3
Analyses of Tumor Burden......................................................................................40
7.5.6.4
Analysis of Subjects Treated beyond Progression ...................................................41
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8
CONVENTIONS....................................................................................................55
9
CONTENT OF REPORTS .....................................................................................56
10
DOCUMENT HISTORY........................................................................................56
APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION 
AND CONVENTIONS FOR SELECT ADVERSE EVENTS, 
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IMMUNE MEDIATED ADVERSE EVENTS AND EVENTS OF 
SPECIAL INTEREST............................................................................61
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS ...............................................63
APPENDIX 3
IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE.........................................................................................65
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ............................................................................11
Table 5-1:
Key Parameters of Sample Size calculation ............................................22
Table 7.10-1:
Tasks and Outcome Variables for Cogstate Assessment..........................53
Table 10-1:
Document History ..................................................................................56
Table 10-2:
Derivation of clustered AE .....................................................................62
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................9
Figure 4.2.1-1:
Graphic Display of PFS Primary Defintion.............................................15
Figure 7.5.3.2-1:
Graphic Display of PFS Accounting for Assessment after 
Subsequent Therapy ...............................................................................39
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2
STUDY DESCRIPTION
2.1
Study Design
This study will enroll subjects with newly-diagnosed glioblastoma (GBM), following surgical 
resection of the tumor. After informed consent is obtained, subjects will enter the screening phase. 
Tumor tissue will be evaluated for MGMT methylation by a central laboratory assay. 
 
 
 
 
 
 
 
 
Post-operative baseline MRI following consensus recommendations, must be obtained prior to 
randomization. It is strongly recommended that this scan be obtained < 72hrs or > 14 days post-
surgery in order to minimize artifact. There is no requirement that this baseline scan be performed 
on a “qualified” machine (a qualified MRI is one that meets the Imaging Manual specifications 
and has been validated with the required phantom scan). If a post-operative MRI is not available, 
a high-quality, contrast-enhanced CT scan may be performed initially, but in this case a contrast-
enhanced MRI must be performed prior to randomization (> 2 weeks post-operative preferred).
Subjects with a central laboratory result of unmethylated MGMT may continue in the screening 
phase, in which eligibility for randomization will be documented and baseline demographic and 
disease information submitted
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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 Figure 2.1-1. All subjects 
who enter the treatment phase, i.e., all randomized subjects, will be followed for safety and 
tolerability, tumor progression and survival. A contrast-enhanced MRI should be performed 4 
weeks (± 7 days) after completing radiation therapy, then every 8 weeks (± 7 days) until 
progression regardless of treatment schedule or dose delays. Tumor progression will be assessed 
using Radiologic Assessment in Neuro-Oncology criteria (RANO). Additional assessments will 
be performed for cognitive function, neurologic function, biomarkers and patient-reported quality 
of life outcomes.
After cessation of 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. All 
subjects in whom disease progression had not been detected at the time study treatment is stopped
will be followed closely for progression with contrast enhanced MRI every 8 weeks (± 7 days) 
until progression. After progression, subjects MUST be followed for survival (primary endpoint); 
subsequent treatments will be reported.
Baseline and all subsequent scans will be submitted to a blinded independent radiology review 
committee (BIRC) for archiving, once the subject is randomized and throughout the study period.
A Data Monitoring Committee (DMC) will meet regularly during the study to ensure that subject 
safety is carefully monitored.
Figure 2.1-1:
Study Design Schematic 
2.1.1
Screening Phase
Subjects will provide consent for enrollment and tumor submission in the peri-operative period, 
so that MGMT status can be determined, but consent for randomization and study treatment should 
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be deferred until MGMT unmethylated status and eligibility is established. The clinical 
circumstances should be considered with respect to the timing of consent.
Following informed consent, subjects with histologic diagnosis of GBM and no evident exclusions 
will be enrolled via a call to an IVRS system, in order to obtain a subject number, after which 
tumor tissue will be submitted to the central laboratory. For details, see a centralized tumor tissue 
assay for MGMT is required for randomization. Therefore, the tumor sample should be submitted 
as soon as possible.
Eligibility will be established and baseline information submitted for subjects with a central 
laboratory result of unmethylated MGMT. A subject cannot be randomized until the result of the 
central laboratory MGMT is entered into the IVRS. Subjects without a confirmed result of 
unmethylated MGMT will be considered screen failures and will not be eligible for randomization. 
If the assay result is methylated or indeterminate MGMT, they may be enrolled onto another BMS 
study (if available) based on the same MGMT assay.
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 < 20mg prednisone or < 3mg 
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 (e.g., 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.
2.2
Treatment Assignment
After informed consent has been obtained, the subject must be enrolled into the study by calling 
an IVRS to obtain the subject number. 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
CA209498 is a randomized study. Central lab confirmation of MGMT un-methylated status must 
be received prior to the IVRS randomization call. Once enrolled in IVRS, enrolled subjects who 
meet all eligibility criteria, and are clinically ready to begin treatment, will be randomized through 
the IVRS. The following information is required for randomization: 
•
Subject number
•
Date of birth of subject
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•
Extent of tumor resection: Complete or Partial
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to receive radiotherapy + 
nivolumab (RT+ nivolumab) or radiotherapy + temozolomide (RT + TMZ). 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
Not applicable. This is an open-label study.
2.4
Protocol Amendments
This SAP (version 3.0) incorporates the following amendments:
Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
Revised Protocol 01
(Incorporate Amendment 03)
12-Jan-2016
Added exclusion for subjects with prior 
hypersensitivity to dacarbazine (DTIC); Added 
definition of Suspected, Unexpected Serious Adverse
Event Reaction (SUSAR) and statement of SUSAR 
reporting responsibilities.
Revised Protocol 02
(Incorporates Amendment 04)
24-Feb-016
Corrected the temozolomide dose modification
guidance during maintenance temozolomide dosing; 
modified nivolumab dose delay and discontinuation 
criteria
Revised Protocol 03
(Incorporates Amendment 06 
and Administrative Letter 01)
04-May-2016
Major changes implemented in this Amendment 
include
1) Eligibility criteria
a)
Add exclusion for Gliadel® wafer
b)
Permit baseline MRI to be performed up 
to 72 hours postoperatively. If only CT is 
available, an MRI must be obtained prior 
to randomization.
c)
Modified language for women of child-
bearing potential
2) Modify cutoff values used to define complete 
vs 
partial 
resection 
for
purposes 
of 
randomization
 
 
 
 
 
 
 
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Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
4) Update language throughout to conform with 
the Health Authority requests
 
 
 
 
 
 
 
 
 
6) Clarify treatment plan
a)
Insert guidance for radiation therapy as 
an appendix
(referenced in Section 
3.1.2.2)
b)
Switch from 240mg Q2 wk to 480mg Q4 
wk after 8 doses (rather than 16 weeks)
c)
Aligned start of nivolumab and start of 
temozolomide to
within 7 days of 
randomization
d)
Clarify 
that 
TMZ 
dosing 
is 
per 
institutional standards and update dose 
modification table to conform with 
SmPC
Revised Protocol 04
(Incorporates amendment 08)
09-Nov-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 05
15-Nov-2017
Major changes included are:
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Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
(Incorporates Administrative 
Letters 04 and 05 and 
amendment 09) 
1) Removal 
of 
the 
interim analysis 
for 
superiority of the primary endpoint of OS.
2) Addition of a secondary endpoint that 
evaluated, in newly diagnosed, unmethylated 
MGMT GBM, any relationship between OS 
or PFS and TMB in the RT + nivolumab arm 
compared to the RT + TMZ control arm.
2.5
Data monitoring Committee
An independent Data Monitoring Committee (DMC) has been established to provide oversight of 
safety and efficacy considerations, study conduct, and risk-benefit ratio. Following review, the 
DMC will recommend continuation, modification, or discontinuation of this study based on 
reported safety and efficacy data. Details of DMC responsibilities and procedures are specified in 
the DMC charter1. Representatives of the Sponsor will serve only as coordinators of the committee, 
without having full member responsibilities or privileges. In addition, the Sponsor will 
independently review safety data in a blinded manner to ensure that any safety issues are identified 
and addressed.
3
OBJECTIVES
3.1
Primary
To compare OS of nivolumab in addition to radiation therapy versus temozolomide in addition to 
radiation therapy in subjects with newly diagnosed GBM with unmethylated MGMT tumors after 
surgical resection
3.2
Secondary
•
To compare investigator-assessed PFS of RT + nivolumab versus RT + TMZ
•
To estimate the OS rate at 24 months (OS[24]) of RT + nivolumab versus RT + TMZ
•
To evaluate, in newly diagnosed, unmethylated MGMT GBM, any relationship between OS 
or PFS and tumor mutational burden (TMB) in the RT+nivolumab arm compared to the 
RT+TMZ control arm
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4
ENDPOINTS
4.1
Primary
The primary endpoint is OS. OS is defined as the time between the date of randomization and the 
date of death due to any cause. A subject who has not died will be censored at the last known alive 
date. 
4.2
Secondary
4.2.1
Progression Free Survival
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 who did 
not die will be censored at the date of last tumor assessment. Subjects who did not have any on 
study tumor assessment and did not have tumor progression or die will be censored at the 
randomization date. 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 
subsequent anti-cancer therapy. Subjects who had surgical resection post start of study treatment 
will be censored at the last tumor assessment date prior to initiation of surgical resection. PFS will 
be determined by investigator reported response based on RANO criteria
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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 4.2.1-1 Alternate censoring 
rules for sensitivity analyses are specified in Section 7.5.3.2.
Figure 4.2.1-1:
Graphic Display of PFS Primary Defintion
4.2.2
Overall Survival at 24 months
Overall survival at 24 months is defined as probability of survival at 24 months based on Kaplan-
Meier method. It will be estimated only when minimum follow-up is 24 months or more. In case 
the minimum follow-up is less than 24 months, but it is judged that data immaturity does not affect 
interpretability of the results, 24 months OS rate will be provided.
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
This is a Phase 3, randomized, open label, multicenter study of RT + nivolumab versus RT + TMZ 
in adult (≥18 years) subjects with newly diagnosed GBM subjects with unmethylated MGMT 
tumors.
Primary objective of the study is to compare the overall survival (OS) of RT+ nivolumab versus 
RT+TMZ in subjects with newly diagnosed GBM subjects with unmethylated MGMT tumors after 
surgery.
The sample size for this study is based on the following assumptions:
1) OS follows exponential distribution
2) Median OS in RT + TMZ arm is 13.0 months (Weller 20095)
3) Hazard ratio (HR) of arm RT + nivolumab vs. RT + TMZ is 0.72, translated to median OS 
improvement of 5.0 months (13.0 months vs. 18.0 months for arm RT + TMZ and arm RT 
+ nivolumab, respectively)
At least 390 events (i.e., death) provide 90% power to detect a hazard ration (HR) of 0.72 with an 
overall type 1 error of 0.05 (two-sided). This translates to an observed HR of 0.82 (median OS of 
13.0 vs. 15.8 months) or less resulting in a statistically significant improvement.
Approximately 550 subjects will be randomized to the two arms (RT +nivolumab vs. RT + TMZ) 
in a 1:1 ratio stratified by complete or partial resection at baseline. Accrual will take approximately 
10 months. The total duration of the study from start of randomization to final analysis of OS is 
expected to be approximately 33 months (10 months of accrual + 23 months of follow-up 
(Table 5-1)
Power calculations were done using East v 6.3.
Table 5-1:
Key Parameters of Sample Size calculation
Assumptions
Analysis
Goal/Timing 
(from first 
subject 
randomized)
Significant 
Nominal
p-value
Probability for 
declaring 
superiority 
Under HA/H0
α = 0.05
Final 
390
Superiority 
Observed nominal 
90%/ 5%
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Table 5-1:
Key Parameters of Sample Size calculation
Assumptions
Analysis
Goal/Timing 
(from first 
subject 
randomized)
Significant 
Nominal
p-value
Probability for 
declaring 
superiority 
Under HA/H0
Power = 90%
Control arm (RT+TMZ)
median OS = 13.0 months;
Treatment arm 
( RT + Nivolumab)
Median OS = 18.0 months
HR = 0.72
Superiority
OS events/
33 months
p-value
≤ 0.05
No Superiority 
nominal
p-value
> 0.05
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
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. Evaluations (laboratory tests, pulse 
oximetry and vital signs) on the same date and time of the first dose of study treatment will 
be considered as baseline evaluations.
−
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 on or prior to the first dose of study treatment:
♦For laboratory tests, the latest non missing labs value on or before first dose date (and 
time if collected) will be used as the baseline in the analyses. For 'LIPASE' and 
'GLUCOSE', for treated subjects only, the last predose assessment with non-missing 
toxicity grade will be considered as baseline. If multiple assessments exist with the 
same collection date (and time if collected) and entry date and time, then the first 
observation is used as baseline.
 
 
 
 
 
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•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and 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). For subjects who are off 
study treatment, AEs will be included if event occurred within a safety window of 30 days 
(or 100 days depending on the analysis) after the last dose of study treatment. No 
“subtracting rule” will be applied when an AE occurs both pre-treatment and post-
treatment with the same preferred term and grade.
−
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. For subjects who are off study treatment, evaluations should be within a 
safety window of 30 days (or 100 days depending on the analysis) after the last dose of 
study treatment.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IVRS system
•
Arm RT+TMZ: Radiotherapy + Temozolomide
•
Arm RT+N: Radiotherapy + Nivolumab
The treatment group “as treated” will be the same as the arm as randomized by 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.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as 
randomized”.
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.
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•
All Treated subjects: All randomized subjects who received at least one dose of study drug.
•
TMB evaluable subjects: All randomized subjects who have a baseline TMB value.
•
Response evaluable subjects: Randomized subjects with measurable lesions at baseline.
 
Unless otherwise specified, the safety analyses will include all treated subjects.
Unless otherwise specified, the efficacy analyses will include all randomized subjects.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment group using 
the mean, standard deviation, median, minimum, and maximum values.
Time-to-event variables (e.g. time-to resolution) will be analyzed using the Kaplan-Meier 
technique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method6 (using log-log transformation for constructing the confidence intervals7).
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
7.1.1
Adverse Events, Serious Adverse Events, Multiple events, Select 
Adverse Events, Other Events of Special Interest and Immune-Mediated 
Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug
was delayed”.
Adverse event that led to dose delay of the oral drug (similarly defined as dose omission or dose 
interruption) will be coded with action “Drug was interrupted”.
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Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
events results will be graded for severity using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the most recent version of the criteria at the time of the database lock will 
be used.
In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.9). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms8 in order to collapse adverse event records into unique records based on 
the preferred term. These data will be presented as the rate per 100 person-years of exposure. These 
analyses will take into account all on-treatment events (allowing more than 1 event per subject) 
and the total exposure time. The person-year exposure will be computed as the sum over the 
subjects’ exposure expressed in years where the exposure time is defined as 
•
(Date of last dose of study treatment - date of first dose of study treatment + 31 days (or 
101 days, depending on the analysis))/365.25, for subject who are off study treatment and were 
followed for at least 30 days (or 100 days, depending on the analysis) after last dose of study 
treatment.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 30 days (or 
100 days depending on the analysis) after last dose of study treatment.
7.1.1.1
Select Adverse Events
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
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The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/sub-categories.
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution,
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory when applicable.
Further details on the definitions of select adverse event, time-to onset and time-to resolution are 
described in APPENDIX 1.
7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category (e.g. Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre 
Syndrome, Pancreatitis Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, 
Rhabdomyolysis Event, Graft Versus Host Disease). The list of MedDRA preferred terms used to 
identify OEOSI is revisited quarterly and updated accordingly. The preferred terms used for the 
selection at the time of the database lock by categories will be provided.
7.1.1.3
Immune-Mediated Adverse Events
In order to further characterize AEs of special clinical interest analysis of immune-mediated AEs 
(IMAE) will be conducted. Immune-mediated AEs are specific events (or groups of PTs describing 
specific events) that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, 
rash, endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis), and other specific events, considered as potential immune-mediated 
events by investigator, that meet the definition summarized below: 
•
those occurring within 100 days of the last dose, 
•
regardless of causality,
•
treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, 
hypothyroidism/thyroiditis, 
hyperthyroidism, 
diabetes 
mellitus, 
and 
hypophysitis are considered IMAEs regardless of immune-modulating medication use, since 
endocrine drug reactions are often managed without immune-modulating medication).
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
The list of MedDRA preferred terms used to identify Immune-Mediated adverse events is revisited 
quarterly and updated accordingly. The preferred terms used for the selection at the time of the 
database lock by categories will be provided.
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
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Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be first analyzed using International System of Units (SI). 
Analyses will be repeated using US conventional units.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
sub-category and laboratory test code sequence number.
 
 
 
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 unknown or methylated MGMT status (using central lab)
•
Subjects with KPS < 70
 
•
Subjects with start of treatment more than 52 days after surgery. 
•
Subjects without baseline MRI scan
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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. This analysis will be performed on the all enrolled 
subjects population only.
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. This analysis will be performed only on the all treated subjects population.
A subject listing for all treated subjects will be provided showing the subject’s off treatment date 
and whether the subject continue in the treatment period along with the reason for going off
treatment period. 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 demographic and baseline characteristics will be summarized by treatment group. 
All baseline presentations will identify subjects with missing measurements. Listings will also be 
provided.
•
Age (descriptive statistics)
•
Age category I (< 65, ≥65)
•
Age category II (< 65, ≥65 - < 75, ≥75)
•
Sex (Male vs. Female)
•
Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or other 
Pacific Islander, Other)
•
Region (US/Canada, Europe, Rest of the World)
•
Disease diagnosis (Glioblastoma, Gliosarcoma)
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•
RPA Class (III, IV, V, Other)
•
Type of Surgery (Complete Resection, Partial Resection, Other)
•
Baseline Karnofsky performance status (100%, 95%, 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
lesions.
•
Pre-treatment events: summarized by worst CTC grade presented by SOC/PT
Summary table (cross-tabulation) by treatment group for stratification factor (extent of tumor 
resection: complete vs partial) will be provided to show any discrepancies between what was 
reported through IVRS vs. CRF at baseline. This summary will be performed based on all 
randomized subjects.
A listing of randomization scheme presenting randomized treatment group and as treated treatment 
group will be provided for all randomized subjects.
7.3.3
Medical History
General medical history will be listed by subject. 
7.3.4
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 radiotherapy (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 listing by subject will also be provided 
including prior/current non study medication.
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7.3.5
Baseline Examinations
Subjects with abnormal baseline physical examination will be listed by subject and will be 
tabulated by examination criteria (e.g. neck, cardiovascular, lungs, etc.), by treatment group.
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) / 30.4375
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 if ≤8 doses are taken.
Cycle duration (i)(wk) = 4, for the last cycle if > 8 doses are taken
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 treatment will be presented by treatment group 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
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The following parameters will be summarized (descriptive statistics) by phase (induction and 
maintenance) for subjects treated with temozolomide:
•
Duration of Treatment (in weeks)
•
Cumulative dose (in mg/m²)
•
Number of subjects that received less than 90% of planned dose
For maintenance phase only
•
Number of subjects with dose escalation to 200mg/m²
For nivolumab and temozolomide: 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.
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:
•
Duration of radiotherapy (in weeks)
•
Cumulative dose (in Gy)
•
Number of subject that received less than 90% of planned dose
7.4.2
Modifications of Study Therapy
7.4.2.1
Nivolumab Dose delays
Each nivolumab infusion may be delayed. A dose will be considered as actually delayed if the 
delay is exceeding 3 days (i.e. greater than or equal to 4 days from scheduled dosing date) for 
nivolumab. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized:
•
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
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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
7.4.2.3
Temozolomide Dose Modifications
The following parameters will be summarized by phase (induction and maintenance) 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.
 
 
 
 
 
 
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7.4.3.3
Subsequent Cancer Therapy
Number and percentage of subjects receiving subsequent cancer therapies will be summarized. 
Categories include: 
•
Subsequent systemic therapy 
•
Subsequent surgery for treatment of tumors (restricted to tumor resection)
•
Subsequent radiotherapy for treatment of tumors
A by-subject listing of subsequent cancer therapy will also be produced for all randomized 
subjects.
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7.5
Efficacy
Unless otherwise specified, the primary population will consist in the all randomized subjects and 
the analysis will be performed by treatment group as “randomized”.
Unless stated otherwise, whenever a stratified analysis is specified, the following stratification 
factors (recorded at randomization as per IRT) will be used:
•
Extent of tumor resection (complete or partial)
7.5.1
Overall Survival 
7.5.1.1
Primary Analysis
The primary objective of the study is to compare the overall survival between treatment groups in 
all randomized subjects.
Overall survival will be compared between the treatment groups using stratified log-rank test (5% 
alpha level), the two-sided log-rank p-value will be reported. The stratified hazard ratio between 
the treatment groups will be presented along with the 95% CI.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (e.g. 12, 18, 24 months, depending on the minimum follow-up) will be presented along with 
their associated 95% CIs. These estimates will be derived from the Kaplan Meier estimate and 
corresponding CIs will be derived based on Greenwood formula for variance derivation and on 
log-log transformation applied on the survivor function. Minimum follow-up must be longer than 
the timepoint to generate the estimate. In case the minimum follow-up is less than the timepoint, 
but it is judged that data immaturity does not affect interpretability of the results, the estimate will 
be provided.
The status of subjects who are censored in the OS 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, withdraw consent, never treated)
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-values of less than 0.1 will indicate a potential 
nonconstant treatment effect. In that case, additional exploratory analyses may be performed.
A by-subject listing will be presented including treatment arm, OS, whether the subject was 
censored, and if censored, the subject’s status.
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7.5.1.2
OS sensitivity Analyses
The following OS sensitivity analyses will be performed:
1) OS will be compared between treatment groups using a two-sided unstratified 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 the randomized subjects.
3) OS will be compared between the treatment groups using a two-sided stratified log-rank 
test in All treated subject population, using arm, as randomized. This analysis will be 
performed only if the proportion of randomized but never treated subjects exceeds 5%.
4) 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)
c) Performance Status (Karnofsky scale) (≤80, > 80)
The level of the covariate normally associated with the worst prognosis will be coded as the 
reference level. The hazard ratio associated with treatment and with each of the baseline 
covariates will be presented along with associated 95% CIs.
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, African American, Asian, Other)
•
RPA class (III, IV, V, other)
•
Smoking status (yes vs. no, unknown)
•
Baseline Performance Status (Karnofsky scale) (≤80, > 80)
•
Baseline Pathology (Glioblastoma vs. Gliosarcoma)
•
Baseline Corticosteroid use (No, Yes)
If a subgroup category has less than 10 subjects in a treatment group, then HR will not be reported 
for that subgroup.
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7.5.1.4
Subject Follow-Up
The extent of follow-up 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) in months 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 (defined by last patient last visit date), will be summarized 
in months by treatment group. Subjects who died and subjects with a Last Known Date Alive on 
or after LPLV will have a 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.
Minimum follow-up for OS, defined as the time from cutoff date to last subject’s randomization
date, will be summarized in months for all randomized subjects.
7.5.2
Interim Analysis 
No interim analyses is planned for this study.
7.5.3
Progression Free Survival
7.5.3.1
Primary Analysis
The PFS curves for each treatment group will be estimated using the Kaplan-Meier (KM) product-
limit method. Median PFS and the corresponding two-sided 95% confidence intervals using the 
log-log transformation will be computed.
PFS will be compared between the two randomized arms using two-sided (5% alpha level) 
stratified log-rank test. This comparison will only be tested if OS comparison is positive.
In addition, a stratified Cox proportional hazards regression model will be used to estimate hazard 
ratio between treatment groups along with the 95% CI.
PFS rates at 6, 9, 12, and 18 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.
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)
•
No baseline tumor assessment
•
No on-study tumor assessment and no death
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•
Received subsequent anti-cancer therapy 
A by-subject listing will be presented including treatment arm, PFS, whether the subject was 
censored, and if censored, the subject’s status.
7.5.3.2
Sensitivity Analysis
Sensitivity analyses of PFS will also be performed using the following modification:
1) PFS accounting for assessment after subsequent therapy. It will be defined similar to the 
primary definition except that events (progression or death) and tumor assessments that 
occurred after subsequent anticancer therapy or diagnostic surgical resection will be taken 
into account (see censoring scheme 1 for sensitivity analysis in Figure 7.5.3.2-1). 
Figure 7.5.3.2-1:
Graphic Display of PFS Accounting for Assessment after Subsequent 
Therapy
2) PFS not considering clinical progression as event: It will be defined same as the primary 
definition except not considering clinical progression as progression event.
3) PFS accounting for assessment after subsequent therapy and not counting clinical 
progression as event: It will be defined same as sensitivity analysis #1 defined above except 
not considering clinical progression as progression event.
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7.5.4
Overall Survival Rate at 24 Months
The OS[24] for each treatment group will be estimated using the Kaplan-Meier (KM) product-
limit method and the corresponding two-sided 95% confidence intervals using log-log 
transformation will be computed. There will be no hypothesis testing for this endpoint.
7.5.5
Relationship between OS or PFS and TMB
This analysis will not be generated at the time of the primary lock, because - due to limited tissue 
availability and the need to use the samples for the MGMT promoter methylation bridging study -
TMB analysis was put on hold.
7.5.6
Other Efficacy Analyses 
7.5.6.1
Analysis of Objective Response Rate
The number and percentage of subjects in each category of BOR per investigator (complete 
response [CR], partial response [PR], stable disease [SD], progressive disease [PD], or unable to 
determine [UTD]) will be presented, by treatment group. Estimates of response rate, along with its 
exact two-sided 95% CI by Clopper and Pearson9 will be presented, by treatment group. This 
analysis will be carried out on response-evaluable subjects.
A by-subject listing of best overall response will be presented including treatment group, best 
overall response per investigator and dates of CR/PR/progression.
A by-subject listing of per time point tumor assessments per investigator will be presented.
7.5.6.2
Time to Tumor Response and Duration of Response
Duration of response (DOR) and time to response (TTR) will also be evaluated for subjects who 
achieved confirmed PR or CR. The DOR for each treatment group will be estimated using the 
Kaplan-Meier (KM) product limit method and will be displayed graphically. A table will be 
produced presenting number of events, number of subjects involved, medians, and 95% CIs for 
the medians. The two-sided 95% CI in each treatment group will be computed based on a log-log 
transformation method. 
TTR, which does not involve censoring, will be summarized by treatment group in all responders 
using descriptive statistics.
A by-subject listing will be presented including treatment group, time to response, duration of 
response, whether the subject was censored for duration of response, and, if so, the reason. 
7.5.6.3
Analyses of Tumor Burden
The magnitude of reduction in tumor burden in response evaluable subjects with on-study tumor 
assessment will be summarized descriptively.
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The 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 with on-study tumor assessment, a waterfall plot showing the 
best reduction in measurable lesion based will be produced. 
•
For response-evaluable subjects with on-study tumor assessment, a plot of individual subjects’ 
percent change in measurable lesion tumor burden from baseline will be produced.
7.5.6.4
Analysis of Subjects Treated beyond Progression
The following analysis may be conducted for subjects treated with RT plus nivolumab who are 
progressed: 
•
Summary of demographic and baseline characteristics by two groups (treated beyond initial 
progression or not treated beyond initial progression)
•
Evaluation of survival for patients treated beyond initial progression vs. not treated beyond 
initial progression by a landmark analysis 
•
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
•
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
 
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7.6.14
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
 
 
 
 
 
 
 
 
 
 
 
 
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9
CONTENT OF REPORTS
All analyses described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Additional exploratory analyses may be performed. Refer to the Data 
Presentation Plan for mock-ups of all tables and listings.
10
DOCUMENT HISTORY
Table 10-1:
Document History
Version Number
Author
Description
3.0
Revision Date: 15-Jan-2019
Section 2 Study Description: Multiple changes are made in section 2 
Study description in accordance with the amendments of the 
protocol.
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.
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Table 10-1:
Document History
Version Number
Author
Description
 
 
 
 
 
 
 
.
Sections 4.2.2 Overall Survival at 24 months, 7.5.1.1 Primary 
Analysis: A text is added that survival rate estimates can also be 
produced for timepoints beyond the minimum follow-up if it is 
judged appropriate.
Section 4.3 Exploratory Endpoint(s) is restructured: Subsection for 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5 SAMPLE SIZE AND POWER: “The progression free 
survival (PFS) , overall survival at 24 months (OS[24]), and OS and 
PFS in TMB-high patients are secondary endpoints. OS[24] is 
included as secondary endpoint to evaluate the improvement in long 
term survival.” is deleted as irrelevant in this section.
 
 
 
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Table 10-1:
Document History
Version Number
Author
Description
Section 7.2.2 Relevant Protocol Deviations: new deviation “Subjects 
without baseline MRI scan”.
 
 
 
Section 7.3.1 Subject Disposition: Analysis population is specified; 
description of listings is updated to be compliant with the CRF and 
support the tables.
 
 
 
 
Section 7.3.4 Prior Therapy: Summaries of agents by name and by 
ATC class are specified.
Section 7.4.1 Administration of Study Therapy: The denominator for 
duration of treatment in months is corrected to 30.4375; definition of 
the last cycle length is corrected; terms “Dose Intensity”, “Relative 
Dose intensity” and the definitions are made compliant; populations 
for exposure analysis are restricted to subjects treated with a 
particular drug; definition of TMZ Dose (mg/m2) is corrected to be 
defined via BSA instead of weight; the following analyses for TMZ 
maintenance phase is removed: Cycles of treatment, Number of 
subjects completing 6 cycles; 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 7.4.2.1 Nivolumab Dose delays: Definition of a delayed dose 
is added.
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 7.4.3.3 Subsequent Cancer Therapy is moved from 7.5. 
Efficacy; subsequent surgeries for “Other” reason and with a 
specification which includes ‘RESECTION’ will be accounted for 
subsequent therapy.
Section 7.5. Efficacy: Use of the stratification factor is specified.
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Table 10-1:
Document History
Version Number
Author
Description
Section 7.5.1.1 Primary Analysis: a by-subject listing is added.
Section 7.5.1.2 OS sensitivity Analyses: The covariate of prior 
surgery is delete from the multivariate analysis since the model is 
stratified by IVRS resection which would correlate with the 
covariate.
Section 7.5.3.1 Primary Analysis: Censoring categories are added; a 
by-subject listing is added.
Section 7.5.3.2 Sensitivity Analysis: Table 7.5.3.2-1 is replaced by 
figure 7.5.3.2-1.
Section 7.5.5 Relationship between OS or PFS and TMB: new 
analysis.
 
 
 
Section 7.6 Safety: Reference to Core Safety SAP is replaced by the 
appropriate text due to retirement of Core Safety SAP.
-
 
 
 
 
 
 
 
 
 
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Table 10-1:
Document History
Version Number
Author
Description
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Throughout the document: 
Multiple changes in the structure and language were made for the 
sake of compliance with the IO core SAP and without modification 
of the text meaning;
Multiple editorial changes.
2.0
Revision Date: 19-Sep-2018
Revised SAP according to protocol amendment 09. Major changes 
included in this amendment are:
Removal of the interim analysis for superiority of the primary 
endpoint of OS.
Addition of a secondary endpoint that evaluated, in newly 
diagnosed, unmethylated MGMT GBM, any relationship between 
OS or PFS and TMB in the RT + nivolumab arm compared to the 
RT + TMZ control arm.
1.0
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APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
1) For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
a) If only day is missing then impute as the first day of the month; 
b) If both day and month are missing then then impute as 01JAN of the year; 
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c) If date is completely missing or invalid then leave missing. 
2) B. For data collected on other CRF pages (deemed to be on-treatment/subsequent 
surgeries): 
a) If only day is missing then 
i)
If month and year of surgery match month and year of first dose date then impute 
the missing date as the date of first dose; 
ii) If month and year of surgery don't match month and year of first dose date then 
impute as first day of that month and year; 
b) If both day and month are missing then impute as maximum between 01JAN of the 
year and date of the first dose; 
c) If date is completely missing or invalid then leave missing. 
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