A Randomized Phase II/III Open-Label Study of Ipilimumab and Nivolumab Versus Temozolomide in Patients With Newly Diagnosed MGMT (Tumor O-6-Methylguanine DNA Methyltransferase) Unmethylated Glioblastoma
Phase: PHASE2
Conditions: Gliosarcoma, MGMT-Unmethylated Glioblastoma
Sponsor: National Cancer Institute (NCI)

 
For Protocol Amendment 3 to NRG-BN007, A Randomized Phase II/III Open-Label Study of 
Ipilimumab and Nivolumab Versus Temozolomide in Patients With Newly Diagnosed MGMT 
(Tumor O-6-Methylguanine DNA Methyltransferase) Unmethylated Glioblastoma 
 
NCI/Local Protocol #:  NRG-BN007 
 
NCI Protocol Version Date: January 17, 2023 
 
Section 
Change 
Global 
Formatting was corrected and the protocol version date was updated. 
Cover pages 
Contact information was updated for Dr. Manasawala and Dr. Wolchok. 
CTSU Contact 
Information 
8.0 
8.1 
8.2 
8.3 
13.1 
13.3 
13.4 
 
Text was updated per current CTSU, NCTN, and NRG Oncology logistics. 
6.3 
Reference to the Hepatic AE Management Algorithm was added to the 
Pancreatitis table for clarity.  
9.2 
The ipilimumab supply section was updated in response to CTEP’s November 3, 
2022, Request for Amendment for NCI studies using PMB-supplied ipilimumab. 
14.4-14.1 
Logistics were clarified. 

NRG-BN007 
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Version Date:   January 17, 2023 
NRG ONCOLOGY  
 
NRG-BN007  
(ClinicalTrials.gov NCT 04396860) 
 
A RANDOMIZED PHASE II/III OPEN-LABEL STUDY OF IPILIMUMAB AND 
NIVOLUMAB VERSUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY 
DIAGNOSED MGMT (TUMOR O-6-METHYLGUANINE DNA 
METHYLTRANSFERASE) UNMETHYLATED GLIOBLASTOMA 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (17-JAN-2023) 
Principal Investigator/  
Neuro-Oncology 
Andrew B. Lassman, MD  
Columbia University Irving Medical Center  
710 West 168th Street 
New York, NY 10032 
212-342-0871/FAX 212-342-1246 
ABL7@cumc.columbia.edu  
 
Neuro-Oncology Co-Chair 
Fabio Iwamoto, MD 
Columbia University Irving Medical Center  
710 West 168th Street 
New York, NY 10032 
212-342-0571/FAX 212-342-1246 
fi2146@cumc.columbia.edu 
 
Neurosurgery Co-Chair 
Andrew E. Sloan, MD, FAANS, FACS 
University Hospitals-Case Medical Center 
Case Comprehensive Cancer Center of Case 
Western Reserve University School of Medicine 
11100 Euclid Blvd, HAN 524 
Cleveland, OH 44106 
216-320-1960 
Andrew.Sloan@UHhospitals.org 
Radiation Oncology Co-Chair 
Minesh Mehta, MD 
Miami Cancer Institute 
Radiation Oncology Department 
8900 N. Kendall Drive  
Miami, FL 33176  
786-527-8014/FAX 786-533-9416  
MineshM@baptisthealth.net  
 
Radiation Oncology Co-Chair 
Tony J. C. Wang, MD 
Department of Radiation Oncology 
Columbia University Irving Medical Center 
622 West 168th Street 
New York, NY 10032 
212-305-5050/FAX 212-305-5935 
tjw2117@cumc.columbia.edu 
 
Neuropathology Co-Chair 
Ken Aldape, MD 
Center for Cancer Research, National Cancer Institute  
Building 10, Room 2S235 
Bethesda, MD 20892 
301-480-5010 
kenneth.aldape@nih.gov 
 

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Neuropsychology Co-Chair 
Jeffrey Wefel, PhD 
The University of Texas MD Anderson Cancer 
Center 
1515 Holcombe Boulevard 
Houston, TX 77030 
713-563-0514/FAX 713-794-4999  
jwefel@mdanderson.org 
 
Patient-Reported Outcomes and  
Quality of Life Co-Chair 
Vinai Gondi, MD 
Northwestern Medicine Cancer Center 
Warrenville 
Brain and Spine Tumor Center 
4405 Weaver Parkway  
Warrenville, IL 60555 
630-352-5350/FAX  630-352-5349 
vgondi@chicagocancer.org 
 
Medical Physics Co-Chair 
Alonso Navar Gutierrez, PhD 
Miami Cancer Institute 
Radiation Oncology Department 
8900 N. Kendall Drive  
Miami, FL 33176  
786-527-7631/FAX 786-533-9510  
AlonsoG@baptisthealth.net 
 
Neuroradiology Co-Chair 
Mohammed Manasawala, MD 
WellSpan Health-York Cancer Center 
37 Monument Road, Suite 101 
York, PA 17403 
717-851-2217 
mmanasawala@wellspan.org 
Translational Medicine Co-Chair 
Mark R. Gilbert, MD 
National Cancer Institute 
National Institutes of Health 
Bloch Bldg. 82, Rm. 237 
9030 Old Georgetown Rd. 
Bethesda, MD  20892 
240-760-6023/301-480-2246 
Mark.gilbert@nih.gov  
 
Biomarker Co-Chair 
Erik P. Sulman, MD, PhD 
Laura and Isaac Perlmutter Cancer Center at  
NYU Langone Health 
522 1st Ave, Smilow Bldg, Rm 801C 
New York, NY 10016 
646-501-6153 
erik.sulman@nyulangone.org 
 
Medical Immunotherapy Co-Chair 
Jedd D. Wolchok, MD, PhD 
New York-Presbyterian/Weill Cornell Medical 
Center 
525 E 68th Street 
New York, NY 10065 
646-962-6131/FAX 646-422-0453 
jwolchok@med.cornell.edu 
 
Senior Statistician 
James Dignam, PhD 
NRG Oncology Statistics and Data Management 
Center and University of Chicago 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
773-834-3162 
DignamJ@nrgoncology.org  
 
 
 
 
 
 
 
 
 
 

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Version Date:   January 17, 2023 
 
 
 
NRG Oncology Contact Information 
Data Managers: For questions concerning eligibility 
or data submission 
Micheala (Liz) Wise, CCRC; and 
Sherrell Carter  
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3221 and 215-574-3213  
wisel@nrgoncology.org and 
carters@nrgoncology.org 
RTQA: For questions concerning the RT data and 
submission via TRIAD 
Denise Manfredi, BS, RT(T); and  
George Ballinger, RT (R)(T) 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-2755 and 215-574-3163 
dmanfredi@acr.org and gballinger@acr.org 
RTQA: For questions concerning RT Credentialing 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org  
RTQA:  For questions concerning TRIAD software 
Triad-Support@acr.org 
Protocol Development: For questions concerning 
protocol and informed consent versions & amendments 
Kathryn Okrent 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0856 
okrentk@nrgoncology.org  
Brain Tumor Committee Chair  
Minesh Mehta, MD 
(see protocol cover page/Radiation Oncology 
Co-Chair role for contact information) 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Ipilimumab 
PMB 
732442 
 
DCTD, NCI 
Nivolumab 
PMB 
748726 
Temozolomide 
Commercial 
362856 
 
 
 
 
Participating Sites 
 U.S. 
 Canada  
 Approved International Member Sites 

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Document History 
 
Version Date 
Amendment 3 
January 17, 2023 
Amendment 2 
April 8, 2022 
Amendment 1 
February 9, 2021 
Initial 
July 9, 2020 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

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NRG ONCOLOGY 
 
NRG-BN007 
 
A RANDOMIZED PHASE II/III OPEN-LABEL STUDY OF IPILIMUMAB AND 
NIVOLUMAB VERSUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY 
DIAGNOSED MGMT (TUMOR O-6-METHYLGUANINE DNA 
METHYLTRANSFERASE) UNMETHYLATED GLIOBLASTOMA 
 
 
CONTACT INFORMATION  (17-JAN-2023) 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trials Support Unit 
(CTSU) via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
http://www.ctsu.org,            
and select  Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org 
to receive further instruction 
and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-CTSU (2878) or 
CTSURegHelp@coccg.org 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN). 
OPEN  is accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email: 
1-888-823-5923, or  
ctsucontact@westat.com. 
 
. 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Refer to the data submission 
section of the protocol for 
further instructions.  
 
. 
 

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The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org).  Access to the CTSU members’ website is managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration 
system and requires user logging in with a CTEP-IAM username and password or linked ID.me 
account (ID.me accounts are required for all newly created CTEP-IAM accounts and by July 1, 
2023 for all users). 
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the  Roster Maintenance application and 
in most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the CTSU members’ website. 
For clinical questions (i.e., patient eligibility or treatment-related)  
Contact the study data manager listed on the NRG Oncology contact information table on the 
protocol cover page. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org 
Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/ 
 
 
 
 
 

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TABLE OF CONTENTS 
SCHEMA .......................................................................................................................................10 
1. OBJECTIVES ............................................................................................................................11 
1.1  
Primary Objective ..................................................................................................11 
1.2  
Secondary Objectives .............................................................................................11 
1.3  
Exploratory Objectives ..........................................................................................11 
2. BACKGROUND .......................................................................................................................11 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA ..................................................................15 
3.1 
Eligibility Criteria  .................................................................................................16 
3.2 
Ineligibility Criteria ...............................................................................................18 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..................20 
5. TREATMENT PLAN/REGIMEN DESCRIPTION..................................................................24 
5.1 
Systemic Therapy  ..................................................................................................25 
5.2 
Radiation Therapy ..................................................................................................27 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................36 
5.4 
Duration of Therapy ...............................................................................................38 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................39 
6.1  
Temozolomide .......................................................................................................39 
6.2   
Nivolumab and Ipilimumab: General Guidelines ..................................................43 
6.3 
Nivolumab and Ipilimumab ...................................................................................43 
6.3.1  Treatment of Nivolumab/Ipilimumab-Related Infusion Reactions .......................44 
6.3.2  Nivolumab and Ipilimumab Overall Dosing Delays .............................................45 
7. ADVERSE EVENTS REPORTING REQUIREMENTS ..........................................................52 
7.1   
Protocol Agents ......................................................................................................52 
7.2  
Adverse Events and Serious Adverse Events ........................................................52 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
CTEP Study Agents ...............................................................................................53 
7.4 
Adverse Events for Commercial Study Agents: Temozolomide ...........................62 
7.5 
Adverse Events and PRO-CTCAE ........................................................................62 
7.6 
Expedited Reporting of Adverse Events ................................................................63 
7.7 
Routine Reporting Requirements for Adverse Events ...........................................67 
7.8  
NRG Responsibility for Reporting Serious Adverse Events to Health 
Canada....................................................................................................................67 
7.9 
Pregnancy ...............................................................................................................67 
8. REGISTRATION AND STUDY ENTRY PROCEDURES .....................................................68 
8.1       Cancer Trials Support Unit Registration Procedures  ............................................69 
8.2  
RT-Specific Pre-Registration Requirements ..........................................................74 
8.3  
Patient Enrollment .................................................................................................76 
8.4 
Medidata Patient Cloud ePRO Registration ..........................................................77 

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9. DRUG INFORMATION ...........................................................................................................78 
9.1   
Agent Ordering and Agent Accountability ............................................................78 
9.2  
Investigational Study Agent: Ipilimumab ..............................................................80 
9.3 
Investigational Study Agent: Nivolumab ...............................................................81 
9.4 
Commercial Agent: Temozolomide .......................................................................83 
10. PATHOLOGY/BIOSPECIMEN .............................................................................................84 
10.1  Central Histology Confirmation ............................................................................84 
10.2  MGMT-STP27 Testing ..........................................................................................84 
10.3 
Biospecimen Submission Tables  ..........................................................................86 
11. SPECIAL STUDIES (NON-TISSUE/BIOSPECIMEN) .........................................................89 
11.1 Neurocognitive Function (NCF) and Patient-Reported Quality of Life (QOL) ........89 
12. Modality Reviews ....................................................................................................................91 
12.1 
Radiation Therapy Quality Assurance Reviews ....................................................91 
12.2 
Medical Neuro-Oncology Modality Quality Assurance Reviews .........................92 
13. DATA AND RECORDS .........................................................................................................92 
13.1 
Data Management/Collection ................................................................................92 
13.2 
Summary of Data Submission ...............................................................................93 
13.3 
Data Quality Portal ................................................................................................95 
13.4 
Rave-CTEP-AERS integration ..............................................................................95 
13.5 
Global Reporting/Monitoring ................................................................................96 
14. STATISTICAL CONSIDERATIONS ....................................................................................97 
14.1 
Study Design ..........................................................................................................97 
14.2 
Study Endpoints .....................................................................................................98 
14.3 
Primary Objectives Study Design ..........................................................................98 
14.4 
Study Monitoring of Primary Objectives .............................................................100 
14.5 
Accrual/Study Duration Considerations ..............................................................101 
14.6 
Secondary Objectives Study Design ....................................................................102 
14.7 
Gender/Ethnicity/Race Distribution .....................................................................107 
REFERENCES ............................................................................................................................109 
APPENDIX I ...............................................................................................................................112 
APPENDIX II ..............................................................................................................................114 
APPENDIX III .............................................................................................................................122 
APPENDIX IV.............................................................................................................................128 
APPENDIX V ..............................................................................................................................129 
APPENDIX VI.............................................................................................................................130 

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APPENDIX VII ...........................................................................................................................131 
 
 
 

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NRG-BN007 
SCHEMA (08-APR-2022) 
 
 
STEP 1 REGISTRATION 
Central Pathology Review for confirmation of glioblastoma (GBM) histology and of 
unmethylated MGMT promotor status  
NOTE: Tumor tissue must be received and central review confirmation completed before 
STEP 2 registration can occur.* 
↓ 
STEP 2 REGISTRATION  
 
STRATIFY 
x Recursive partitioning analysis (RPA) (III vs IV vs V) 
x Intent to use Optune (yes vs no) 
 
 
RANDOMIZE (1:1) 
↓ 
↓ 
Arm 1 
Radiation Therapy 
plus 
Concomitant temozolomide 
plus 
Adjuvant temozolomide  
 
(Optune allowed) 
 
 
Arm 2 
Radiation Therapy 
plus 
Concomitant ipilimumab and nivolumab  
plus 
Adjuvant ipilimumab and nivolumab  
 
(Optune not allowed) 
 
See Section 5.1 for agent treatment details and Section 5.2 for radiation therapy details.  
*Patients with methylated MGMT may be considered for enrollment on NRG-BN011. Please see 
Section 10.2 for additional information. 
 
 
 
 
 
 

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1. OBJECTIVES 
1.1 Primary Objective 
1.1.1 Phase II: To determine if adding ipilimumab and nivolumab to radiotherapy significantly 
prolongs progression-free survival (PFS) versus adding temozolomide to radiotherapy in 
patients with newly diagnosed glioblastoma (GBM) without MGMT promoter 
methylation 
1.1.2  Phase III: To determine if adding ipilimumab and nivolumab to radiotherapy significantly 
prolongs overall survival (OS) versus adding temozolomide to radiotherapy in patients 
with newly diagnosed GBM without MGMT promoter methylation 
 
1.2 Secondary Objectives  
1.2.1 To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs 
PFS versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM 
without MGMT promoter methylation for the phase III part of the study 
1.2.2 To determine if adding ipilimumab and nivolumab to radiotherapy significantly increases 
the 2-year OS rate versus adding temozolomide to radiotherapy in patients with newly 
diagnosed GBM without MGMT promoter methylation 
1.2.3 To evaluate the safety of adding ipilimumab and nivolumab to radiotherapy via 
comparative frequency between arms of specific adverse events of interest and frequency 
summaries for all adverse event types 
1.2.4 To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding 
temozolomide to radiotherapy on patient reported outcomes (PROs), as measured by the 
MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly 
diagnosed GBM without MGMT promoter methylation 
1.2.5 To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding 
temozolomide to radiotherapy on selected PRO-CTCAE items in patients with newly 
diagnosed GBM without MGMT promoter methylation 
1.2.6 To evaluate the impact of adding ipilimumab and nivolumab to radiotherapy versus 
adding temozolomide to radiotherapy on neurocognitive function (NCF) in patients with 
newly diagnosed GBM without MGMT promoter methylation 
 
1.3 Exploratory Objectives 
1.3.1  To explore biomarkers in pre-treatment archival tumor tissue that may predict efficacy of 
ipilimumab and nivolumab as measured by OS, PFS, and 2-year OS rate, such as but not 
limited to 
 PDL1 expression 
 Mutational burden 
1.3.2 To explore (in the two treatment separately) whether the MGMT protein expression 
correlates with clinical outcomes including OS, PFS, and 2-year OS rate  
1.3.3 To evaluate if MGMT protein expression may be predictive of differential treatment 
effects between the two treatment arms 
 
 
2. BACKGROUND 
GBM remains the most common and aggressive primary brain cancer in adults and is almost 

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universally fatal.  Median survival is approximately 18 months despite multimodality 
therapy.  Temozolomide was demonstrated to prolong survival when added to radiotherapy 
concurrently and sequentially in 2005. (Stupp, Mason et al. 2005)  Since then, most clinical 
trials for newly diagnosed GBM have incorporated maximal safe surgical resection followed 
by radiotherapy with concurrent and adjuvant temozolomide as the standard of care, and 
experimental agents have been added on to this backbone including recent prior NRG 
Oncology/RTOG Foundation trials such as RTOG 0525 and 0825, as well as NRG-BN002 
and AbbVie M13-913/RTOGF 3508.  Immunotherapy with checkpoint inhibitors 
(ipilimumab targeting CTLA-4, nivolumab targeting PD-1) have revolutionized the treatment 
of other human cancers, particularly lung and melanoma.  However, their efficacy in gliomas 
is unclear.  Ongoing industry-sponsored trials by BMS (NCT02667587, CheckMate-548; 
NCT02617589, CheckMate-498) are testing the efficacy of nivolumab in newly diagnosed 
GBM when added to the post-operative radiation setting with or without temozolomide.  
However, no current ongoing trials are testing the combined effects of ipilimumab and 
nivolumab in newly diagnosed GBM to our knowledge. Although the combination has been 
more toxic than either ipilimumab or nivolumab alone in many cancers, extrapolation from 
other tumor types, particularly melanoma, suggests that combined therapy is also more 
efficacious than either alone, particularly in those with very low PD-L1 expression in pre-
treatment tumor tissue (Wolchok, Chiarion-Sileni et al. 2017) such as most GBMs.  In 
addition, during the last 5 years, medical oncologists and neuro-oncologists have now 
participated in trials of ipilimumab, nivolumab, and other in-class agents (e.g., 
pembrolizumab), including NTCN trials such as NRG-BN002 (phase I trial of RT with 
temozolomide followed by either nivolumab, ipilimumab, or both), gaining comfort with 
identification and management of associated toxicities.  NRG-BN002 in particular, 
demonstrated no increased toxicity from combined treatment with ipilimumab and nivolumab 
compared to either drug alone [Sloan AE, Gilbert M et al, 2018 ASCO abstract].  Finally, 
enthusiasm for immunotherapy approaches remains high among patients seeking trials.  
Therefore, NRG Oncology, with a long history of rapid accrual to studies for newly 
diagnosed GBM, will embark on the current study. 
While patients on NRG-BN002 received nivolumab and/or ipilimumab only in the adjuvant 
(post-radiation) setting, other trials in the interim have combined these agents with 
radiotherapy and/or temozolomide (e.g., NCT02667587, CheckMate-548; NCT02617589, 
CheckMate-498).  In addition, comfort with toxicity management among treatment 
physicians has improved since accrual to NRG-BN002 began in 2015.  Finally, both 
preclinical and clinical data suggest synergy from auto-vaccination and antigen exposure 
when radiation is combined with checkpoint blockade.(Vatner, Cooper et al. 2014) 
We will mirror the design of NCT02617589 (CheckMate-498: newly diagnosed MGMT 
unmethylated GBM, randomized to radiation plus temozolomide versus radiation plus 
nivolumab, open-label) and multiple other studies ongoing or planned for newly diagnosed 
GBM that omit temozolomide from the experimental arm for patients with GBMs without 
MGMT promoter methylation.  We will omit temozolomide and study the MGMT 
unmethylated population not because of some proposed benefit restricted to that population; 
rather, the potential benefit of temozolomide (if any) is limited without MGMT promoter 
methylation, (Hegi, Diserens et al. 2005), omitting temozolomide will ameliorate its potential 
immunosuppressive effects (particularly lymphopenia) that could reduce immunotherapy 
efficacy, and both elements will simplify the study design.  Therefore, patients in the 

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experimental arm will not receive temozolomide in the current trial design.  Finally, survival 
in patients with MGMT unmethylated tumors is unfortunately shorter than those with 
methylated tumors; therefore, the required time for follow-up, trial completion, and result 
reporting will be shorter than for a trial that either focuses on the MGMT methylated 
population or allows MGMT methylated status for eligibility.  It is also important to note that 
in CheckMate-498, omitting temozolomide in the experimental arm and omitting a placebo 
in the standard arm were not barriers to accrual, and the trial completed accrual rapidly and 
without difficulty.  Should this trial prove positive, then a future study could consider 
including temozolomide and/or study in patients with MGMT methylated disease.    
With regard to ongoing trials, one study of nivolumab in recurrent GBM sponsored by BMS 
(CheckMate-143) failed to show improvement over bevacizumab, both when used as single 
agents.  However, large doses of corticosteroids at the initiation of treatment was not 
exclusionary.  Recent data clearly demonstrate that corticosteroids reduce immune responses 
to vaccine therapies and prevent maturation and activation of naïve T cells in response to 
immune checkpoint inhibitor (Giles, Hutchinson et al. 2018, Kes.   kin, Anandappa et al. 
2019).  Therefore, with over 40% of the patients on Checkmate-143 on corticosteroids at 
initiation of treatment, an efficacy signal for immunotherapy may have been lost.  
Furthermore, patients with rapidly progressing and bulky tumors were also eligible.  This 
potentially confounded the study as GBM are among the most immunosuppressive tumors 
known, due to secretion of TGF-B, INO, PGE2, IL-4, IL-10, potentiation of Tregs and 
sequestration of lymphocytes to bone marrow.  In addition to the immunosuppressive effects 
of tumors, such bulky tumors also likely required steroids making weaning difficult if not 
impossible.  As such sufficient time on drug may not have elapsed for therapeutic effect.  
Furthermore, the only 2 interventions that received FDA approval after trials demonstrated 
survival prolongation for newly diagnosed GBM in the last 50 years, temozolomide (Stupp, 
Mason et al. 2005) and NovoTTF (Optune) (Stupp, Taillibert et al. 2015), both failed to 
prolong median survival for recurrent GBM (Yung, Albright et al. 2000, Stupp, Wong et al. 
2012).  The ongoing CheckMate studies for newly diagnosed GBM used nivolumab alone 
rather than combinations of nivolumab and ipilimumab. 
With regard to other available therapies for newly diagnosed GBM, Gliadel will not be 
allowed, consistent with precedence for other ongoing studies.  Gliadel wafers have long 
been FDA- approved but are exclusionary for nearly all newly diagnosed studies, and its use 
will be exclusionary in the current trial.   
Finally, as described above, corticosteroids can abrogate efficacy of immune checkpoint 
inhibitors.  Therefore, we will require for eligibility only patients on no corticosteroids.  This 
criterion will also serve as a surrogate for disallowing patients with large unresected tumors 
with surrounding edema without requiring a threshold of post-operative residual tumor 
volume that would be both arbitrary and difficult to enforce.  Extent of resection is captured 
as part of the recursive portioning analysis (RPA), which will serve as a stratification factor.  
It remains theoretically possible that imbalance in extent of resection may result because the 
RPA also accounts for other prognostic factors; however, this approach is compromise that 
will permit the simplest study design. 
Of note, although pseudoprogression from radiation therapy and temozolomide may be 
exacerbated by immunotherapy, (Okada, Weller et al. 2015, Ranjan, Quezado et al. 2018) we 
do not believe the existing data from the ongoing NRG phase I trial (NRG-BN002), or other 

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trials, is sufficiently compelling to support a phase III trial with OS as an endpoint (even with 
early futility analyses) in the absence of phase II data.  Therefore, we will perform a 
traditional phase II/III study: with PFS as the primary endpoint in phase II and OS in phase 
III, but will also incorporate an evaluation of OS use if the PFS signal is ambiguous as 
detailed below.  Accruals to phase II will count toward phase III goals.  We recognize the use 
of PFS is an imperfect metric of efficacy for phase II, and the risk of declaring the phase II 
falsely negative because of pseudoprogression is of concern.  However, in RTOG 0525 as 
well as other trials for newly diagnosed GBM (other than antiangiogenic therapies that can 
falsely prolong PFS through pseudoresponse), PFS ultimately correlated with OS despite the 
potential confounding effects of pseudoprogression and the absence of central radiology 
review.  Therefore, we believe this approach, while imperfect, is the best way to balance the 
leveraging of existing data without exposing a large number of patients to a potentially toxic 
therapy in phase II without supportive phase II data, taking into account OS as below.  
Finally, ipilimumab and nivolumab can induce substantial systemic toxicity as well as 
encephalopathy.  While in many cases based on Common Terminology Criteria for Adverse 
Events (CTCAE) the adverse events reportedly resolve, dedicated symptom and 
neurocognitive function (NCF) measures with demonstrated clinical significance have not 
carefully followed and characterized these side effects.  Therefore, we will collect patient 
reported outcome (PRO) symptom and NCF test data to evaluate the effects of ipilimumab 
plus nivolumab compared to temozolomide added to radiation therapy to determine the 
clinical benefit of improved PFS and OS. 
There are no competing studies to our knowledge of combined temozolomide, radiation 
therapy, CTLA-4 inhibition, and PD-1 inhibition in newly diagnosed GBM.  Whether the 
ongoing BMS-sponsored trials of nivolumab (without ipilimumab) are positive or negative, 
this trial continues to have justification as it uses the dual drug approach which demonstrated 
superiority to nivolumab alone in some patients with other cancers, such as melanoma. 
(Wolchok, Chiarion-Sileni et al. 2017).  The combination at the doses proposed herein was 
also reasonably well tolerated as demonstrated in NRG-BN002.(Sloan, Gilbert et al. 2018). 
,As in ALLIANCE A071102, we will allow Optune, stratifying by intent to use, to ameliorate 
concerns about impediments to accrual that could result from drop-out, particularly on the 
control arm, by disallowing Optune. 
Multiple ongoing trials, including NRG-BN002 (Sloan, Gilbert et al. 2018) demonstrated the 
toxicity profile of immunotherapy agents in GBM is qualitatively similar to that in other 
tumor types.  As reported at ASCO 2018, NRG-BN002 was a phase I study of ipilimumab 
(3mg/kg), nivolumab (3mg/kg), and the combination (1mg/kg and 3mg/kg, respectively) 
followed by an expansion cohort for the combined treatment of adults with confirmed 
unifocal, supratentorial newly diagnosed GBM after gross or near total resection. Treatment 
with immune-checkpoint inhibitors (ICIs) started after standard chemo-radiotherapy 
(radiation and temozolomide) along with adjuvant temozolomide; starting dosing of ICIs 
were at target with dose reduction planned for toxicity. The primary endpoint was the dose 
limiting toxicity (DLT) from start of ICIs to 8 weeks after for each arm. A standard up-and-
down design was used, with 6 evaluable patients enrolled at a given dose level.  32 patients 
were enrolled at 9 institutions, 6 accrued to each arm and 14 to the expansion cohort. One 
patient was not treated, yielding 31 analyzable.  Median age was 54 years (range: 23-74), 
68% were men and 84% were white.  Overall, treatment was well tolerated with a 16% rate 

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of Grade 4 events; the combination did not have an increased toxicity rate over the single 
agent arms, and there was no reported Grade 5 event.  One DLT was seen in each single-
agent arm; none was noted in the combination arm.  Median follow-up time was 7.1 months 
(range: 0.5-21.3) for all analyzable patients, at which time 10 of the 31 had progressed (32%) 
and 8 had died (26%), 7 of which were attributed to disease progression.  Median PFS was 
16.3 months (95% CI: 8.3-not reached) with a 1-year PFS rate of 53.2% (95% CI: 29.7-
76.6%). Median survival was 20.6 months (95% CI: 13.4-23.6).  These toxicity and survival 
results are encouraging, follow-up is ongoing, and the current trial herein is an extension of 
NRG-BN002 to test efficacy definitively. 
As mentioned above, there are two ongoing BMS-sponsored trials for newly diagnosed 
GBM.  However, accrual is complete to both, and both use nivolumab alone as the 
immunotherapy, and neither incorporate ipilimumab.  In more detail, CheckMate-498 is for 
patients with MGMT unmethylated GBM, comparing nivolumab versus temozolomide (each 
with radiation therapy); CheckMate-548 is for MGMT methylated cases, comparing 
nivolumab versus placebo (each with radiation therapy and temozolomide).   
Our design extends that of both trials which had no restriction on tumor size or extent of 
resection, and specifically extends that of CheckMate-498 which also omitted temozolomide 
in MGMT-unmethylated cases, did not incorporate a placebo, and completed accrual rapidly. 
The design of CheckMate-498 further supports our design by omitting temozolomide in 
MGMT unmethylated cases.  Of note, CheckMate-498 accrued rapidly, with approximately 
550 patients enrolled over approximately 12 months, despite the lack of placebo control and 
omission of temozolomide (https://clinicaltrials.gov/ct2/show/NCT02617589). 
 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Statistics and Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page).  
 
Inclusion of Women and Minorities 
NIH policy requires that women and members of minority groups and their subpopulations 
be included in all NIH-supported biomedical and behavioral research projects involving 
NIH-defined clinical research unless a clear and compelling rationale and justification 
establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is 
not an acceptable reason for exclusion except when the study would duplicate data from 
other sources.  Women of childbearing potential should not be routinely excluded from 
participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 

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3.1 
Eligibility Criteria (08-APR-2022) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Prior to Step 1 Registration 
3.1.1  No known IDH mutation. (If tested before step 1 registration, patients known to have 
IDH mutation in the tumor on local or other testing are ineligible and should not be 
registered). 
3.1.2  Availability of FFPE tumor tissue block and H&E stained slide to be sent for central 
pathology review for confirmation of histology and MGMT promoter methylation status 
(See Sections 3.1.1, 3.1.2, and 10). Note that tissue for central pathology review and 
central MGMT assessment must be received by the NYU Center for Biospecimen 
Research and Development (CBRD) on or before postoperative calendar day 23. If tissue 
cannot be received by postoperative calendar day 23, then patients may NOT enroll on 
this trial as central pathology review will not be complete in time for the patient to start 
treatment no later than 6 weeks following surgery. Results of central pathology review 
and central MGMT analysis will generally be conveyed to NRG Oncology within 10 
business days of receipt of tissue. Note: In the event of an additional tumor resection(s), 
tissue must be received within 23 days of the most recent resection and the latest 
resection must have been performed within 30 days after the initial resection. Surgical 
resection (partial or complete) is required; a limited biopsy is not allowed because it will 
not provide sufficient tissue for MGMT analysis.  
x Note:  The central pathology review and central MGMT results determine eligibility.  
Therefore, patients may be offered the opportunity to consent REGARDLESS of 
local pathology and MGMT results, and consent can occur BEFORE local pathology 
interpretation is finalized and BEFORE local MGMT testing is conducted. 
 
3.1.3  Contrast-enhanced brain MRI within 3 days after surgery.  
 MRI with Axial T2 weighted FLAIR{preferred} or T2 TSE/FSE and 3D contrast-
enhanced T1 sequences are required.  
 3D pre contrast-enhanced T1 sequences are strongly suggested. 
3.1.4 Women of childbearing potential (WOCBP) and men who are sexually active with 
WOCBP must be willing to use an adequate method of contraception hormonal or barrier 
method of birth control; or abstinence during and after treatment (see Section 9.0).  
3.1.5 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
 
 
Prior to Step 2 Registration 

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3.1.6   Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of 
glioblastoma) confirmed by central pathology review (See Section 10 for details);  
Note: diagnoses of “Molecular glioblastoma” per the c-IMPACT-NOW criteria or “CNS 
grade 4” per the WHO 2021 criteria are NOT relevant; 
3.1.7    MGMT promoter without methylation confirmed by central pathology review (See 
Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for 
analysis, fails MGMT testing, or has indeterminate or methylated MGMT promoter are 
excluded.  
x Note: central pathology review and central MGMT results determine eligibility; local 
pathology or MGMT results cannot be used for eligibility/randomization. 
x Note: Patients with methylated MGMT may be considered for enrollment on NRG-
BN011. Please see Section 10 for additional information. 
 
3.1.8 IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 
R132H) must be performed as part of standard of care and no mutation must be found (i.e 
IDH wildtype).  (If a mutation is identified then the patient will be ineligible and must be 
registered as ineligible at Step 2.)  
x Note: This test is not being performed in real time as part of central review and will  
not be provided to sites from a centrally performed test. 
3.1.9 History/physical examination within 28 days prior to Step 2 registration; 
3.1.10 Karnofsky Performance Status (KPS) ≥ 70 within 28 days prior to Step 2 registration; 
3.1.11 Neurologic Function assessment within 28 days prior to Step 2 registration; 
3.1.12 Age ≥ 18 years;  
3.1.13 Adequate hematologic, renal, and hepatic function within 7 days prior to Step 2 registration 
defined as follows: 
 
hemoglobin 
 
≥10 g/dl (Note: the use of transfusion or other 
intervention to achieve Hgb ≥10.0 g/dl is acceptable) 
 
leukocytes  
 
≥2,000/mm3 
 
absolute neutrophil count 
 
≥1,500/mm3 
 
platelets 
 
 
≥100,000/mm3 
 
total bilirubin 
 
≤1.5× institutional/lab upper limit of normal (ULN) 
 
AST(SGOT)  
 
 
  
≤2.5 × ULN 
 
ALT(SGPT) 
≤2.5 × ULN 
 
serum creatinine 
≤1.5× ULN  
OR 
 
creatinine clearance (CrCl) 
≥50 mL/min (if using the Cockcroft-Gault formula 
below): 
 
 
CrCl (mL/min)  = 
[140 – age (years)] x weight (kg) 
{x 0.85 for female patients} 
 72 x serum creatinine (mg / dL) 
 
3.1.14 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
 
Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible if 
they have an undetectable HCV viral load. 

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3.1.15 For women of childbearing potential (WOCBP), negative serum or urine pregnancy test 
within 7 days prior to Step 2 registration.  Note that it may need to be repeated if not also 
within 3 days prior to treatment start (see section 4)  
x 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) or who is not postmenopausal.  
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 
in the absence of other biological or physiological causes.   
 
3.2 
Ineligibility Criteria (08-APR-2022) 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.2.1 Prior therapy for tumor except for resection.  For example, prior chemotherapy, 
immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed 
(including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, 
ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, 
PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the 
tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or 
immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), 
Gliadel wafer, radiotherapy, radiosurgery, gamma knife, cyber knife, vaccine or other 
immunotherapy, brachytherapy, or convection enhanced delivery;  
x Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection 
(FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during 
surgery to aid resection is not exclusionary and is not considered a chemotherapy 
or intracerebral agent 
3.2.2 Current or planned treatment with any other investigational agents for the study cancer 
3.2.3 Definitive clinical or radiologic evidence of metastatic disease outside the brain 
3.2.4 Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ 
and melanoma in situ) unless disease free for a minimum of 2 years 
3.2.5 Prior radiotherapy to the head or neck that would result in overlap of radiation therapy 
fields  
3.2.6 Pregnancy and nursing females due to the potential teratogenic effects and potential risk 
for adverse events in nursing infants. 
3.2.7 History of severe hypersensitivity reaction to any monoclonal antibody.  
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ipilimumab, nivolumab, or temozolomide 
3.2.9 On any dose of any systemically administered (oral, rectal, intravenous) corticosteroid 
within 3 days prior to Step 2 registration (see also section 4). Inhaled, topical, and ocular 
corticosteroids are allowed without limitation but must be recorded. Note that treatment 
with systemically administered corticosteroid after initiating study treatment is allowed as 
needed. 

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3.2.10 Patients with known immune impairment who may be unable to respond to anti-CTLA 4 
antibody.  
3.2.11 History of interstitial lung disease including but not limited to sarcoidosis or pneumonitis. 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, defined as New York Heart Association Functional 
Classification III/IV (Note:  Patients with known history or current symptoms of cardiac 
disease, or history of treatment with cardiotoxic agents, should have a clinical risk 
assessment of cardiac function using the New York Heart Association Functional 
Classification), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
3.2.13 Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
3.2.14 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids, are excluded, as are patients on active 
immunosuppressive therapy.  These include but are not limited to:  patients with a history 
of immune-related neurologic disease, CNS or motor neuropathy,  multiple sclerosis, 
autoimmune (demyelinating)  neuropathy, Guillain-Barre syndrome, myasthenia gravis; 
systemic autoimmune disease such as autoimmune vasculitis [e.g., Wegener’s 
Granulomatosis]), systemic lupus erythematosus (SLE), connective tissue diseases (e.g., 
systemic progressive sclerosis), scleroderma, inflammatory bowel disease (IBD), 
Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal 
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome, Hashimoto’s 
thyroiditis, autoimmune hepatitis are excluded because of the risk of recurrence or 
exacerbation of disease. 
o Exceptions:  patients with a history of the following conditions are not excluded, 
unless receiving active immunosuppressive therapy: 
o vitiligo 
o Type I diabetes 
o rheumatoid arthritis and other arthropathies 
o Sjögren’s syndrome and psoriasis controlled with topical medication and 
patients with positive serology, such as antinuclear antibodies (ANA)  
 anti-thyroid antibodies should be evaluated for the presence of 
target organ involvement and potential need for systemic treatment 
but should otherwise be eligible.  
3.2.15 Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, GI 
obstruction and abdominal carcinomatosis which are known risk factors for bowel 
perforation are also excluded 
3.2.16 Current or planned therapy with warfarin 
 
 

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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
(08-APR-2022) 
PRE-TREATMENT ASSESSMENTS  
Assessments 
Prior to Step 1 
Registration 
Prior to Step 2 
Registration 
(calendar days)  
Prior to 
Treatment  
(calendar days) 
Hepatitis B virus surface antigen (HBV sAg) 
and Hepatitis C (HCV RNA) (if applicable) 
 
≤28 days  
 
IDH testing performed as part of routine care 
If positive, patient 
will not be eligible 
If positive, patient 
will not be eligible 
 
Submission of tissue for central pathology 
review and central MGMT analysis* 
 
As soon as possible 
after surgery.  . 
 
Contrast-enhanced Brain MRI  
Within 3 days after 
surgery 
 
 
History/physical examination (to include 
height/weight and cardiac disease risk 
assessment and additional cardiac evaluation 
including lab tests and cardiology 
consultations as clinically indicated including 
EKG, CPK, troponin, ECHO cardiogram) 
 
≤28 days 
 
Karnofsky performance status and neurologic 
function 
 
≤28 days 
 
Steroid dose documentation 
 
≤3 days 
≤3 days 
CMP (inc AST/ALT and serum creatinine or 
creatinine clearance) 
 
≤7 days 
 
TSH (with reflex to T4) 
 
 
≤28 days  
(Arm 2 only) 
CBC with differential (inc ANC, platelets, 
Hgb, leukocytes) 
 
≤7 days 
 
Serum or urine pregnancy test (women of 
childbearing potential; See Section 3.1 for 
definition) 
 
≤7 days 
≤3 days (only 
required if the test 
performed prior to 
step 2 registration 
is not also within 3 
days prior to 
treatment start) 
Patient-reported outcomes: 
x 
MDASI-BT 
x 
PRO-CTCAE 
 
 
≤28 days 
Neurocognitive function: 
x 
HVLT-R 
x 
TMT  
x 
COWA 
 
 
≤28 days 
Serum, plasma, and whole blood for banking 
(for patients who consent to biobanking for 
future research; see Section 10 for details) 
 
 
Prior to radiation 
*Tissue must be received by postoperative calendar day 23 or the case will be ineligible. Local MGMT 
results are not required to be available prior to consent, enrollment, or tissue submission. Eligibility is based 
solely on central review. 
 

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        ASSESSMENTS DURING TREATMENT 
Assessments 
Time Point 
 
Concurrent 
Treatment 
 
4 weeks post 
RT completion 
  (-3 days) 
Arm 1 
Adjuvant Phase  
(28 day cycles) 
Day 28 (+/-3 days, 
unless otherwise 
specified) of each 
cycle, prior to 
starting the next 
cycle  
Arm 2 
Adjuvant Phase  
(28 day cycles) 
Day 28 (+/-3 days, 
unless otherwise 
specified) of each 
cycle, prior to 
starting the next 
cycle 
Contrast-enhanced 
Brain MRI* 
 
X 
≤14 days prior to odd 
numbered cycles 
(starting with cycle 3) 
≤14 days prior to odd 
numbered cycles 
(starting with cycle 3) 
CMP (to include 
AST/ALT/Total 
Bilirubin) 
Weekly 
X 
X  
 
X 
And on Day 15 (+/- 3 
days) prior to Nivo 
dose  
TSH with reflex to 
T4  
(Arm 2 only) 
≤ 3 days prior to 
each dose of 
Ipilimumab  
X 
 
≤14 days prior to every 
other Nivo dose 
CBC with 
differential, ANC, 
platelets, Hgb, 
leukocytes 
Weekly 
X 
X 
And on Day 21 
(±2days) 
X 
History/physical 
examination 
 
X 
X 
X 
Karnofsky 
performance status 
and neurologic 
function 
 
X 
X 
X 
Adverse event 
evaluation 
Weekly  
X 
X 
X 
Steroid dose 
documentation 
Weekly  
X 
X 
At the time of each 
Nivo dose 
Patient-reported 
outcomes:** 
x 
MDASI-BT  
x 
PRO-CTCAE 
 
 
≤14 days prior to 
cycles 1, 3, and 5 
≤14 days prior to 
cycles 1, 3, and 5 
Neurocognitive 
function:** 
x 
HVLT-R  
x 
TMT  
x 
COWA 
 
 
≤14 days prior to 
cycles 1, 3, and 5 
≤14 days prior to 
cycles 1, 3, and 5 

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Serum and plasma for 
banking (for patients 
who consent to 
biobanking for future 
research; see Section 
10 for details) 
 
 
≤14 days prior to 
cycles 1 and 3 
≤14 days prior to  
cycles 1 and 3 
Documentation of 
Optune usage: Arm 1 
only 
 
 
X 
 
 
*Note that in a limited number of patients receiving immune checkpoint inhibitor therapy, hypophysitis 
was diagnosed by imaging studies through enlargement of the pituitary gland.  All brain MRI scans 
must also note the presence or absence of incidental enlargement of the pituitary gland, and if observed 
must prompt further clinical and/or laboratory endocrine evaluation as required per local investigator 
discretion.  
**Patient-reported outcomes and neurocognitive function assessments should be performed as close to 
the day of the contrast-enhanced MRI as possible and before the patient receives the results of the MRI. 
Assessments must be completed regardless of progression or discontinuation of treatment. (If the 
patient discontinues treatment prior to cycle 1, 3 or 5, the assessment is still required to be completed at 
the time that cycle would have occurred. Refer to the due date in RAVE). 
 

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ASSESSMENTS IN FOLLOW-UP 
Assessments 
Time Point 
Note: Assessments completed post progression, with the 
exception of Patient Reported Outcomes, Neurocognitive 
Function, and Adverse Event Evaluation will be left to the 
discretion of the treating physician. All patients are followed 
for survival status. 
From end of treatment 
Q 3 months for 1 
Year 
3, 6, 9, 12 months 
(+/-14 days) 
Q4 months for 
Year 2 
16, 20, 24 months 
(+/-14 days) 
Q6 months until 
death 
30, 36, 42, 
months etc 
(+/-28 days) 
Contrast-enhanced Brain MRI  
X 
X 
X 
History and Physical 
examination 
X 
X 
X 
Karnofsky performance status 
and neurologic function 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
Patient-reported outcomes:* 
x MDASI-BT 
x PRO-CTCAE 
X  
at 12 month only  
X  
at 24 month only 
 
Neurocognitive function:* 
x HVLT-R  
x TMT  
x COWA 
X  
at 12 month only  
X  
at 24 month only 
 
Documentation of Optune 
usage (Arm 1 only) 
 
Required until or unless 
initiation of other non-protocol 
disease modifying therapy 
X 
X 
X 
Steroid dose documentation 
X 
X 
X 
* Patient-reported outcomes and neurocognitive function assessments should be performed as 
close to the day of the contrast-enhanced MRI as possible and before the patient receives the 
results of the MRI. If an MRI was not completed, these assessments are still required. Refer to 
the due dates in RAVE. 
 
Definition of Disease Assessments 
Response and progression will be evaluated in this study using an adaptation of the Response 
Assessment in Neuro-Oncology criteria (Wen et al, J Clin Oncol. 2010 Apr 10;28(11):1963-72. 
doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15) with modification such that the first MRI 
performed following completion of radiotherapy is the baseline MRI for determination of 
radiographic disease.   
 
If PD is confirmed, as stated below, then treatment must be discontinued.   
 

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Note that this trial is not collecting response or best response; rather treatment is planned to 
continue until either 6-12 adjuvant (post-RT) cycles of temozolomide (arm 1) or indefinitely 
until Progressive Disease (arm 2).  Therefore, the only response designation of relevance is 
Progressive Disease or NOT Progressive Disease (Not-PD). 
 
Response will be assessed by the treating investigator.  If there is ambiguity regarding whether 
the patient has suffered PD, then treatment can continue with reassessment (imaging, clinical) 
after no more than 2 additional cycles.  If PD is confirmed at that time, then the date of PD in the 
CRF should be changed to the first and earlier time point at which PD was suspected. If PD is 
ambiguous, patients should continue protocol therapy. 
 
PD less than 12 weeks after radiotherapy completion is defined as any of the following:  
1. New enhancement outside of the radiation field (beyond the high-dose region or 80% isodose 
line) on diagnostic imaging.  
2. Unequivocal evidence of viable tumor on histopathologic sampling (eg, solid tumor areas [i.e., 
> 70% tumor cell nuclei in areas], high or progressive increase in MIB-1, proliferation index 
compared with prior biopsy, or evidence for histologic progression or increased anaplasia in 
tumor).  
 
Note: Given the difficulty of differentiating true progression from pseudoprogression, clinical 
decline alone, in the absence of radiographic or histologic confirmation of progression, will not 
be sufficient for definition of progressive disease in the first 12 weeks after completion of 
concurrent treatment. 
 
PD greater than or equal to 12 weeks after radiotherapy completion is defined as any of the 
following: 
1. New contrast-enhancing lesion outside of radiation field.  
2. Increase by at least 25% in the sum of the products of perpendicular diameters of contrast 
enhancing disease between the first post-radiotherapy scan (not a pre-radiotherapy scan), or a 
subsequent scan with smaller tumor size, and a scan at 12 weeks or later following completion of 
radiotherapy on stable or increasing doses of corticosteroids. 
3. Clinical deterioration not attributable to concurrent medication or comorbid conditions  
4. In addition, patients will be declared as having suffered PD (clinically) if they fail to return for 
evaluation as a result of deteriorating condition.    
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION (09-FEB-2021) 
Treatment Overview (Please refer to Section 5.1 and 5.2 for complete information) 
Protocol treatment must begin within 6 weeks following surgery.  
 
ARM 1: Participants randomized to Arm 1 will receive radiation therapy (60 Gy/2 Gy 
fractions) plus concomitant temozolomide (75 mg/m2/d X 42 days during RT), followed by 
adjuvant temozolomide150-200 mg/m2/d on days 1-5 of a 28 day cycle X 6-12 cycles).  If PD 
is ambiguous, patients should continue protocol therapy. 
ARM 2: Participants randomized to Arm 2 will receive radiation therapy (60 Gy/2 Gy 
fractions) plus concomitant ipilimumab and nivolumab, followed by adjuvant ipilimumab and 
nivolumab  (ipilimumab 1 mg/kg q 4 weeks X 4 doses; nivolumab 3 mg/kg q 2 weeks until 

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progressive disease). If PD is ambiguous, patients should continue protocol therapy. 
 
Protocol Treatment 
Arm 1 Arm 2 
Dose 
Radiation 
X 
X 
60 Gy/2 Gy fractions 
Temozolomide 
X 
 
Concomitant: 75 mg/m2/d X 42 days 
Adjuvant: 150-200 mg/m2/d after RT for 6 cycles; 
up to 12 cycles allowed at the discretion of the 
treating investigator 
Ipilimumab 
 
X 
1 mg/kg q 4 weeks  X4 doses 
Nivolumab 
 
X 
3 mg/kg* q 2 weeks until progressive disease 
*After a course of ipilimumab is discontinued or completed, if nivolumab is to be continued as 
monotherapy, dosing can continue at 3mg/kg weight-based, or change to 240 mg flat dose at the 
discretion of the treating investigator, every 2 weeks +/- 3 days. 
 
Treatments above continue until/unless one of the criteria in section 5.4 are met (disease 
progression, intolerable toxicity, withdrawal of consent, etc.) 
 
5.1 
Systemic Therapy (08-APR-2022) 
 
Protocol treatment must begin within 6 weeks following surgery. 
 
5.1.1 
Arm 1: Temozolomide (standard of care arm) 
Temozolomide is to be administered continuously from day 1 of radiation therapy to 
the last day of radiation (including weekends and holidays) at a daily oral dose of 75 
mg/m2, typically for 42 days but allowing up to a maximum of 49 days in the event of 
delays or interruptions in radiotherapy. Following completion of radiotherapy, 
approximately 4 weeks (+/- 3 days) later, “adjuvant” cycles will begin and are defined 
as 28 days.  Patients will receive 6 (to 12) cycles of adjuvant temozolomide at a dose 
of 150-200 mg/m2 on days 1-5 of a 28 day cycle. Treatment with 6 adjuvant cycles of 
temozolomide is required (absent a protocol-specified reason to discontinue early), and 
up to 12 cycles is permitted at the discretion of the treating investigator if consistent 
with local practice.  More than 12 cycles of adjuvant temozolomide is not allowed. 
 
The dose will be determined using the BSA calculated prior to concurrent treatment. 
The BSA will be re-calculated prior to every other adjuvant treatment cycle and if a 
change in more than 10% in weight has occurred, the dose of temozolomide must be 
adjusted according to the new BSA. The daily dose will be rounded to the nearest 5 
mg.  More frequent or more stringent dose adjustments for changes in weight are 
allowed but not required. Capsules of temozolomide are available in 5, 20, 100, 140, 
180, and 250 mg. Note: do not open, crush, or chew capsules; capsules must be 
swallowed whole.   
 
Optune use in the adjuvant phase of treatment is permitted per standard prescribing 
language and can be started after completion of concurrent treatment. Usage must be 
documented prior to odd numbered cycles. Optune use is not permitted during 
concurrent treatment. 

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5.1.2 
Arm 2: Ipilimumab and Nivolumab (investigational treatment arm) 
Patients will not receive temozolomide during study treatment. 
 
Optune use is not permitted.  
 
When infusions of ipilimumab and nivolumab are given on the same day, 
nivolumab is to be administered first, separate infusion bags and filters must be 
used for each infusion. 
 
Ipilimumab 
Starting concurrently with radiotherapy (Day 1), patients will receive ipilimumab 
1mg/kg intravenously over 90 minutes every 4 weeks x 4 doses (3 doses during 
concurrent treatment, and 1 dose during cycle 1 of adjuvant phase  Weight will be re-
calculated prior to every dose of ipilimumab; if a change in more than 10% in weight 
has occurred, the dose of must be adjusted according to the new weight. More 
stringent dose adjustments for changes in weight (such as for changes by less than 
10% or with every dose rather than every other dose) are allowed but not required. 
Note:  Infusion days are allowed +/- 3 days, except for concurrent day 1, which must 
occur on the same day as the start of RT.  
 
Nivolumab 
Starting concurrently with radiotherapy (Day 1), patients will receive nivolumab 
3mg/kg intravenously over 30 minutes every 2 weeks (5 doses during concurrent 
treatment and then 2 doses during each cycle of adjuvant phase) until either disease 
progression or another reason to discontinue protocol therapy outlined in section 5.4. 
Weight will be recalculated prior to every other dose of nivolumab; if a change in 
more than 10% in weight has occurred, the dose of must be adjusted according to the 
new weight. To reduce patient burden associated with waiting for re-calculation in 
situations when weight is unlikely to change by more than 10%, any documented 
weight collected no more than 2 weeks before the ipilimumab dose may be used, 
including weight collected at home and collected by phone by the investigator or 
designee and then documented in the source.  Conversely, more frequent or more 
stringent dose adjustments for changes in weight are allowed but not required. 
 
The nivolumab infusion must be promptly followed by a saline flush to clear the line 
of nivolumab before starting the ipilimumab infusion. Follow the same infusion 
timing detailed above.. 
 
Although treatment is intended to be continuous, to align with the schedule of events 
on the control (temozolomide) arm, a cycle is defined as 28 days, and cycle 1 begins 
with the first dose of nivolumab administered after radiotherapy to align with sixth 
nivolumab dose, which is approximately 4 weeks after RT completion (week 11). 
 
Therefore, during 6 weeks of radiotherapy, patients will receive 
 Day 1:  nivolumab and ipilimumab #1  

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 Day 15: nivolumab 
 Day 29:  nivolumab and ipilimumab #2  
After RT ends, 
 Day 43 (typically day following completion of radiotherapy):  nivolumab  
 Day 57 (approximately 2 weeks following completion of radiotherapy):  
nivolumab and ipilimumab #3 
Adjuvant Phase starts here 
 Day 71 (approximately 4 weeks following completion of radiotherapy):  
nivolumab  
 Day 85 (approximately 6 weeks following completion of radiotherapy):  
nivolumab and ipilimumab #4  
 Day 99 (approximately 8 weeks following completion of radiotherapy) and 
every 14 days thereafter:  nivolumab 
 
Notes:  All infusion days are allowed +/- 3 days 
After a course of ipilimumab is discontinued or completed, if nivolumab is to be continued as 
monotherapy, dosing can continue at 3mg/kg weight-based, or change to 240 mg flat dose at the 
discretion of the treating investigator, every 2 weeks +/- 3 days. 
Any treatment administered prior to the start of the Adjuvant Phase (Day 71/Week 11) will be 
considered as concurrent treatment phase.  
 
 
Treatment Schedule 
 
Concurrent Phase of Treatment 
Adjuvant Phase 
 
Week 1 
(Day 1) 
Week 3 
(Day 15)  
Week 5 
(Day 29) 
Week 7 
(Day 43) 
Week 9 
(Day 57) 
Week 11 
(Day 71) 
Week 13 
(Day 85) 
Week 15 
(Day 99) 
then every 
2 weeks 
RT 
X 
 
 
 
 
 
Ipi 
X 
 
X 
 
X 
 
X 
 
Nivo X 
X 
X 
X 
X 
X 
X 
X 
 
See Section 6 and Appendix II for toxicity management. 
 
 
5.2 
Radiation Therapy (09-FEB-2021) 
 
Concurrent phase of treatment must begin within 6 weeks after resection. 
 
See Section 8.2 for information on installing TRIAD for submission of digital RT data.  
 
Radiation Therapy Schema  
60 Gy will be given in 30 fractions over 6 weeks (5 days per week). However, for 
purposes of nomenclature, the “concurrent phase of treatment” continues until the 
beginning of week 11 (day 71) as in the table above (Section 5.1.2). 

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5.2.1 Treatment Technology 
 
This protocol requires photon treatment. 3D-CRT, fixed gantry-IMRT, helical tomotherapy, and 
volumetric modulated arc therapy (VMAT) are allowed, subject to protocol localization and 
dosimetry constraints.  Although very limited in availability, if a center chooses to, and has a 
credentialed MR-Linac, photon therapy delivery using this technology is permissible as long as 
the dosimetric guidelines are met.  Proton therapy is not permissible on this protocol, because of 
an ongoing protocol specifically addressing its role (NRG-BN001). 
 
Treatment shall be delivered with megavoltage (MV) machines of a minimum energy of 6 MV 
photons. Selection of the appropriate photon energy(ies) should be based on optimizing the 
radiation dose distribution within the target volume and minimizing dose to non-target normal 
tissue. Source skin distance for SSD techniques or source axis distance for SAD techniques must 
be at least 80 cm. Electron, particle, or implant boost is not permissible. IMRT delivery will 
require megavoltage radiation therapy machines of energy ≥ 6 MV. 
 
Treatment is performed using a sequential boost to the contrast-enhancing region of the target. 
Patient-specific quality assurance is highly recommended prior to start of treatment and is 
described in Section 5.2.10. 
 
5.2.2 Immobilization 
 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be achieved 
using appropriate clinical devices.  A 3-point or 5-point thermoplastic mask, with a headrest, is 
strongly recommended, but other options (for example BOS frame, etc.) are also allowed.  
Patients will be treated in a supine position. Additional immobilization devices such as a bite 
block and/or knee-wedge are permitted.  Not using an immobilization device is NOT permitted. 
 
5.2.3 Simulation Imaging 
 
A planning CT scan of the cranial contents with 3.0 mm slice thickness or less will be required.  
Intravenous contrast is recommended as per institutional guidelines, but not mandated.  For 
photon planning, the institution must have an established relationship between CT number and 
electron density.  The planning CT will be fused with the pre- and post-operative MRI scans. 
Rigid registration is permitted, but deformable fusion is not permitted, given the multitude of 
different deformational algorithms, several of which have not been centrally validated.  Image 
fusion must be performed by a qualified medical physicist or by a dosimetrist under the 
supervision of a qualified medical physicist, and reviewed by the attending physician.  We 
strongly recommend that the following MR sequences be fused with the planning CT: 
1. Preoperative T1 + contrast axial series 
2. Preoperative F T2 weighted LAIR (or equivalent), or alternatively T2 axial series.   
3. Postoperative T1 + contrast axial series (must be obtained within ≤3 days of surgery). 
4. Postoperative T2 weighted FLAIR (or equivalent), or alternatively T2 axial series. 
The postoperative MRI scan must be obtained ≤3 days after surgical resection. If >3 week have 

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elapsed between surgical resection and radiotherapy planning, a repeat postoperative MRI with 
T2 weighted/FLAIR and contrast enhanced T1 sequences is highly recommended for 
radiotherapy planning purposes. Target volume delineation will be based upon the 
postoperative contrast-enhanced and T2 weighted FLAIR (preferred over conventional T2) 
MRI, although the preoperative image should also be evaluated, commensurate with standard 
practice. Preoperative MRI is therefore encouraged to be used as an assistive tool for contouring. 
 
5.2.4 Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable. 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
GTV_4600 
GTV to receive 46 Gy 
Required 
CTV_4600 
CTV to receive 46 Gy 
Required 
PTV_4600 
PTV to receive 46 Gy 
Required 
GTV_6000 
GTV to receive 60 Gy 
Required 
CTV_6000 
CTV to receive 60 Gy 
Required 
PTV_6000 
PTV to receive 60 Gy 
Required 
 
Detailed Specifications 
 
GTV_4600: Either the T2 weighted FLAIR (or the conventional T2) on the post-operative MRI 
scan, inclusive of all contrast-enhancing T1 abnormality on the post-operative MRI and the 
surgical cavity. Areas of vascular infarction or compromise of normal brain should be excluded 
if they are deemed to not be part of the original pre-operative T2 weighted FLAIR or 
conventional T2 abnormality, and a comparison of the pre- and post-operative scans will assist in 
this process.  As a guide, we recommend the following sequential and step-wise process: 
a. Contour the GTV_4600 using the T2 weighted FLAIR (or conventional T2) 
abnormality on the post-op MRI scan, and include the surgical cavity on the T1 post 
contrast scan. 
b. Contour the GTV_4600 T2 weighted FLAIR (or conventional T2) abnormality on the 
preop scan and include the T1 enhancing tumor. 
i. 
Do not switch between T2 weighted FLAIR and conventional T2 
for the pre and post op scans.  Use only the T2 weighted FLAIR or 
only the conventional T2 on both sequences. 
c.  Compare the GTV_4600 on the postop scan vs. the preop scan. 

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i. In general, the volume of GTV_4600 on the preop scan should be 
larger than on the postop scan, and none of the postop volume should 
expand outside the preop volume. 
ii. If the postop GTV_4600 expands outside the preop GTV_4600, 
review with neurosurgery/diagnostic radiology to exclude any possible 
areas of infarction, vascular compromise, etc., especially if the post-op 
scan is ≤3 days after surgery. 
iii. In some instances, the postop GTV_4600 will be larger than the preop 
volume because of disease progression, especially if several weeks 
have elapsed between the 2 scans; in this case, once you have 
confirmed that the volumetric discrepancy is not because of a vascular 
event, use the larger postop GTV_4600  for planning purposes. 
iv. In some instances the postop GTV_4600 will be larger than the preop 
GTV_4600  because the surgical cavity and resection path extend 
beyond the preop T2 weighted FLAIR (not common) abnormality; in 
this case, once you have confirmed that the volumetric discrepancy is 
not because of a vascular event, use the larger postop GTV_4600 for 
planning purposes. 
CTV_4600: Is defined as the GTV_4600 plus a margin of 2 cm, which may be reduced around 
natural barriers to tumor growth such as the skull, ventricles, falx, etc. to as low as 0 mm to 
"fixed" barriers, i.e., bone, and falx and as low as 3 – 5 mm to “non-rigid” barriers such as brain 
stem, ventricles, etc.  In the uncommon situation that there is no surrounding T2 weighted 
FLAIR and/or conventional T2 abnormality, the CTV 4600 in those instances should include the 
post-operative MRI enhancement and the surgical resection cavity plus a 2 cm margin, with 
reduction permitted as described above.  In those uncommon situations where an extensive polar 
lobectomy has been achieved, and no true residual disease or surgical cavity is present, 
GTV_4600 will be defined only by the residual postop T2 weighted FLAIR abnormality, and the 
CTV will reflect a 2 cm margin expansion, using the same guidelines as above. 
GTV_6000: Contrast enhancing T1 abnormality and the surgical cavity on the post-operative 
MRI scan.  Areas of vascular infarction or compromise of normal brain should be excluded if 
they are deemed to not be part of the original pre-operative tumor volume, and a comparison of 
the pre- and post-operative scans will assist in this process.  The exception to this is the polar 
tumor, e.g., temporal lobe, frontal lobe, or occipital lobe tip, where a gross total resection is 
achieved, and no post-operative "cavity" remains, consequential to the partial or total lobectomy.  
For these uncommon patients, GTV_6000 will be defined as either the conventional T2 or the T2 
weighted FLAIR abnormality on the post-operative MRI scan, i.e., in these cases, GTV_4600 = 
GTV_6000. 
CTV_6000: Is defined as the GTV_6000 plus a margin of 2 cm.  The CTV_6000  margin may be 
reduced around natural barriers to tumor growth such as the skull, ventricles, falx, etc. to as low 
as 0 mm to "fixed" barriers, i.e., bone, and falx and as low as 3 – 5 mm to "non-rigid" barriers 
such as brain stem, ventricles, etc..  
PTV_4600 and PTV_6000: In general the PTV is the CTV plus a geometric 5 mm expansion in 
all dimensions. This can be reduced to 4 mm if daily volumetric (3D) or non-volumetric (2d) 
IGRT is utilized. The PTV may extend beyond bony margins and the skin surface.  

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5.2.5 
Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table 
below.  The structures marked as “Required” in the table must be contoured and 
submitted with the treatment plan. Structures marked as “Required when applicable” 
must be contoured and submitted when applicable.   
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed.  Capital letters, spacing and use of underscores must be 
applied exactly as indicated. 
 
Standard Name 
 
Description 
 
Validation 
(Required/Required when 
applicable/Optional) 
Brain 
Whole brain 
parenchyma 
Required 
BrainStem 
Brainstem 
Required 
Cochlea_L 
Left cochlea 
Optional 
Cochlea_R 
Right cochlea 
Optional 
OpticChiasm 
Chiasm 
Required 
OpticChiasm_PRV 
Chiasm planning risk 
volume 
Required 
OpticNrv_L 
Left optic nerve 
Required 
OpticNrv_R 
Right optic nerve 
Required 
OpticNrv_PRV_L 
Left optic nerve 
planning risk volume 
Required 
OpticNrv_PRV_R 
Right optic nerve 
planning risk volume 
Required 
Lens_L 
Left lens 
Required 
Lens_R 
Right lens 
Required 
Retina_L 
Left retina 
Required 
Retina_R 
Right retina 
Required 
Glnd_Lacrimal_L 
Left lacrimal gland 
Required 
Glnd_Lacrimal_R 
Right lacrimal gland 
Required 
SpinalCord 
Spinal Cord 
Required 
 
Detailed Specifications 
All structures must be contoured on the planning CT, using the postoperative MRI for guidance. 
All structures should be reviewed on both CT and registered MRI images. 
 
Lens_L, Lens_R, Retina_L, Retina_R, OpticNrv_L, OpticNrv_R:  Due to variance in eye 
position between the CT and MRI, if possible, the structures should be contoured using the CT 
dataset only.  At times, for contouring the optic nerves, as they exit through the bony canal, 
switching the CT sequence between soft-tissue and bone windows is useful. The retina is defined 

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as the innermost of the three layers that form the wall of the eyeball.  Please contour the 5 mm 
posterior wall of the eye.   
OptNrv_PRV_L:  Left optic nerve should be expanded by a volumetric expansion of 3 mm. 
OptNrv_PRV_R:  Right optic nerve should be expanded by a volumetric expansion of 3 mm. 
OpticChiasm:  Located above the pituitary fossa, the optic chiasm includes both anterior and 
posterior limbs.  Frequently, the fused T2 weighted/FLAIR MRI is useful for identify and 
validating the chiasm contour, especially the coronal MRI; therefore, in some cases it may be 
necessary to fuse a coronal MR sequence clearly demarcating the chiasm, or reformatting thin 
slice MR axial images into coronal views.  Please note that the MR position of the chiasm is only 
for guidance for contouring on the CT dataset, due to potential variation in CT/MRI fusion. 
OpticChiasm_PRV:  Optic chiasm should be expanded by a volumetric expansion of 3 mm. 
BrainStem:  Brainstem contour should include all three components:  midbrain, pons, and 
medulla.  The brainstem is bordered superiorly by the tentorial incisures and inferiorly by the 
foramen magnum.  It can be visualized on post-operative MRI sequence, but should be 
confirmed on CT dataset due to potential variation in CT/MRI fusion. 
SpinalCord:  Spinal cord should be contoured, wherever possible, on the CT dataset only. 
Brain:  Whole brain parenchyma includes all intracranial contents, inclusive of target volumes.  
Because some volumetric change could have occurred in the whole brain parenchyma due to 
evolving post-operative changes, it is recommended, whenever possible to contour the whole 
brain parenchyma using the CT dataset only. 
Cochlea_L, Cochlea_R:  It is strongly recommended that the left and right cochlea be contoured 
using the CT dataset on bone window. 
Glnd_Lacrimal_L, Glnd_Lacrimal_R:  The lacrimal gland is located supero-laterally to the 
extraconal portion of the orbit, medial to the zygomatic process of the frontal bone and is 
superior to the lateral rectus muscle and lateral to the superior rectus muscle.   
 
5.2.6 Dose Prescription 
 
The initial target volume will be treated to 46 Gy in 23 fractions. After 46 Gy, the conedown or 
boost volume will be treated to a total of 60 Gy, with seven additional fractions of 2 Gy each (14 
Gy boost dose). Isodose distributions for the initial target volume (PTV_4600) and the conedown 
target volume (PTV_6000) are required on all patients. A composite plan is required showing the 
respective target volumes.  
 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priority table should be used 
during dose optimization.  It is important to remember that ideal plans might not be achievable in 
all cases.  Thus, the Compliance Criteria table could be different than the information given here.  

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Cases will be scored using the Compliance Criteria table. 
Target 
Standard Name 
Dose [Gy] 
Fraction Size 
[Gy] 
# of 
fractions  
Dose specification 
technique 
PTV_4600 
46 
2.0 
23 
At least 95% of PTV 
receives 46 Gy 
PTV_6000 
60 
2.0 
30 
≥95% of PTV should 
receive ≥ 60 Gy 
 
 
5.2.7 Compliance criteria 
 
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table.  The Per Protocol and Variation Acceptable categories are both considered 
to be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation 
Acceptable category can include more challenging plans that do not fall at or near the ideal 
results.  A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are 
considered to be suboptimal and additional treatment planning optimization is recommended. 
 
Normalization of Dose: The plan is normalized such that at least 95% of the PTV_6000 volume 
receives the prescription dose of 60 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
Target Volume Constraints and Compliance Criteria 
 
Name of 
Structure 
Dosimetric 
parameter* 
Per Protocol 
Variation 
Acceptable 
PTV_4600 
D95% [Gy] 
>=46 
>=43.7 
PTV_6000 
D95% [Gy] 
59.25-60.75 
57.0-63.0 
D10% [Gy] 
<=63 
<=65.12 
D0.03cc [Gy] 
<=64.0 
<=66.0 
Per Protocol range is excluded from Variation Acceptable range. 
 
 
 
Normal Structure Constraints and Compliance Criteria 
 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
BrainStem 
D0.03cc [Gy] 
<=55 
<=60 
OpticNrv_PRV_L 
or 
OpticNrv_PRV_R 
D0.03cc [Gy] 
<=55 
<=60 

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OpticChiasm_PRV 
D0.03cc [Gy] 
<=55 
<=60 
Brain 
D5% [Gy] 
<=65 
<=67 
Retina_L or 
Retina_R 
D0.03cc [Gy] 
<=45 
<=50 
Lens_L or Lens_R 
D0.03cc [Gy] 
<=7 
<=10 
Glnd_Lacrimal_L or 
Glnd_Lacrimal R 
D0.03cc [Gy] 
<=40 
<=45 
Cochlea_L or 
Cochlea_R 
Mean dose 
<=45 
<=50 
SpinalCord 
D0.03cc [Gy] 
<=50 
 
Per Protocol range is excluded from Variation Acceptable range. 
 
Exceptions: 
 
1. SpinalCord does not have a Variation Acceptable; Deviation Unacceptable occurs when 
SpinalCord dose limit for Per Protocol is not met. 
2. Deviation Unacceptable occurs when dose limits for Variation Acceptable are not met for 
both OptNrv_PRV_L and OptNrv_PRV_R; or OptNrv_PRV_L if the subject does not 
have a serviceable vision in the right eye; or OptNrv_PRV_R if the subject does not have 
a serviceable vision in the left eye.  The optic nerve or chiasm dose will not be scored 
as unacceptable if the patient has no serviceable vision in the concerned eye (or both 
eyes in the case of chiasmal dose); it is therefore imperative that this information be 
clearly provided. 
3. Deviation Unacceptable occurs when dose limits for Variation Acceptable are not met for 
both Retina_L and Retina_R; or Retina_L if the subject does not have serviceable vision 
in the right eye; or Retina_R if the subject does not have serviceable vision in the left eye.  
The retinal dose will not be scored as unacceptable if the patient has no serviceable 
vision in that eye (or both eyes if that is the case); it is therefore imperative that this 
information be clearly provided. 
4. Exceeding the dose limits for Variation Acceptable for Lens_L or Lens_R will not be 
scored as Deviation Unacceptable. 
5. Exceeding the dose limits for Variation Acceptable for Cochlea_L or Cochlea_R will not 
be scored as Deviation Unacceptable. 
6. Exceeding the dose limits for Variation Acceptable for Lacrimal Gland_L or Lacrimal 
Gland_R will not be scored as Deviation Unacceptable. 
 
Delivery Compliance criteria 
 
 
Per Protocol 
Variation Acceptable 
Start date   
≤ 6 weeks after surgery 
None 
Overall Treatment time 
≤ 46 days 
47 – 49 days 
Interruptions 
≤ 4 days 
5 – 7 days 
 

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5.2.8 Treatment Planning Priorities and Instructions 
 
- Treatment planning priorities 
1. 
SpinalCord 
2. 
BrainStem 
3. 
OpticChiasm_PRV 
3.  
OpticNrv_PRV_L and OpticNrv_PRV_R 
4.  
PTV_4600 
5.  
PTV_6000 
6.  
Brain 
7.  
Retina_L and Retina_R 
8. 
Gland_Lacrimal_L and Glnd_Lacrimal_R 
9. 
Lens_L and Lens_R 
 
- Required algorithms  
For photon treatment planning, acceptable choices of algorithm are listed at 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf.  An algorithm that is not included in this list must be 
credentialed by IROC Houston. For Convolution/Superposition type algorithms, dose should be 
reported as computed inherently by the given algorithm. For Monte Carlo or Grid Based 
Boltzmann Solver algorithms, conversion of Dm (dose-to-medium) to Dw (dose-to-water) 
should be avoided.  Dm, computed inherently by these algorithms, should be reported. These 
principles hold for Pencil Beam type algorithms and for homogeneous dose calculations when 
allowed for a clinical trial. 
 
- Primary dataset for dose calculation 
Planning CT image is the primary dataset for dose calculation.  
 
-Dose matrix resolution 
Dose grid size should be <= 3 mm in all directions. 
 
5.2.9 Patient specific QA 
For photon IMRT plans, patient specific QA is highly recommended. QA is performed by 
delivering the plan onto a phantom and measuring the dose using an ion chamber array or other 
2D/3D device. The recommended patient specific QA criteria is for 90% of the comparison 
points to pass a ±3%/3mm Gamma Index analysis. 
 
5.2.10 Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy 
and precision throughout its entire process from target and normal tissue delineation, to radiation 
delivery, to adaptation of therapy to anatomic and biological changes over time in individual 
patients. In this section we use the terminology IGRT to focus on image-guidance at the time of 
radiation delivery to ensure its adherence to the planned treatment. IGRT should be credentialed 
by IROC when IGRT is used for patient setup. 
 
Imaging should be performed at least once per week. Daily IGRT is highly recommended for 

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IMRT and image-guidance is per individual institutional standards and the margins stated in 
Section 5.2.4. Acceptable IGRT methods include orthogonal kV imaging, cone beam or in room 
diagnostic CT with referenced geometry to treatment machine (ex. CT on rails) or tomotherapy 
based fan beam imaging. 
 
Use of 4 mm PTV margin expansion is based on the requirement that IGRT will be used for 
daily setup and localization. 
 
Image registration may be performed based on bony structures and/or existing implanted fiducial 
markers. It is important to include as much of the anatomy of this structure as possible to ensure 
correct alignment of the head. Caution should be taken to avoid excess repeat imaging on a 
given treatment day to minimize subject dose outside the treatment region, and steps to 
control subject position to less than 3 mm should not be taken. 
 
Setup errors identified on IGRT images of > 1 mm or > 1 degree should be corrected. 
 
Management of Radiation Dose to the Patient from IGRT 
NRG Oncology is concerned about the estimated doses given from IGRT, and is committed to 
limiting the imaging dose when IGRT is used in any of its protocols. This can be accomplished by 
avoiding the use of this technology to make small changes in patient positioning that are within 
the stated PTV margins. The imaging dose to the patient may become significant if repeated studies 
are done for patients with severe set up problems (e.g. requiring frequent corrections that are larger 
than the PTV margins). It is recommended that patients demonstrating severe set up problems 
during the first week of treatment be moved to a treatment with larger margins.  
 
5.2.11 
Case Review  
See section 12.1 for details.  
 
5.3 
General Concomitant Medication and Supportive Care Guidelines (08-APR-2022) 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. Specific 
permitted supportive/ancillary care and concomitant medications include but are not 
limited to the following: 
 Anticonvulsants 
 Antiemetics 
 Anticoagulants other than warfarin 
o Pulmonary embolism and deep venous thrombosis are known complications of 
glioblastoma. They can be treated per investigator discretion other than with 
warfarin.   
 Antidiarrheals 
 Analgesics 
 Hematopoietic Growth Factors 
 Highly active antiretroviral therapy (HAART) 

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 Note that systemic (oral, rectal, intravenous) corticosteroids are disallowed within 3 
days prior to step 2 registration and within 3 days prior to the first administration of 
study treatment, but are allowed as needed after that although doses must be submitted 
as part of the data submission process. Inhaled, topical, and ocular corticosteroids are 
permitted without limitation.  
 
Herbal and Nutritional Supplements 
The concomitant use of herbal therapies is not recommended, as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However the 
use of general nutritional foundation supplements will be allowed including: calcium 
with vitamin D and/or minerals, Omega3s (fish oil), Vitamin B6, Vitamin B12, a basic 
multivitamin , L-glutamine, or probiotics oral supplements will be permitted at long as at 
or below the FDA approved recommended dose allowance (RDA) by a healthcare 
provider.   Herbal-based multivitamins are not allowed. Any additional supplements will 
need prior review and approval by the Principal Investigator/Neuro-Oncology Chair, Co-
Chair, or NRG Oncology approved designee. 
 
Pneumocystis carinii prophylaxis 
Prophylaxis against P. carinii pneumonia is strongly recommended for all patients receiving 
temozolomide during radiotherapy, such as (but not limited to): trimethoprim-
sulfamethoxazole (Bactrim forte, Bactrim DS) 1 tablet 3 times per week or monthly 
pentamidine inhalations (300 mg via aerosol monthly) or dapsone 100 mg po each day 
(except in patients with G6-PD deficiency) or atovoquone (1500 mg of suspension po qd 
with food). Prophylaxis is strongly recommended to continue for the duration of 
radiotherapy, regardless of the lymphocyte count. 
 
5.3.2 Prohibited and Restricted Therapies 
 
All Patients 
Concomitant systemic or local anti-cancer medications or treatments are prohibited in 
this study (with the exception of Optune, which is allowed in Arm 1 only), before 
progression, including but not limited to:  
x Any non-study anti-cancer directed agent (investigational or non-investigational) 
x Any other investigational agents 
x Any other CTLA-4 inhibitors or agonists 
x CD137 or other immunologic activation agonists 
x Immunosuppressive agents 
x Bevacizumab 
x Lomustine 
x Radiotherapy except as outlined 
x Radiosurgery (including stereotactic radiosurgery, gamma knife, cyber knife) 
x Diet changes or other medications with a goal of treating the tumor (such as 
ketogenic diet or metformin in the absence of diabetes mellitus) 
x Laser interstitial thermal therapy (LITT). 

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 Laser interstitial thermal therapy (LITT) that completely ablates the tissue 
does not exclude active recurrence; patients who undergo LITT after 
enrollment should be considered to have pursued alternate therapy, protocol 
therapy must be discontinued, and the patient should be considered 
unevaluable for progression as of the date of the first MRI concerning for 
progression. 
 
In addition, treatment with warfarin is not permitted. 
 
Patients Randomized to Arm 1  
No additional Arm-specific restrictions 
 
Patients Randomized to Arm 2  
Patients may use standard vaccines.  Where possible, routine vaccination for influenza, 
pneumococcal pneumonia, and COVID-19 should be given prior to the start of therapy 
but may be administered during treatment when clinically indicated. Vaccination should 
be given when there is enough separation to distinguish any vaccine reactions from drug 
toxicity.  There is no experience using live attenuated vaccination during ipilimumab 
therapy, so that live vaccine should be used cautiously during treatment.   
 
5.3.3 Participation in Other Trials  
Patients are not allowed to participate in other therapeutic trials of interventions with 
anticancer therapy as a goal (drug, device, diet, or other) before progression.  However, 
trials that do not add experimental agents are allowed (e.g. imaging trials, quality of life, 
seizure, prevention/treatment, etc). In addition, adjuncts that were already administered at 
the time of surgery designed to guide or enhance surgical resection (e.g., 5-ALA, 
fluorescein) are not exclusionary. 
 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 Disease progression 
o Patients who undergo tumor-directed surgery during protocol therapy for 
suspected recurrence or to distinguish treatment effect (i.e., 
pseudoprogression) from tumor recurrence who are found to have active 
tumor on local pathologic analysis must be discontinued.  The date of 
progressive disease must be backdated to the date of first suspected 
progression.  Patients without active tumor may continue on protocol therapy.   
 Intercurrent illness that prevents further administration of treatment 
 Adverse event(s) which require(s) permanently going off study treatment (see also 
Section 6 and specific algorithms in Appendices II and III) 
 Any dosing interruption lasting >6 weeks, with the following exceptions:  Dosing 
interruptions >6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Medical Neuro-Oncology Study Chair/designee.  Prior to re-
initiating treatment in a subject with a dosing interruption lasting >6 weeks, the 

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Medical Neuro-Oncology Study Chair/designee must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted. 
 Patient decides to withdraw consent for participation in the study 
 General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 Arm 1:  completion of 6 cycles of adjuvant cycles of therapy, with up to 12 total 
adjuvant cycles permissible at the discretion of the treating investigator 
 Note that Optune may continue indefinitely at the discretion of the treating 
investigator (Arm 1). 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 
NOTE:  PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action. 
 
6.1  
Temozolomide (08-APR-2022) 
 
Temozolomide During Concomitant Radiation Therapy 
No dose reduction will be made, but delay or discontinuation of temozolomide 
administration will be decided weekly according to hematologic and non-hematologic 
adverse events (AEs), as specified below.  
If one or more of the following are observed:  
- ANC < 1.5 x 109/ L 
- Platelet count < 100 x 109/ L 
- Grade 3 treatment-related non-hematologic AE (except alopecia, nausea and vomiting 
unless the patient has failed maximal antiemetic therapy, and fatigue) 
 
then treatment with concomitant temozolomide will be withheld until all of the following 
conditions are met:  
- ANC ≥ 1.5 x 109/L  
- Platelet count ≥ 100 x 109/L  
- Grade ≤ 1 non-hematologic AE (except alopecia, nausea and vomiting unless the patient 
has failed maximal antiemetic therapy, and fatigue)   
 
In case of hematologic AE as defined above, a complete blood count (CBC) should be 
performed at least twice weekly. In case of non-hematologic AE, the patient must be 
assessed at least weekly with relevant laboratory test(s). As soon as all of the above 
conditions are met, the administration of temozolomide must resume at the same dose as 
used initially.  
If one or more of the following are observed:  
- ANC < 0.5 x 109/L (Grade 4)  
- Platelet count < 25 x 109/L (Grade 4) 
- Grade 4 treatment-related non-hematologic AE (except alopecia, nausea and vomiting 
unless the patient has failed maximal antiemetic therapy) 

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then treatment with concomitant temozolomide must be stopped.  
Adjuvant temozolomide treatment (below) can be initiated if hematologic adverse events 
resolve (platelet > 100 x 109/L and ANC > 1.5 x 109/L). A delay of up to 6 weeks is 
permitted to allow for resolution of adverse events. 
If the administration of temozolomide has to be interrupted, the radiotherapy will proceed 
normally. Missed doses of temozolomide during the concurrent phase of treatment with 
radiotherapy will not be made up at the end of radiotherapy. The total number of days and 
total dose of temozolomide will be recorded on the temozolomide CRF.  
If the duration of radiotherapy exceeds 7 weeks, then concomitant treatment with 
temozolomide must be stopped after 49 days of temozolomide treatment.  
 
Cases of hepatic injury, including fatal hepatic failure, have been observed in patients 
enrolled in clinical studies utilizing the agent temozolomide.  In addition, it was noted 
that liver toxicity may occur several weeks or more after initiation of treatment or after 
temozolomide discontinuation. For patients with significant liver function abnormalities, 
the risks and benefits of treatment continuation should be carefully considered. 
 
 
Summary of Temozolomide Delay or Discontinuation During Concomitant Radiation 
Therapy 
AE 
Value 
Grade 
Action 
ANC 
≥ 0.5 and < 1.5 x 109/L 
  
Delay temozolomide 
until: 
---ANC ≥  1.5 x 109/L 
---Platelet ≥ 100 x 109/L 
---Non-hem AE d 
Platelet count 
≥ 25 and < 100 x 109/L  
 
Non-hematologic 
(except nausea/vomiting 
unless the patient has 
failed maximal 
antiemetic therapy and 
fatigue) 
 
NA 
3 
ANC 
< 0.5 x 109/L 
4 
Stop concomitant 
temozolomide 
Platelet count 
< 25 x 109/L 
4 
Non-hematologic 
(except nausea/vomiting 
unless the patient has 
failed maximal 
antiemetic therapy) 
 
NA 
4 
 
Concomitant temozolomide, if radiotherapy is interrupted  
If radiotherapy has to be interrupted for technical or medical reasons unrelated to the temozolomide 
administration, then treatment with daily temozolomide may continue at the discretion of the 
treating investigator. If radiotherapy has to be permanently interrupted then treatment with daily 
temozolomide can stop or be continued at the discretion of the treating investigator; if stopped, 
temozolomide can resume with the initiation of the adjuvant phase of treatment. 

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Post-Radiation (Adjuvant) Temozolomide 
Dosing is based on adverse events (AEs) during the prior treatment cycle. If multiple AEs are seen, 
the dose administered should be based on the dose reduction required for the most severe grade of 
any single AE. 
Dose Level 
Temozolomide Dose, 
mg/m2/day 
Remarks 
-2  
100  
Reduction if prior AE  
-1 
125 
Reduction if prior AE 
 0  
150  
Starting dose cycle 1 (adjuvant)  
+1 
200 
Escalated dose at cycle 2, for 
cycles 2-12 (see dose escalation 
description) 
 
Delay 
On day 1 of each cycle (up to 9 days prior, coinciding with day 21 +/- 2 days of the prior cycle), 
ANC ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and all treatment-related grade 3 or 4 non-
hematologic AEs (except nausea and vomiting unless the patient has failed maximal antiemetic 
therapy and fatigue) must have resolved (to grade ≤ 1).  
 
If these re-treatment parameters are not met, the treatment will be delayed to a maximum of 6 
consecutive weeks with parameters rechecked at least weekly. If, after 6 weeks of delay, re-
treatment parameters are not met: then any further adjuvant treatment with temozolomide must be 
stopped.  
Dose escalation 
If, during the first cycle, all treatment-related non-hematologic AEs observed were grade ≤ 2 
(except nausea and vomiting unless the patient has failed maximal antiemetic therapy and fatigue) 
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. 
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 cannot be 
escalated in further cycles (3-12).  
 
Dose reductions 
If any treatment-related non-hematologic AE observed was grade > 2 (except nausea and vomiting 
unless the patient has failed maximal antiemetic therapy and fatigue) and/or if platelets < 50 x 
109/L and/or ANC < 1 x 109/L, then the dose should be reduced by one dose level. For patients 
who would require dose reductions to a dose level < 100 mg/m2/day, temozolomide will be 
stopped. Also, if any of the same non-hematologic grade 3 AE recurs (except nausea and vomiting 
unless the patient has failed maximal antiemetic therapy and fatigue) after reduction for that AE, 
then temozolomide will be stopped.  
 
If any treatment-related non-hematologic AE observed was grade 4 (except nausea and vomiting 
unless the patient has failed maximal antiemetic therapy and fatigue) then adjuvant temozolomide 

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treatment should be stopped.  
 
 Subsequent cycles (3-6 and up to 12 allowed): Any dose reductions of temozolomide will 
be determined according to (1) non-hematologic AE during the preceding treatment cycle, 
as well as (2) the nadir (lowest/worst) ANC and platelet counts observed. No dose 
escalation should be attempted. The same dose reductions as for the second cycle should 
be applied.  
 
 Important: If the dose was reduced or delayed for adverse events, there will be no dose 
escalation.  
 
The reason(s) for dose reduction and/or delay must be documented in the CRF.  
 
Summary of Dose Modification or Discontinuation During Post-Radiation Temozolomide  
Worst Non-Hematologic AE (except alopecia, nausea and vomiting unless the patient 
has failed maximal antiemetic therapy and fatigue) 
During the Previous Cycles 
Grade 
Dose Modification 
0-2 
No dose modifications for non-hematologic AEs. Dose escalations (only for 
cycle 2) or reductions based on ANC and platelet counts are applicable.  
3 
Reduce by one dose level (except nausea and vomiting unless the patient has 
failed maximal antiemetic therapy and fatigue). Dose modifications 
(escalations or reductions) based on ANC and platelet counts are not 
applicable. No further escalation is possible. If the same non-hematologic 
grade 3 AE recurs (except alopecia, nausea and vomiting) after reduction for 
that AE, then stop. 
4 
Stop (except nausea and vomiting unless the patient has failed maximal 
antiemetic therapy and fatigue). Dose modifications (escalations or 
reductions) based on ANC and platelet counts are not applicable. 
 
Nadir Values 
Platelets 
 
≥100 x 109/L  
50 – 99 x 109/L  
< 50 x 109/L  
 
≥ 1.5 x 109/L  
Escalation to DL 1 
(cycle 2 only)  
Dose unchanged  
Reduce by 1 dose 
level  
ANC  ≥1 & <1.5 x 
109/L  
Dose unchanged  
Dose unchanged  
Reduce by 1 dose 
level  
 
< 1 x 109/L  
Reduce by 1 dose 
level  
Reduce by 1 dose 
level  
Reduce by 1 dose 
level  
 
Note: A complete blood count must be performed 21 days (± 48 hours) after the first daily 
dose of each adjuvant treatment cycle.  
Hematologic AE on Day 1 of Each Cycle (≤ 3 days before) 
AE  
Delay 

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ANC< 1.5 x 109/L and/or 
Platelet count < 100 x 109/L 
Delay up to 4 weeks until all resolved. If 
unresolved after 4 weeks then stop. If resolved, 
dose delay/reductions based on non-hematologic 
AEs are applicable. If treatment has to be delayed 
for AEs, then no escalation is possible.  
 
 
Non-Hematological AE (except for alopecia, nausea and vomiting unless 
the patient has failed maximal antiemetic therapy and fatigue)  
on Day 1 of Each Cycle (≤ 3 days before) 
Grade 
Delay 
2-3 
Delay up to 4 weeks  until all resolved (to grade ≤ 1). If unresolved after 
4 weeks, then stop. If resolved, dose delay/reductions based on ANC and 
platelets are applicable. If treatment has to be delayed for AEs, then no 
escalation is possible.  
 
 
 
6.2  Nivolumab and Ipilimumab: General Guidelines (08-APR-2022) 
 
 
If treatment is delayed >6 weeks for an adverse event the ipilimumab and nivolumab must be 
permanently discontinued.  
 
Any patients who require additional immune suppressive treatment beyond steroids must 
discontinue nivolumab and ipilimumab. 
 
Patients requiring > two dose delays for the same event should discontinue nivolumab and 
ipilimumab. 
 
Please note that in some cases the treatment algorithms recommend steroids if symptoms do not 
resolve in 5-7 days.  However, this recommendation is not meant to delay steroid treatment at 
any time it is clinically indicated.   
 
Patients may be dose-delayed for evaluation and restarted depending on results.  
Any patient started on corticosteroids initially who is determined to not require steroid treatment 
for an autoimmune adverse event may resume therapy after a 2-week observation period without 
further symptoms at the discretion of the PI or investigator. 
 
 
 
6.3 
Nivolumab and Ipilimumab ( (17-JAN-2023) 
 
There are no dose modifications for nivolumab and ipilimumab. 
 

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6.3.1  
Treatment of Nivolumab/Ipilimumab-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, urticaria, angioedema, pruritis, arthralgias, hypo- or hypertension, 
bronchospasm, or other symptoms.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met.  
Infusion reactions should be graded according to NCI CTCAE version 5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as medically appropriate: 
 
Remain at bedside and monitor subject until recovery from symptoms.  
 
For Grade 1 symptoms  
(Mild reaction; infusion interruption not indicated; intervention not indicated)  
 
Infusion rate may be slowed or interrupted and restarted 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 
patient closely.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab and ipilimumab 
administrations, slowing infusion rate as above. 
 
 
For Grade 2 symptoms   
(Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; close observation for 
recurrence and treatment  medications may need to be continued for 24-48 hours).   
 
Stop the nivolumab and ipilimumab infusions, begin an IV infusion of normal saline, 
and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor patient 
until resolution of symptoms.  Corticosteroid 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 patient closely.  If symptoms recur, re administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the patient until resolution of symptoms.  
The amount of study drug infused must be recorded on the electronic case report form 
(eCRF). 

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The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and (acetaminophen) (or paracetamol) 325 to 
1000 mg should be administered at least 30 minutes before additional nivolumab and 
ipilimumab administrations.  If necessary, corticosteroids (recommended dose: up to 
25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms:  
(Severe reaction) 
 
Grade 3 symptoms: prolonged [i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal 
impairment, pulmonary infiltrates]).   
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated).  
Nivolumab and ipilimumab will be permanently discontinued 
 
Immediately discontinue infusion of nivolumab and ipilimumab.  Begin an IV 
infusion of normal saline, and bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
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.  Patient should be 
monitored until the investigator is comfortable that the symptoms will not recur.   
 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis.  Remain at bedside and monitor patient until recovery from symptoms.  
 
Other guidance: 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids).  Additional 
treatment prior to next dose as per guidelines above.  
 
Please note that late occurring events including isolated fever and fatigue may 
represent the presentation of systemic inflammation.  Please evaluate accordingly.  
 
6.3.2  
Nivolumab and Ipilimumab Overall Dosing Delays 
All dose management decisions apply to both ipilimumab AND to nivolumab. When 
assessing dose management, please use the tables below and refer to the 
Nivolumab/Ipilimumab Management Algorithms in Appendix II for further 
guidance.  
 
 
Decisions to delay nivolumab and ipilimumab dose must be made on specified safety 
criteria.  Treatment with nivolumab and ipilimumab will be delayed (or discontinued) 

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if the subject experiences at least one adverse event, specified below, considered by 
the investigator to be “possibly,” probably,” or “definitely” related to nivolumab 
and/or ipilimumab treatment. 
Adverse events considered “unlikely” or “unrelated” to nivolumab and
ipilimumab treatment do not require a dose delay.
A delay of up to 6 weeks is permitted to allow for resolution of adverse events.
Grade 1 
Management/Next Dose for Nivolumab/Ipilimumab
No change in dose.  
Grade 2 
Hold until Grade 1 OR baseline (exceptions as noted below). 
Grade 3 
Hold until Grade 1 OR baseline and patient no longer on steroid 
treatment if initiated (exceptions as noted below). Permanently 
discontinue for events with a high likelihood of morbidity or 
mortality with recurrent events. 
Grade 4 
Discontinue nivolumab/ipilimumab.
Recommended management:  As clinically indicated  
o
Any Grade 2 drug-related uveitis or 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 should 
discontinue nivolumab/ipilimumab.
o
Any Grade 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying organ 
pathology with electrolyte replacement, hormone replacement, insulin or that 
does not require treatment does not require discontinuation.  
o
Any AE, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject 
with continued study drug dosing should discontinue nivolumab/ipilimumab.  
Skin Rash and Oral
Lesions
Management/Next Dose for Nivolumab/Ipilimumab
Grade 1 
Continue nivolumab/ipilimumab *. Consider symptomatic therapy (e.g., 
antihistamines, topical steroids).
Grade 2 
Hold* until ≤ Grade 1 .  Resume dose.  
Grade 3 
Hold* until ≤ Grade 1.  Resume dose at investigator discretion  
Grade 4 
Discontinue nivolumab/ipilimumab
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral 
lesions of bullous pemphigus/pemphigoid.  Pruritus may occur with or without skin rash and 

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should be treated symptomatically if there is no associated liver or GI toxicity.  Note skin rash 
typically occurs early and may be followed by additional events particularly during steroids 
tapering. If Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or drug reaction 
with eosinophilia and systemic symptoms (DRESS) is suspected, withhold 
nivolumab/ipilimumab and refer the patient for specialized care for assessment and treatment. If 
SJS, TEN or DRESS is diagnosed, permanently discontinue nivolumab/ipilimumab.  
Recommended management:  AE management guidelines 
Liver Function:  
AST, ALT, 
Bilirubin
Management/Next Dose for Nivolumab/Ipilimumab
Grade 1
Continue nivolumab/ipilimumab. Increase frequency of LFT monitoring. 
Grade 2 
Hold until Grade 1 or baseline.  Increase frequency of monitoring to every 
3 days. If returns to baseline, resume routine monitoring and resume 
nivolumab/ipilimumab. If elevations persist >5-7 days, start 0.5-1 
mg/kg/day methylprednisolone or oral equivalent. Resume dose at 
investigator discretion.
Grade 3 
Hold until Grade 1 or baseline. Start 1 to 2 mg/kg/day 
methylprednisolone IV or IV equivalent.
Grade 4 
Discontinue nivolumab/ipilimumab. Start 2 mg/kg/day 
methylprednisolone IV or IV equivalent.
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.  
Holding drug to evaluate liver function test (LFT) changes and early treatment are 
recommended.  LFT changes may occur during steroid tapers from other events and may occur 
together with other GI events including cholecystitis/pancreatitis. 
Please note:  Grades for liver function follow UNL rather than multiples of baseline.
Recommended management:  see Hepatic AE management algorithm 
  
Grade 1 
Management/Next Dose for Nivolumab/Ipilimumab
Continue treatment. Symptomatic treatment for diarrhea.
Grade 2 
Hold nivolumab/ipilimumab.  Symptomatic treatment for diarrhea. If 
improves to grade 1, resume dose. If symptoms persist >5-7 days, start 
0.5-1 mg/kg/day methylprednisolone or oral equivalent. Resume dose at 
investigator discretion when improved to grade 1.
Grade 3 
Hold nivolumab/ipilimumab. Start 1 to 2 mg/kg/day methylprednisolone 
IV or IV equivalent. Resume dose at investigator discretion when 
improved to grade 1.
Grade 4 
Discontinue nivolumab/ipilimumab. 

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See GI AE Algorithm for management of symptomatic colitis.   
Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care. Evaluation for all patients for additional causes includes C. diff, acute and self-
limited infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.   
Recommended management:  see GI AE management Algorithm  
  
  
Pancreatitis 
Amylase/Lipase   
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Continue dose if asymptomatic at investigator discretion.   
Grade 2  
Continue dose if asymptomatic at investigator discretion.  If 
symptomatic, resume at same dose  when resolved  
Grade 3  
Continue at same dose if asymptomatic at investigator discretion.  
Patients should have imaging study when clinically indicated (grade 3 
symptomatic pancreatitis) before resuming treatment.  Patients who 
develop diabetes mellitus should discontinue nivolumab/ipilimumab.   
Grade 4  
Hold until grade 2.  Resume dose if asymptomatic.  Patients who are 
symptomatic should have imaging study prior to resuming treatment 
and when clinically indicated.  Patients who develop grade 4 
symptomatic pancreatitis or diabetes mellitus should discontinue 
nivolumab/ipilimumab.   
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes 
mellitus and diabetic ketoacidosis (DKA).  Lipase elevation may occur during the period of 
steroid withdrawal and with other immune-mediated events or associated with colitis, hepatitis, 
and patients who have asymptomatic lipase elevation typically have self-limited course and 
may be retreated.  
 
Recommended management of symptomatic pancreatitis: see the Hepatic AE Management 
Algorithm. 
  
  
Pneumonitis  
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Hold dose pending evaluation and resolution to baseline including 
baseline pO2.  Resume dose after pulmonary and/or infectious disease 
(ID) consultation excludes lymphocytic pneumonitis.   
Grade 2  
Hold dose pending evaluation. Resume dose after pulmonary and/or ID 
consultation excludes ipilimumab/nivolumab and associated 
lymphocytic pneumonitis as the cause of the pneumonitis.  Resume 
nivolumab/ipilimumab if improves to grade 1. If symptoms persist >5-7 
days, start 0.5-1 mg/kg/day methylprednisolone or oral equivalent. 
Resume dose at investigator discretion when improved to grade 1. 

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Grade 3  
Hold dose pending evaluation.  Resume dose after pulmonary and/or ID 
consultation excludes ipilimumab/nivolumab and associated 
lymphocytic pneumonitis as the cause of the pneumonitis; otherwise, 
discontinue nivolumab/ipilimumab. Hospitalize, start 2 to 4 mg/kg/day 
methylprednisolone IV or IV equivalent. 
Grade 4  
Discontinue nivolumab/ipilimumab. Hospitalize, start 2 to 4 mg/kg/day 
methylprednisolone IV or IV equivalent. 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified, including influenza.  Most 
patients with respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be 
required and analysis of lavage fluid for lymphocytic predominance may be helpful.  Patients 
with new lung nodules should be evaluated for sarcoid like granuloma.  Please recommend 
seasonal influenza killed vaccine for all patients. Consult Pulmonary and Infectious Disease 
early. 
Recommended management:  See Pulmonary AE Management Algorithm   
  
  
Other GI 
Nausea/Vomiting   
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Continue dose.   
Grade 2  
Hold pending evaluation for gastritis, duodenitis, and other immune 
AEs or other causes.  Resume at same dose after resolution to ≤ Grade 
1.    
Grade 3  
Hold pending evaluation until ≤ Grade 1.  Resume dose.  If symptoms 
do not resolve within 7 days with symptomatic treatment, patients 
should discontinue nivolumab/ipilimumab.  
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
  
  
Fatigue 
Management/Next Dose for Nivolumab/Ipilimumab  
  
Grade 2 
Continue dose. 
Grade 3  
Hold until ≤ Grade 2.  Resume at same dose.  
Grade 4  
Discontinue nivolumab/ipilimumab.  
Fatigue is the most common AE associated with immune checkpoint therapy.  Grade 2 or 
greater fatigue should be evaluated for associated or underlying organ involvement including 
pituitary, thyroid, and hepatic, or muscle (CPK) inflammation.   
  
  
Neurologic events  
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Continue nivolumab/ipilimumab. Monitor symptoms.   

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Grade 2 
Hold dose pending evaluation and observation.  Start 0.5-1 mg/kg/day 
methylprednisolone or oral equivalent. Resume nivolumab/ipilimumab 
when improved to baseline. Resume nivolumab/ipilimumab for 
peripheral isolated n. VII (Bell’s palsy).  
Grade 3 
Discontinue nivolumab/ipilimumab. Start 1 to 2 mg/kg/day 
methylprednisolone IV or IV equivalent.
Grade 4 
Discontinue nivolumab/ipilimumab. Start 1 to 2 mg/kg/day 
methylprednisolone IV or IV equivalent.
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), GB syndrome, and myasthenia gravis should be off study treatment.
Recommended management:  See Neurologic AE Management Algorithm  
Management/Next Dose for Nivolumab/Ipilimumab
Grade 1 
*Hold pending evaluation for evidence of adrenal insufficiency or 
hypophysitis. Asymptomatic thyroid stimulating hormone (TSH) 
elevation may continue treatment while evaluating the need for thyroid 
replacement. 
Grade 2 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids, patients must be stable on no more than 
physiologic replacement corticosteroids for 2 weeks. 
Resume dose.  
Grade 3 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids, patients must be stable on no more than 
physiologic replacement corticosteroids for 2 weeks. 
Resume dose. 
Grade 4 
Discontinue nivolumab/ipilimumab. 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered Grade 3 events.  
Isolated thyroid or testosterone deficiency may be treated as Grade 2 if there are no other 
associated deficiencies and adrenal function is monitored.  
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of 
any kind.  *Note patients with thyroiditis may be retreated on replacement therapy.  Patients 
must be evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment.
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses of corticosteroids. 

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Please note that grading and for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic 
meningitis or encephalitis should be considered grade 3 events.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine 
testing including cortisol, ACTH, TSH and T4 must be obtained to document baseline.  
 
Recommended management:  See Endocrine Management Algorithm   
  
  
Renal 
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1.  Start 0.5-1 mg/kg/day methylprednisolone or oral 
equivalent. Resume dose.  
Grade 3  
Hold until ≤ Grade 1.  Start 0.5-1 mg/kg/day methylprednisolone or oral 
equivalent. Resume dose.  
Grade 4  
Discontinue nivolumab/ipilimumab. Start 1 to 2 mg/kg/day 
methylprednisolone IV or IV equivalent. 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever.   
  
 
Fever   
Management/Next Dose for Nivolumab/Ipilimumab  
Grade 1  
Evaluate and continue at dose.  
Grade 2  
Hold until ≤ Grade 1.  Resume at dose.  
Grade 3  
Hold until ≤ Grade 1.  Resume at dose.  
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever.   
See section 6.4.1 – Treatment of Nivolumab/Ipilimumab -Related Infusion Reactions.    
  
 
 
Cardiac *   
Management/Next Dose for  
Nivolumab + Ipilimumab Cardiac Toxicities  
Grade 1 
Hold dose pending evaluation and observation.**  Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain 
history EKG, CK (for concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 days.  If troponin and labs normalize 
without evidence of myocarditis may resume therapy.   If labs worsen 
or symptoms develop then treat as below.   

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Cardiac *   
Management/Next Dose for  
Nivolumab + Ipilimumab Cardiac Toxicities  
Grade ≥2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone and immune suppression as clinically indicated.   If 
no improvement within 24 hours consider adding either infliximab, 
ATG or tacrolimus. May resume therapy if there is a return to baseline 
and myocarditis is excluded or considered unlikely. 
Grade ≥2 with 
confirmed 
myocarditis   
Discontinue nivolumab and ipilimumab.  Admit to CCU (consider 
transfer to nearest Cardiac Transplant Unit).  Treat as above.  Consider 
high dose methylprednisolone   
Add ATG or tacrolimus if no improvement. Discontinue nivolumab and 
ipilimumab. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  Protocol Agents 
 
Investigational Agents 
The investigational agents administered in NRG-BN007, ipilimumab and nivolumab,  are 
being made available under an IND sponsored by CTEP.  For ipilimumab and nivolumab, 
determination of whether an adverse event meets expedited reporting criteria, see the 
reporting table in Section 7.4 of the protocol. 
Commercial Agents 
The commercial agent in NRG-BN007 is temozolomide. For temozolomide, determination 
of whether an adverse event meets expedited reporting criteria, see the reporting table in 
Section 7.4 of the protocol. 
 
 
7.2 Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 

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PRO-CTCAE is not intended for expedited reporting, real time review, or safety 
reporting. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
Clinician graded CTCAE is the AE (adverse event) safety standard.  PRO-CTCAE items 
are to complement CTCAE reporting.  Patients will respond to PRO-CTCAE items but 
no directed action will be taken.  Patient responses to the PRO-CTCAE may lead to 
additional assessment by the clinician; the responses should be reviewed.  PRO-CTCAE 
is not intended for expedited reporting, real time review or safety reporting. PRO-
CTCAE data are exploratory and not currently intended for use in data safety monitoring 
or adverse event stopping rules. 
NOTE:  PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action.  PRO-CTCAE may lead to additional 
evaluation by the clinician; their response should not be overlooked.   
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP Study 
Agents (09-FEB-2021) 
 
7.3.1 
Ipilimumab 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ipilimumab (MDX-010, NSCs 732442 and 720801) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 

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Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for 
Ipilimumab (MDX-010). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.10, March 29, 20191 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other (episcleritis)2  
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis2 (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
General disorders and 
administration site conditions - 
Other (Systemic inflammatory 
response syndrome [SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)4 
  
INFECTIONS AND INFESTATIONS 
  
 
 
 Infections and infestations - 
Other (aseptic meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
  
 
Aspartate aminotransferase 
increased 
 
  
 
 
Lymphocyte count decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (exacerbation 
of pre-existing diabetes mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle weakness 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Ataxia 
  
 
Facial nerve disorder2 
 
  
 
Guillain-Barre syndrome2 
 
  
 
Headache 
 
  
 
Myasthenia gravis2 
 
  
 
 
Nervous system disorders - 
Other (immune-mediated 
encephalitis)2 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - Other 
(mental status changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - Other 
(granulomatous tubulointerstitial 
nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
Respiratory failure 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(lung infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, 
autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic 
colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, and adrenal insufficiency), ocular manifestations (e.g., uveitis, iritis, 
conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 
additional treatments. 

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3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving 
allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These complications may occur 
despite intervening therapy between receiving Ipilimumab (MDX-010) and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Ipilimumab (MDX-010) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - 
Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal disorders - 
Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; 
Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) 
 
 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 

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7.3.2  
Nivolumab (NSC 748726) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Nivolumab (NSC 748726) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
Nivolumab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
     Version 2.4, December 2, 20201 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3   
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(immune-mediated hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - 
Other (sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 
(Gr 2) 
 
CD4 lymphocytes decreased 
 
 CD4 lymphocyte decreased 
(Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy   
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders - 
Other (immune-mediated 
nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Nivolumab being a member of class of agents involved in the inhibition of “immune checkpoints”, may 
result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation and 
proliferation.  This may result in autoimmune disorders that can include (but are not limited to) 
autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic 
meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune 
thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia 
systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic encephalitis, 
hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders 
(e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may 
occur despite intervening therapy between receiving Nivolumab and allo-SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
 
 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal 
disorders - Other (mouth sores); Vomiting 

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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune 
thrombotic microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory 
infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other 
(protein total decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder 
- Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
 
7.4 
Adverse Events for Commercial Study Agents: Temozolomide  
Refer to the package insert for detailed pharmacologic and safety information 
 
 
7.5 
Adverse Events and PRO-CTCAE (09-FEB-2021) 
PRO-CTCAE 
The PRO-CTCAE instrument will be used to assess patient reported toxicity outcomes.  
 
PRO-CTCAE is a validated instrument developed by the National Cancer Institute to assess 
clinical trial toxicity outcomes by patient report; it complements information collected by 
physician-reported CTCAE. PRO-CTCAE is available in English and French for this study.  
 
Assessments will be collected as specified in the Section 4 assessment tables. 
 
The patient-reported AEs that will be assessed using PRO-CTCAE are listed in the table 
below. These adverse events are considered expected and, if reported, should also be 
clinician graded using the CTCAE v.5 
 

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CTCAE v.5  
PRO-CTCAE Items With Attributes 
Abdominal pain 
Abdominal pain (frequency, severity, interference 
Rash maculo-papular 
Rash (presence) 
Pruritus 
Itching (severity) 
Myalgia 
Muscle pain (frequency, severity, interference 
Arthralgia 
Joint pain (frequency, severity, interference 
Injection site reaction 
Pain and swelling at injection site (presence) 
Chills 
Chills (frequency, severity) 
Headache 
Headache (frequency, severity, interference) 
Mucositis oral 
Mouth/throat sores (severity, interference) 
Dry skin 
Dry skin (severity) 
Alopecia 
Hair loss (amount) 
Cough 
Cough (severity, interference) 
Dysgeusia 
Taste changes (severity) 
Dizziness 
Dizziness (severity, interference) 
Edema 
Swelling (frequency, severity, interference) 
Hot flashes 
Hot flashes (frequency, severity) 
 
7.6 
Expedited Reporting of Adverse Events 
All adverse events (AEs) are submitted for expedited reporting protocol-specific rules 
evaluation using the Medidata Rave data management system. All AEs will be evaluated 
by the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) to determine whether expedited reporting is recommended based on a set of 
programmed expedited reporting rules. AEs identified as meeting the programmed 
expedited reporting requirements can then be submitted in CTEP-AERS. A deep link in 
Rave will take the user directly to CTEP-AERS where the expedited report may be 
completed and submitted via CTEP-AERS. 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the link in RAVE.  
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP by telephone at 301-897-7497 and NRG Oncology by phone at 1-215-
574-3191.  An electronic report must be submitted immediately upon re-establishment of 
the Internet connection. 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
7.6.1 Expedited Reporting Methods 
x Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour 
notification must be submitted within 24 hours of learning of the adverse event Each 
CTEP-AERS-24-hour notification must be followed by a complete report within 5 
days.  

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x Supporting source documentation is requested by CTEP as the IND sponsor for this 
study and by NRG as needed to complete adverse event review. Supporting source 
documentation should include the protocol number, patient ID number, and CTEP-
AERS ticket number on each page; fax supporting documentation to CTEP at 301-
897-7404 and contact NRG Oncology at 1-215-574-3191.  A serious adverse event 
that meets expedited reporting criteria outlined in the AE Reporting Tables but is 
assessed by the CTEP-AERS as “an action not recommended” must still be reported 
to fulfill NRG safety reporting obligations. Sites must bypass the “NOT 
recommended” assessment; the CTEP-AERS allows submission of all reports 
regardless of the results of the assessment.  
7.6.2 Expedited Reporting Requirements for Adverse Events  
 
Arm 1 Expedited Reporting Requirements 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 

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x 
Unexpected Grade 4 and all Grade 5 AEs 
 
Clinician graded CTCAE is the AE safety standard. PRO-CTCAE items are to complement 
CTCAE reporting.  Patients will respond to PRO-CTCAE items but no protocol directed 
action will be taken.   
 
 

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Arm 2: Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERs within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
Clinician graded CTCAE is the AE safety standard. PRO-CTCAE items are to complement 
CTCAE reporting.  Patients will respond to PRO-CTCAE items but no protocol directed 
action will be taken.  
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 

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None 
 
7.6.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.6.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
AE reporting unless otherwise specified. 
 
7.7 
Routine Reporting Requirements for Adverse Events (09-FEB-2021) 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
7.7.1 Reporting PRO-CTCAE  
Symptomatic Adverse Events reported by patients through PRO-CTCAE are not to be 
used for direct safety reporting. 
 
7.8  
NRG Responsibility for Reporting Serious Adverse Events to Health Canada  
NRG will provide expedited reports of SAEs to Health Canada for those events which 
meet regulatory requirements for expedited reporting, i.e. events which are BOTH serious 
AND unexpected, AND which are thought to be related to protocol treatment.  
 
7.9 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 90 days after the last dose of study drug must be 

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reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (17-JAN-2023) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to NCI-
sponsored trials to register and with their qualifications and credentials and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). The 
RCR is a self-service online person registration application with electronic signature and 
document submission capability. 
 
RCR utilizes five person registration types. 
x Investigator (IVR) — MD, DO, or international equivalent; 
x Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
x Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
x Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and; 
x Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
 
 
 
 
 
RCR requires the following registration documents: 

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Documentation Required 
 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
✔ 
✔ 
✔ 
 
 
GCP training 
 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
 
✔ 
 
 
 
 
CV (optional) 
 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account with a linked ID.me account (the latter required immediately 
for the new CTEP-IAM accounts, and by July, 2023 for all users)  participate in NCI clinical 
trials supported by the Cancer Trials Support Unit (CTSU) and to access all CTEP and CTSU 
websites and applications. In addition, IVRs and NPIVRs must list all clinical practice sites and 
Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR 
to allow the following: 
x Addition to a site roster; 
x Selection as the treating, credit, or drug shipment investigator or consenting person 
OPEN; 
x Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
x Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval) or consenting/treating/drug shipment investigator in OPEN or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1       Cancer Trials Support Unit Registration Procedures  (17-JAN-2023) 
 
This study is supported by the NCI CTSU. 
 
IRB Approval  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies open to 
the National Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases. In addition, U.S.-based sites must accept the NCI 
CIRB review to activate new studies at the site after March 1, 2019. Local IRB review 
will continue to be accepted for studies that are not reviewed by the CIRB, or if the study 
was previously open at the site under the local IRB. International sites should continue to 

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submit Research Ethics Board (REB) approval to the CTSU Regulatory Office following 
country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
x Local IRB documentation; 
x IRB-signed CTSU IRB Certification Form; and/or 
x Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria  for the site to be able have an 
Approved status following processing of the IRB/REB approval record: 
x Have an active CTEP status; 
x Have an active status at the site(s) on the IRB/REB approval and on at least one 
participating roster; 
x If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
x Include the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
x List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
x Have the appropriate CTEP registration type for the protocol.  
 
 
Additional Requirements for Protocol NRG-BN007 Site Registration 
Additional site requirements to obtain an approved site registration status include: 
x An active Federal Wide Assurance (FWA) number; 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
x An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only);  
x Compliance with all applicable protocol-specific requirements (PSRs);  

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x Neurocognitive Function Testing Certification  
Institutions must meet certification requirements for administering neurocognitive 
assessments. Upon review and successful completion of the Neurocognitive 
Certification, Dr. Wefel will notify the certified examiner, NRG Headquarters, 
and CTSU that the examiner has successfully completed this requirement.  
 
See protocol-specific material on CTSU members’ website for certification 
requirements 
 
x Radiation/Imaging Requirements 
This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to 
add or remove associated providers, access the Provider Association page from 
the Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at 
least one Imaging and Radiation Oncology Core (IROC) provider to participate 
on trials with an RTI component. Enrolling sites are responsible for ensuring that 
the appropriate agreements and IRB approvals are in place with their RTI 
provider. An individual with a primary role on  a treating site roster can update 
the provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster 
Browser under the RUMS section on the CTSU website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
Houston to verify credentialing status or to begin a new modality credentialing 
process.  
 
To complete protocol-specific credentialing the RTI provider or enrolling site 
should follow instructions in protocol section 8.2 to submit documentation or 
other materials to the designated IROC Quality Assurance (QA) center. Upon the 
IROC QA center approving the RTI provider for the study modality, the 
institution will need to upload their approval letter to the  Regulatory and Roster 
Maintenance applications to comply with the protocol-specific requirement, 
unless otherwise noted at the bottom of the IROC Credentialing Approval 
notification. IROC will continue to copy the provider and/or enrolling site on 
modality approvals. 
 
Upon site registration approval in the Regulatory application, enrolling site may 
access OPEN to complete enrollments. If the study is using the IROC integration 
suite, the enrolling site will select their credentialed provider treating the subject in 
the OPEN credentialing screen and may need to answer additional questions related 
to treatment in the eligibility checklist.   
 
Additional Requirements for Sites in Canada  
 

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Prior to clinical trial commencement, sites in Canada must also complete and submit 
the following documents to the CTSU via the Regulatory Submission Portal: 
 Clinical Trial Site Information Form,  
 Qualified Investigator Undertaking Form  
 Research Ethics Board Attestation Form 
 Protocol Signature Page  
 Investigator Brochure Signature Page  
 List of Laboratories  
 SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  
 SIV/Training Confirmation of Completion Form – Qualified Investigator (please 
refer to the activation memo for details)  
 IRB/REB approved consent (English and native language versions*; Submit to 
NRG Regulatory (CanadianRegulatory@NRGOncology.org) prior to IRB/REB 
submission for review. 
*Translation of documents is critical. The institution is responsible for all 
translation costs. All regulatory documents, including the IRB/REB approved 
consent, must be provided in English and in the native language. Certification of 
the translation is optimal but due to the prohibitive costs involved NRG will 
accept, at a minimum, a verified translation. A verified translation consists of the 
actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational letterhead/stationery that includes the 
professional title, credentials, and signature of the translator as well as signed 
documentation of the review and verification of the translation by a neutral third 
party. The professional title and credentials of the neutral third party translator 
must be specified as well. 
 
The following items are collected By NRG Oncology Regulatory on a yearly or biyearly 
basis:   
 IRB/REB Membership Roster  
 Laboratory Certificates and Normal Values  
 CVs for Qualified Investigator and Sub-Investigators noted on the DTL 
 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster. To view/download site registration forms:   
x Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; or linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for all 
users); 
x Click on Protocols in the upper left of the screen 

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o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select NRG and 
protocol number NRG-BN007. 
x 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go 
to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-
866-651-CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction 
and support. 
 
 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
x Click on Regulatory  at the top of the screen; 
x Click on Site Registration; and 
x Enter the site’s  5-character CTEP Institution Code and click on Go: 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
Delegation of Tasks Log (DTL)  
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study. 
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 

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completing the DTL are available in the Help Topics button in the DTL application and 
describeDTL task assignments, CI signature, and CTEP registration requirements,as well 
as include a Master Task List. 
 
8.2       RT-Specific Pre-Registration Requirements  (17-JAN-2023) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, IROC Houston will notify 
your institution when all credentialing requirements have been met and the institution is 
RT credentialed to enter patients onto this study.  IROC will automatically send the 
approval to the Regulatory Support System (RSS) to comply with the protocol-specific 
requirement, unless otherwise noted at the bottom of the IROC Credentialing Approval 
notification..   
 
 
 
RT   
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment 
Modality 
 
Photon 
Key Information 

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Credentialing Status 
Inquiry Form 
X 
To determine if your institution has completed the 
requirements above, please complete a “Credentialing 
Status Inquiry Form” found under Credentialing on the 
IROC Houston QA Center website 
(http://irochouston.mdanderson.org). 
Facility 
Questionnaire 
X 
The IROC Houston electronic facility questionnaire 
(FQ) should be completed or updated with the most 
recent information about your institution.  To access this 
FQ, email irochouston@mdanderson.org to receive 
your FQ link. 
Phantom Irradiation 
X 
An IMRT Head & Neck phantom study provided by the 
IROC Houston QA Center must be successfully 
completed. Instructions for requesting and irradiating the 
phantom are found on the IROC Houston web site 
(http://irochouston.mdanderson.org).  
IGRT 
X 
Only institutions interested in using reduced margins 
will be required to compete this credentialing step. 
Instructions for IGRT credentialing may be found on the 
IROC Houston website 
(http://irochouston.mdanderson.org).   
 
Credentialing Notification Issued to: 
Institution 
Institution will be credentialed for the treatment modality that they intend 
to use on all patients. IROC Houston QA Center will notify the institution 
and NRG Headquarters that all desired credentialing requirements have 
been met. 
 
 
8.2.1 Digital RT Data Submission to NRG Using TRIAD 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
TRIAD Access Requirements: 
x A valid CTEP-IAM account and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for all 
users); 
x Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR; 
x TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD and may submit images for credentialing purposes, or for enrollments to which 
the provider is linked in OPEN. 
 

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TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3       Patient Enrollment  (17-JAN-2023)Patient registration can occur only after evaluation 
for eligibility is complete, eligibility criteria have been met, and the study site is listed as 
‘approved’ in the CTSU RSS.  Patients must have signed and dated all applicable consents 
and authorization forms.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
x A valid CTEP-IAM account and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023, for all 
users); 
x To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
x A Delegation of Tasks Log (DTL) is required for the study and the registrar(s) 
must hold the OPEN Registrar task on the DTL for the site; and 
x Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. A DTL is required for the study, and the IVR 
or NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
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x Patient has met all eligibility criteria within the protocol stated timeframes; and  
x All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
8.3.2 Patient-Initiated Consent Withdrawal from the Study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no 
future follow up data to be submitted to NRG Oncology), the study applicable form 
should be completed in Medidata Rave to report the patient’s consent withdrawal. 
NOTE: This should not be done if the patient has only chosen to stop protocol treatment 
and is willing to still be followed.  
 
8.4 
Medidata Patient Cloud ePRO Registration (08-APR-2022) 
This study includes the use of Medidata’s Patient Cloud mobile ePRO (electronic patient-
reported outcomes) application. The Patient Cloud ePRO application allows patients to 
report clinical trial information (patient reported outcomes (PROs)) directly from their 
mobile devices into the Medidata Clinical Cloud. In this document ePRO application 
refers to the application accessed by the site via iMedidata (for patient registration) and 
Rave (to view completed ePRO forms), and Patient Cloud mobile app refers to the app 
accessed by the patient on a mobile device. After the patient is registered to the trial via 
OPEN, and if the patient is willing to participate in electronic data collection, the site 
staff will then complete a registration for the patient to the ePRO application through 
iMedidata. Site staff must complete the required eLearning (assigned in iMedidata) for 
the ePRO application before registering a patient. Information about the training is in the 
ePRO Appendix. The registration to the ePRO application will create a unique patient 
registration code that the site staff will provide to the patient. The patient (with assistance 
from the site staff) should be instructed to download the appropriate ePRO mobile app 
onto his/her own device (IOS, Android, phone or tablet) and use the unique patient 
registration code to create an account. Once the patient's account is set up, the patient will 
be able to complete the submission of patient reported outcomes electronically for the 
trial.   
 
 
There are multiple versions of the Patient Cloud mobile ePRO app available.  Ensure that 
the correct version of the Patient Cloud mobile app is downloaded by the patient by 
verifying the correct version with the study team. Note only one version of the app is 
active per protocol and this protocol is using: 
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For sites providing a shared institutional device for use by multiple patients on site:  
x 
The site staff should assist the patient with registration to the Patient Cloud mobile 
ePRO application and access to the Patient Cloud mobile app, and the patient can 
then complete the electronic data submission independently.  Site staff may need to 
assist patients with logging on to the device at each visit. 
8.4.1 CRA Patient Registration Instructions for ePRO 
Site staff must complete the required ePRO online training (assigned in iMedidata) for 
studies using the ePRO application before registering a patient.  Reference materials for the 
Patient Cloud (current) app can be found at the link below; the landing page contains general 
information as well as links to additional resources on the left side of the screen: 
x Patient Cloud (current) Medidata Learning Tool 
The subject registration process starts in iMedidata.  To register a patient log into iMedidata 
and perform the following steps: 
i. Select the Patient Cloud Registration link for your study 
ii. From the patient management app, select your STUDY and SITE from the drop 
downs and click Launch. 
iii. Register your first patient. Create a subject ID and select a Country / Language from 
the drop down (required data fields). The subject initials are optional, but are helpful 
in identifying which subject ID maps with which activation code. When finished, 
click Add. 
iv. The subject will be added and will include the date the patient was added, the subject 
ID, subject initials, (if included) and a unique auto-generated activation code. The 
activation code is unique for each patient and linked to the subject ID, it is not 
interchangeable. In addition, there is a status section, which indicates if the patient 
has registered. When the patient has registered the status will change from "invited" 
to "registered". 
 
9. DRUG INFORMATION  
 
9.1   
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-

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supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Sites may request an initial 4 vials of ipilimumab and 5 vials of nivolumab once a 
patient has enrolled to Step 1 registration. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status.  Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
 
Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator:  IBCoordinator@mail.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 

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9.2  
Investigational Study Agent: Ipilimumab (NSC 732442)  
 (17-JAN-2023) 
Sites must refer to the Investigator Brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See Section 9.1. 
 
Chemical Name or Amino Acid Sequence: 4 polypeptide chains, 2 identical heavy chains 
with 447 amino acids and 2 identical light chains consisting of 215 amino acids. 
 
Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
 
Classification: Human monoclonal antibody 
 
M.W.: 147,991 Daltons 
 
Mode of Action: Ipilimumab is specific for the CTLA4 antigen expressed on a subset of 
activated T-cells. CTLA4 interaction with the B7 molecule, one of its ligands expressed on 
professional antigen presenting cells, can down-regulate T-cell response. Ipilimumab is, 
thought to act by blocking the interaction of CTLA4 with the B7 ligand, resulting in a 
blockade of the inhibitory effect of T-cell activation.  The CTLA4/B7 creates the 
interaction.  
 
Description: Ipilimumab is a fully human immunoglobulin (IgG1N) with two 
manufacturing processes – ongoing trials have been using substances manufactured using 
Process B.  New clinical trials will be using ipilimumab that is manufactured by Process 
C. The Process C has been developed using a higher producing sub-clone of the current 
Master Cell Bank, and modified cell culture and purification steps.  
  
How Supplied:. In 2023, PMB will transition to a 50 mg/10 mL (5 mg/mL) vial, which 
will replace the 200 mg vial. The 50 mg vial is packaged in a 10-cc Type I flint tubing glass 
vial, stoppered with a 20-mm gray butyl rubber stopper, and sealed with a 20-mm 
aluminum flip-off seal. Each vial includes a 0.7-mL overfill for vial, needle, and syringe 
(VNS) holdup. 
Eachvial is a Type I flint tubing glass vial with gray butyl rubber stoppers and sealed with 
aluminum flip-off seals. 
 
 
Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 

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Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
aIncludes 2.6 mL overfill. 
bNitrogen is used to transfer the bulk solution through the pre-filled and sterilizing 
filters into the aseptic area. 
 
Preparation:  Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, USP 
or 5% Dextrose Injection, USP in concentrations between 1 mg/mL and 4 mg/mL.  
Ipilimumab is stable in a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-ethylhexyl) 
phthalate) IV bag or glass container up to 24 hours refrigerated at (20 to 80 C) or at room 
temperature/ room light.  
 
Recommended safety measures for preparation and handling include protective clothing, 
gloves, and safety cabinets. 
  
Storage: Store intact vials refrigerated at (20 to 80 C), protected from light.  Do not freeze. 
 
Stability: Shelf-life surveillance of the intact vials is ongoing.  Solution as described above is 
stable up to 24 hours refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  Use prepared IV 
solution immediately. Discard partially used vials.  
 
Route(s) of Administration: Intravenous infusion.  Do not administer ipilimumab as an IV 
push or bolus injection. 
 
Method of Administration:  Can use a volumetric pump to infuse ipilimumab at the 
protocol-specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, sterile, non-
pyrogenic, low-protein-binding filter (0.2 micron to 1.2 micron). 
 
Patient Care Implications:  Monitor patients for immune-related adverse events, e.g., 
rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism.  If you 
suspect toxicity, refer to the protocol guidelines for ruling out other causes. 
 
9.3 
Investigational Study Agent: Nivolumab (NSC 748726) (09-FEB-2021) 
Sites must refer to the Investigator Brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See Section 9.1. 
 
Amino Acid Sequence:   4 polypeptide chains, which include 2 identical heavy chains 
with 440 amino acids and 2 identical light chains. 
 
Other Names:   BMS-936558, MDX1106 
 
Classification:   Anti-PD-1MAb 

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M.W.:  146,221 Daltons 
 
Mode of Action:   Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is a negative 
regulatory receptor expressed by activated T and B lymphocytes. Binding of PD-1 to its 
ligands, programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the down-
regulation of lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 
and PD-L2.  Inhibition of the interaction between PD-1 and its ligands promotes immune 
responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. 
 
Description:   Nivolumab Injection is a clear to opalescent, colorless to pale yellow 
liquid; light (few) particulates may be present. The drug product is a sterile, 
nonpyrogenic, single-use, isotonic aqueous solution formulated in sodium citrate, sodium 
chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 
(Tween® 80) and water for injection.  Dilute solutions of hydrochloric acid and/or 
sodium hydroxide may be used for pH adjustment (pH 5.5-6.5). 
 
How Supplied:   Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with 
a 0.7 mL overfill.  It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-
laminated rubber stoppers and aluminum seals. 
 
Preparation:   Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose.  When the dose is based on 
patient weight (i.e., mg/kg), nivolumab injection can be infused undiluted or diluted to 
protein concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 
mg, or 480 mg flat dose), nivolumab injection can be infused undiluted or diluted so as 
not to exceed a total infusion volume of 160 mL. For patients weighing less than 40 
kilograms (kg), the total volume of infusion must not exceed 4 mL per kg of patient 
weight.  During drug product preparation and handling, vigorous mixing or shaking is to 
be avoided. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles. 
 
Storage:  Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and 
protected from light and freezing. Unopened vials can be stored at room temperature (up 
to 25°C, 77°F) and room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation 
of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
 

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Stability:  Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed 
within 24 hours of preparation.  If not used immediately, the infusion solution may be 
stored up to 24 hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of 
the total 24 hours can be at room temperature (up to 25°C, 77°F) and room light.  The 
maximum 8-hour period under room temperature and room light conditions includes the 
product administration period. 
 
CAUTION:  The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent.  Therefore, it is advised that the product be discarded 8 hours after 
initial entry. 
 
Route of Administration:  Intravenous infusion over 30 minutes.  Do not administer as an 
IV push or bolus injection. 
 
Method of Administration:  Administer through a 0.2 micron to 1.2 micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions:  The indirect drug-drug interaction potential of nivolumab 
was assessed using systemic cytokine modulation data for cytokines known to modulate 
CYP enzymes.  There were no meaningful changes in cytokines known to have indirect 
effects on CYP enzymes across all dose levels of nivolumab. This lack of cytokine 
modulation suggests that nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug interaction. 
 
Patient Care Implications: Women of childbearing potential (WOCBP) receiving 
nivolumab must continue contraception for a period of 5 months after the last dose of 
nivolumab. Men receiving nivolumab and who are sexually active with WOCBP must 
continue contraception for a period of 7 months after the last dose of nivolumab. 
 
Availability: Nivolumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. Nivolumab is provided to the 
NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the 
DCTD, NCI (see Appendix I). 
 
9.4 
Commercial Agent: Temozolomide 
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 
9.4.1 Adverse Events 
 
Please refer to the package insert. 
 
9.4.2 Availability/Supply  
 
Drug will be supplied commercially. Please see Section 5.1 for administration 
instructions. Please refer to the current FDA approved package insert provided with each 
drug and the site-specific pharmacy for toxicity information and instructions for drug 

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preparation, handling and storage. 
 
 
10. PATHOLOGY/BIOSPECIMEN 
 
10.1  Central Histology Confirmation (see Section 10.3.1 for submission logistics) 
Representative tissue blocks and corresponding H&E slides that contain diagnostic viable 
tumor are required.  As a guide, at least 1 square centimeter of tissue composed primarily 
of tumor must be present when a slide is cut from the block.  Note that the tissue blocks 
composed primarily of either normal tissue or necrotic tissue are inadequate for 
molecular analysis, as it depends on the presence of viable tumor tissue.  In cases where a 
single block has insufficient tumor, tissue for multiple blocks can be combined to ensure 
specimen adequacy.  Central pathology review will be conducted by the Neuropathology 
Co-Chair, Dr. Ken Aldape or another NRG Oncology-designated pathologist within 3 
business days of receipt of the H&E slide, tumor block and required paperwork. If the 
pathologist determines that the block that was sent is insufficient, the pathologist will 
contact the site in an attempt to obtain additional tissue.  Examples of adequate (RIGHT) 
and inadequate (LEFT) samples are shown below. 
 
10.2  
MGMT-STP27 Testing (see Section 10.3.1 for submission logistics) (08-APR-2022) 
Central testing of tumor MGMT methylation status is now a standard in trials of newly 
diagnosed GBM. We will use of the Illumina EPIC whole genome methylation array to 
determine differences in response to standard of care +/- experimental therapy.  The 
Illumina genome-wide methylation platform is a robust platform that is used at several 
centers for MGMT testing of glioma using the MGMT-STP27 measurement, and this 
model will be used for this protocol. It is considered a locked down assay and the use of 
the Illumina array to measure MGMT methylation determination has been previously 
validated (Bady 2016). It is compatible with the formalin-fixed, paraffin embedded tissue 
specimens that will be required for this trial and has the advantage to offer a rich source 
Examples of  inadequate (left) 
and adequate (right) tissue 
samples for study entry.  In 
both cases a slide was cut 
from the submitted block and 
stained with H&E.  Even 
though the slide on the left 
had tissue diagnostic of 
glioblastoma, the amount of 
tumor will be insufficient for 
molecular testing 
 

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of potential correlative biomarkers for retrospective analyses.  MGMT testing will be 
performed after Step 1 registration. Tissue must be received by the central lab on or 
before postoperative calendar day 23. If tissue cannot be received by postoperative 
calendar day 23, then patients may NOT enroll on this trial as central pathology review 
will not be complete in time for the patient to start treatment no later than 6 weeks 
following surgery. Results will generally be conveyed to NRG Oncology within 10 
business days of receipt of tissue. Patients with MGMT promoter without methylation 
will be randomized to a treatment arm. Patients with inadequate tissue for testing or with 
MGMT promotor with methylation status, indeterminate status, or with test failure will 
not be randomized and will not continue onto the treatment portion of the study. If the 
MGMT is methylated, the patient can be considered for enrollment on NRG-BN011.  The 
MGMT-STP27 profiling will be performed at the Laboratory of the Biomarkers Co-
Chair/designee who will be responsible for conducting these studies and evaluating the 
results. MGMT-STP27 testing was validated in the Clinical Laboratory Improvement 
Amendments (CLIA) laboratory at NYU Langone under CLIA ID number 33D2063212, 
expiration date at time of protocol activation: 6/30/2020. 
x Required Paperwork: ST, P4 forms and pathology report must be included with 
the pathology shipment and must include the NRG protocol number, patient case 
number, patient’s initials, and NRG institution number and name. Specimen 
Transmittal Form listing pathology materials being submitted for Central Tissue 
Evaluation 
x Central Pathology Review Form (P4) must be completed by the local pathologist. 
Include on the P4 form the name, telephone number, email, and fax number of the 
person to notify with the results of the tissue evaluation. 
x Pathology Report documenting that the submitted material contains tumor; the 
report must include the NRG protocol number, patient case number, and the 
patient’s initials. The patient’s name and/or other identifying information should 
be removed from the report. The surgical pathology numbers and information 
must NOT be removed from the report. 
x Tissue evaluation will be required for every case. Dr. Aldape or another NRG 
Oncology designated pathologist will review these materials. See protocol cover 
page for additional contact information. 
x Ship pathology material submissions Monday-Friday by overnight courier: 
x Notify NYU Center for Biospecimen Research and Development (CBRD)  
(cbrdtissuerequest@nyulangone.org) on or before the day of submission: (1) the 
case # that is being submitted for review; (2) the name of the contact person; (3) 
when to expect the sample; and (4) the shipping carrier and tracking number. 
x Central pathology (P4) results will be submitted electronically into the NRG 
database. An email notification about central pathology review results will be sent 
to the site when the P4 form is completed. If the patient is deemed eligible per 
pathology results, the lab will proceed with MGMT testing. 
x MGMT (P5) results will be submitted electronically into the NRG database. A 
second email notification with results of MGMT analysis will be sent to the site 
when the P5 has been completed. The site may then proceed to step 2 registration. 
Only Unmethylated cases may be randomized at step 2. Any other MGMT result 
would require step 2 registration to be reported as a “central review failure”. If 

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there is any tissue related-issue (e.g. not enough tissue), the site will be notified. 
x Since there is a narrow time window within which the review must be completed, 
submission of H& E and tumor blocks should be done as soon as possible to 
ensure sufficient time for review.  NYU CBRD must receive the H&E and tumor 
block within 23 days of surgery, to allow time for review and molecular testing. 
Samples received after this time cannot be accepted. If a sample is received 
beyond day 23 post op, the site will be notified and the tissue will be returned.  
x If the patient does not meet eligibility requirements, all tissue and forms will be 
returned to the participating submitting institution. The site must provide a return 
airbill. 
x If the tissue has already been evaluated by NYU Langone for enrollment to NRG-
BN011 and resulted as unmethylated, those results can be used for enrollment to 
NRG-BN007. The aforementioned paperwork (ST/P4/redacted Pathology report) 
must still be submitted to NYU Langone for NRG-BN007. An email with the 
attached paperwork must be sent to NYU Langone  
#mgmttesting@nyulangone.org and the NRG data managers indicating that 
the tissue has already been processed and the previous results should be used for 
enrollment to NRG-BN007.The following templated email can be used to notify 
the lab: 
Please find attached paperwork for  
BN007 case # __ __ __ __ __- BN007- _0_ _0_ _0_ __ __.  
 
This tissue for this case was processed for enrollment to  
BN011 case # __ __ __ __ __- BN011- _0_ _0_ _0_ __ __. 
 
Please transfer the results from the NRG-BN011 database to the NRG-BN007 
database.  
 
10.3 
Biospecimen Submission Tables (09-FEB-2021) 
10.3.1 Mandatory Specimen Submissions  
See detailed specimen collection/processing/shipping instructions on the protocol-
specific website. 
Mandatory Tissue Submission for Histology Confirmation and MGMT-STP27 Testing (per 
Sections 10.1-10.2) 
1) Required Forms: ST form, pathology reports with accession number and date of procedure with all 
other PHI redacted, P4 form with local pathologist review filled out. 
2) Shipping costs: Sites pay for FFPE shipping costs and returns. 
3) Residual Material: Will be shipped from NYU to the NRGBB-SF once testing is completed and 
banked for patients who consented to banking. If requested by site, the block will be punched using 
three 2mm punches to create a new block and the original block can then be returned to the site. 
For patients who did not consent to banking, the block will be returned when requested by the site.  
H&E slides will remain at the bank for all patients and cannot be returned.  
 
For shipments and questions, contact:  
 
NYU Center for Biospecimen Research and Development (CBRD)  
Medical Science Building  

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550 First Ave, MSB 238  
New York, NY 10016  
646-501-4268  
Email: #MGMTTesting@nyulangone.org 
 
Specimen Type 
Collection Time Points 
 
Collection Information 
and Requirements/ 
Instructions for Site 
Shipping  
 
H&E slide(s) of Primary 
tumor for central review 
 
Pre-treatment at time of 
surgery 
 
Can be duplicate cut H&E 
slide, does not have to be 
the diagnostic slide. 
 
Ship ambient to NYU 
CBRD by overnight 
courier 
FFPE Block (same as 
H&E) 
 
Pre-treatment at time of 
surgery 
 
FFPE block must be 
submitted for this trial.  
Blocks can be returned after 
testing is completed upon 
request. For patients who 
consented to banking the 
NRGBB will obtain 2mm 
punches prior to returning.  
Ship by overnight carrier 
to NYU CBRD (use cold 
packs during warm 
weather) 
 
10.3.2 Optional Specimen Submissions 
(Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as specified 
per protocol. Sites are not permitted to delete the specimen component from the protocol or from 
the sample consent.) 
 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
website. 
 
This study will include collection of biospecimens for future analyses. An amendment for any 
correlative science studies to be performed on biological samples will be submitted to CTEP, 
NCI for review and approval according to NCTN guidelines or via the Navigator portal after the 
trial has been reported. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 

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Specimen Submission for Biobanking for Future Research 
1) Kits are available for frozen biospecimens from the NRGBB-SF. Send an email to NRGBB@ucsf.edu 
requesting a kit. Allow 5-10 business days for kits to arrive by Fed EX Ground delivery. 
2) Shipping days for frozen specimens: Monday-Wednesday (US sites); Monday-Tuesday (Canadian 
sites). 
3) Shipping costs: One prepaid return label per case for batch shipping of frozen specimens will be 
provided in the US kits from the NRGBB-SF.  
4) Brief processing instructions are provided with kits, and complete versions are available in NRG-
BN007 Pathology and Correlative Science Instructions document posted on the CTSU website. 
 
For  questions, contact:  
NRG Oncology Biospecimen Bank – San Francisco  
UCSF Department of Radiation Oncology  
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271; NRGBB@ucsf.edu 
 
 
Specimen 
Collection Time 
Points 
 
Collection Information and  
Requirements/Instructions 
for Site 
Shipping 
 
H&E slide(s) of 
Primary tumor for 
central review 
Pre-treatment at time 
of surgery 
 
 
Pretreatment: Residual from 
histology/MGMT studies 
 
 
 N/A for site; to be 
batched shipped by 
NYU to NRG 
Oncology 
Biospecimen Bank 
San Francisco for 
patients who consent 
to biobanking of 
residual material. 
FFPE Block (same as 
H&E)  
 
 
 
Pre-treatment at time 
of surgery 
 
Pretreatment: Residual from 
histology/MGMT studies 
 N/A for site; to be 
batched shipped by 
NYU to NRG 
Oncology 
Biospecimen Bank 
San Francisco for 
patients who consent 
to biobanking of 
residual material. 
 
 
 
 
Serum- 10 ml Red top 
tube 
Pre-treatment- Prior to 
radiation 
 
During Treatment: 
Before initiation of 
cycles 1 and 3 of 
adjuvant therapy 
  
Process serum and aliquot a 
minimum of 0.5 ml into each 
of five (5) 1 ml cryovials 
Storage: Freeze and store at  
-80°C and ship frozen on dry 
ice 
 
Batch Ship frozen on 
dry ice by overnight 
courier NRG 
Oncology 
Biospecimen Bank 
San Francisco. 
 
 
 
 
Whole blood for 
Pre-treatment- Prior to 
Collect blood in EDTA tube, 
Batch Ship frozen on 

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DNA 5-10 mL of 
anticoagulated whole 
blood in EDTA tube 
#2 (purple/lavender 
top) and mix 
radiation 
 
-note: If site missed 
this collection, they 
may collect at any 
other time but must 
note this on the ST 
form when submitting 
mix and aliquot a minimum of 
1.5ml blood into three (3) 2ml 
cryovials. 
Freeze and store at  -80°C and 
ship frozen on dry ice 
dry ice by overnight 
courier to NRGBB-SF 
Plasma- 5-10 mL of 
anticoagulated whole 
blood in EDTA tube 
#1 (purple/ lavender 
top) and centrifuge 
Pre-treatment- Prior to 
radiation 
 
During Treatment: 
Before initiation of 
cycles 1 and 3 of 
adjuvant therapy 
Frozen plasma samples 
containing a minimum of 0.5 
mL per aliquot into five (5) 1 
mL cryovials 
Storage:  -80°C and ship 
frozen 
Forms: ST form 
Kits: request from NRG BB-
San Francisco 
Shipping: One prepaid label 
provided for each case for 
batch shipping 
Ship on dry ice by 
Priority Overnight 
Courier to NRG BB-
SF 
 
 
11. SPECIAL STUDIES (NON-TISSUE/BIOSPECIMEN) 
11.1 Neurocognitive Function (NCF) and Patient-Reported Quality of Life (QOL)  
(08-APR-2022) 
11.1.1  Background 
Toxicities seen with immune checkpoint inhibitor (ICI) therapies are much less 
predictable than with other cancer-directed therapies such as chemotherapy and are the 
result of immune activation against other organ systems.  The combination of ipilimumab 
/nivolumab (ipi/nivo) has a 59% rate of Grade III/IV immune related adverse events 
(irAEs) (Larkin 2019). Up to 12% of patients with non-central nervous system disease 
treated with ipi/nivo experience neurologic AEs (nAEs) including encephalopathies, 
hypophysitis, meningitis and headache, though the incidence of nAEs is likely 
underestimated (Cuzzubbo 2017). QOL measures have demonstrated clinically 
meaningful deterioration with this combination for role functioning as well as fatigue in 
patients with melanoma (Schadendorf 2017). Given the high frequency of AEs with 
immunotherapy, patient-reported outcomes have been shown to be an effective 
complementary approach to early toxicity monitoring (Tolstrup 2019).  Additionally, 
prior phase III have shown greater adverse symptom burden and functional interference, 
as well as decreased global health and motor function, following intensification of 
systemic therapy for newly diagnosed glioblastoma (Armstrong 2013). 
 
The occurrence of neurocognitive dysfunction as assayed by rigorous, clinically relevant 
and validated objective neurocognitive tests has not been systematically evaluated.  
Bartels et al (2019) found cognitive impairment in 37% of a heterogeneous sample of 
melanoma patients studied cross-sectionally.  They also found evidence of neuronal 
autoantibodies (e.g., anti-NMDAR) associated with history of ICI treatment, and a 
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patients.  Preclinical mouse models have shown that treatment with ICI therapy produces 
untoward effects on brain including mood disturbance, cognitive impairment, and 
neuroinflammation proving insight on a plausible mechanistic link between ICI therapy 
and nAEs that can influence QOL and cognitive dysfunction (McGinnis 2016).  
 
We hypothesize that the experimental ICI arm will be impact QOL and/or neurocognitive 
function in either of two ways: 1) due to augmented toxicity and neuroinflammation, the 
experimental ICI arm may demonstrate greater decline in QOL and/or neurocognitive 
function; or 2) due to enhanced tumor control, the experimental ICI arm may lead to 
better preservation of QOL and/or neurocognitive function.  Assessment of this 
hypothesis will provide important complementary information to the primary endpoints 
of this trial. In addition, this study will provide the first opportunity in a randomized 
control trial in GBM to evaluate these QOL and neurocognitive function impact of this 
immunotherapeutic approach. 
 
11.1.2  Neurocognitive Function (NCF) Assessments 
Neurocognitive function will be assessed using the Hopkins Verbal Learning Test – 
Revised (Benedict 1998), Trail Making Test (Tombaugh 2004), and the Controlled Oral 
Word Association test (Ruff 1996).  These tests were selected because they are widely used 
and standardized psychometric instruments that have been shown to be sensitive to the 
impact of cancer and the neurotoxic effects of cancer treatment in other clinical trials 
(Gilbert 2014; Meyers 2004; Wefel 2011). The tests have published normative data that 
take into account age and, where appropriate, education and gender.  The tests must be 
administered by a healthcare professional (eg, psychologist, physician, research associate, 
nurse) who is pre-certified by Dr. Wefel (see Section 8.1). 
 
11.1.3  Patient-Reported Quality of Life (QOL) and Adverse Events 
Assessments 
Symptom burden will be assessed using the MDASI-BT-modified (Armstrong. 2006). The 
MDASI-BT has demonstrated reliability and validity in the primary brain tumor patient 
population, including predictive validity for tumor recurrence (Armstrong, Mendoza et al. 
2006, Armstrong, Vera-Bolanos et al. 2011). The MDASI-BT was developed and validated 
for use in the brain tumor patient population and typically requires less than 4 minutes to 
complete.  It consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as 
you can imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms 
included on the instrument are those commonly associated with cancer therapies and those 
associated with neurologic and cognitive symptoms associated with the tumor itself.  The 
MDASI-BT also includes ratings of how symptoms have interfered with different aspects 
of the patient’s life in the last 24 hours. These interference items include: general activity, 
mood, work (includes both work outside the home and housework), relations with other 
people, walking, and enjoyment of life. The interference items are also measured on 0-10 
scales.  
 
Selected PRO-CTCAE items that have demonstrated sensitivity to immunotherapy-
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MDASI-BT in assessing immunotherapy-related adverse events.  Tolstrup and colleagues 
highlighted PRO-CTCAE items that correlate with CTCAE toxicities that very 
commonly or commonly occur with immunotherapy for melanoma patients.  Removing 
items that overlap with MDASI-BT, the following PRO-CTCAE items will be monitored: 
abdominal pain, rash, itching, muscle pain, joint pain, pain and swelling at injection site, 
headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, 
dizziness, swelling, and hot flashes.  The combination of these selected PRO-CTCAE 
items in addition to the MDASI-BT will address all FDA-recommended patient-reported 
outcomes for PD1/PDL1-directed immunotherapy trials (King-Kallimanis 2019). 
 
11.1.4 Administration of NRG-BN007 Patient-Completed Questionnaires and Neurocognitive 
Function (NCF) Assessments 
Patient Population 
All patients enrolled in NRG-BN007 who read English or French will be required to 
participate in the QOL/NCF study.  
 
Time Points for Administration 
See Section 4. 
 
Administration Instructions  
After the baseline assessment, questionnaires may be completed using ePRO (discussed 
in Section 8) or on paper at the visit.  If the patient chooses to complete on paper, 
questionnaires are to be administered at follow-up visits, so that when a follow-up visit is 
delayed, completion of QOL may also be delayed.  QOL should be administered during 
an office visit if at all possible, preferably while the patient is waiting to be seen.  Once 
the questionnaires are completed by the patient, the staff member should review it to 
ensure that no items were unintentionally left blank.  When absolutely necessary, it may 
also be administered by mail or phone.  The completed form will then be data entered 
into Medidata Rave. 
The QOL Coversheets must be completed in Medidata Rave for each scheduled 
patient assessment regardless of whether the assessment was completed or not.  The 
Coversheets notify the NRG SDMC that an assessment either has or has not been 
completed and collects other important information.  If the assessment was 
completed, the Coversheet collects the date of completion and method of completion.  
If the assessment was not completed, the Coversheet collects the reason it was not 
completed.  The questionnaires can be completed by phone or mail if they are not 
completed at an office visit.  
 
The Neurocognitive Function Verification form must also be completed in Medidata 
Rave whether or not the Neurocognitive Function assessment was completed. 
 
 
12. MODALITY REVIEWS 
12.1 
Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology Co-Chairs (Minesh Mehta, MD; Tony J. C. Wang, MD) or NRG 
Oncology Headquarters approved designee will perform an RT Quality Assurance 

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Review after IROC Philadelphia-RT has received complete data in TRIAD. The RT 
reviews will be ongoing and performed remotely. The final cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as IROC-Philadelphia RT 
has received complete data in TRIAD for all cases enrolled, whichever occurs first. The 
scoring mechanism is: Per Protocol, Variation Acceptable, and Unacceptable Deviation. 
 
12.2 
Medical Neuro-Oncology Modality Quality Assurance Reviews 
The Principal Investigator/Neuro-Medical Oncology Co-Chairs (Andrew B. Lassman, 
MD; Fabio Iwamoto, MD) or NRG Oncology Headquarters approved designee will 
perform a Systemic Therapy Assurance Review for temozolomide, ipilimumab, and/or 
nivolumab for all patients who receive systemic therapy in this trial.  The goal of the 
review is to evaluate protocol compliance.  The review process is contingent on timely 
submission of systemic therapy treatment data. The scoring mechanism is: 1) Per 
Protocol, 2) Acceptable Variation, 3) Unacceptable Deviation, and 4) Not Evaluable.   
 
Drs. Lassman/Iwamoto/designee will perform a Quality Assurance Review after NRG 
Data Management Center has received complete data for cases enrolled. The reviews will 
be ongoing and performed remotely. The final cases will be reviewed within 3 months after 
this study has reached the target accrual or as soon as NRG Data Management Center has 
received complete data for all cases enrolled, whichever occurs first. 
 
 
13. DATA AND RECORDS 
13.1 
Data Management/Collection  (17-JAN-2023) 
Medidata Rave is the clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for all 
users); 
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
x 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
x 
Rave Investigator role must be registered as aNon-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
x 
Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those individuals requiring 

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write access to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in, the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in 
the email or log in to iMedidata via the CTSU members’ website  under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name. Site staff who have not 
previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in the Regulatory application will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.   
 
13.2 
Summary of Data Submission (09-FEB-2021) 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.   
 
Summary of All Data Submission: Refer to the CTSU website 
 
See Section 8 for TRIAD account access and installation instructions. See data 
submission table for TRIAD below. 
 
DICOM Items 
DICOM CT Image 
Due Within 1 week of start 
 
 
of RT. Triad Time Point: 
  DICOM Structure 
 
       RT Digital Plan 
 
DICOM Dose (2) Initial & Boost 
 
DICOM Plan (2) Initial & Boost 
All required structures must be labeled per the tables in Sections 

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5.2.4
5.2.5
Imaging needed for RT review:
Preoperative MR (in its entirety)
Postoperative MR (in its entirety)
Additional MRI if used for RT Planning  
See tables in Section 4 for diagnostic MRI sequence 
requirements
Triad Time Points: 
Preoperative
Postoperative
Other
Upon submission of the digital data via TRIAD, complete an online
Digital Data Submission Information Form (DDSI):
https://www.irocqa.org/Resources/TRIAD
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES WILL BE
KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED.
DIAGNOSTIC MRI IMAGING REQUIRED FOR SUBMISSION TO TRIAD
                                                                                                              TRIAD Time Points:       
MRI Brain in its entirety: See bullets below for required and 
strongly suggested acquisition of MRI sequences. Please still 
submit ENTIRE MRI Brain exam
MRI with Axial T2 weighted FLAIR{preferred} or T2 
TSE/FSE and 3D contrast-enhanced T1 sequences are required.
3D pre contrast-enhanced T1 sequences are strongly suggested.
Pre-treatment
During Treatment
Baseline (4 wks post RT)
Follow Up
Progression
Other
Note: For Phase II only, imaging 
for all time points must be 
submitted via TRIAD until 
progression has been confirmed 
by central review. Sites will be 
notified if central review of 
progression does not agree with 
site review. For Phase III, 
imaging for all time points must 
be submitted via TRIAD until 
progression.
NOTE: Please refrain from anonymizing the DICOM header of any exam prior to uploading into the 
TRIAD application. Custom DICOM editing can exclude an exam from the final analysis, due to the 
omission of technical data elements. These elements include, but are not limited to, the study date 
(0008,0020), acquisition date (0008,0022) scanner station name (0008,1010), scanner serial number 
(0018,1000), and any scan acquisition parameter. TRIAD has been uniquely configured to locate and 

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scrub all PHI from the exam’s DICOM header, during the image transfer to ensure the anonymity of 
our trial patients. 
 
 
**Please ensure selection of the correct imaging time point in TRIAD 
 
 
 
13.3 
Data Quality Portal  (17-JAN-2023) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help icon Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form 
Status, and DQP Reports modules. 
 
13.4 
Rave-CTEP-AERS integration  (17-JAN-2023) 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting and facilitates entry 
in CTEP-AERS for those AEs requiring expedited reporting. Sites must initiate 
all AEs for this study in Medidata Rave.    
Treatment-emergent AEs: All AEs that occur after the start of treatment are 
collected in Medidata Rave using the Adverse Event form, which is available for 
entry at each treatment or reporting period and used to collect AEs that start 
during the period or persist from the previous reporting period. AEs that occur 30 
days after the last administration of the investigational study agent/intervention 
are collected using the Late Adverse Event form. 

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Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct; and 
x AEs are recorded and complete (no missing fields) and the form is query free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form (i.e., 
checking the box Send All AEs for Evaluation and save the form).  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited 
reporting. A report is initiated in CTEP-AERS using information entered in 
Medidata Rave for AEs that meet reporting requirements. The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata Rave 
Expedited Reporting Evaluation form. Contact the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU members’ website: 
x Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and   
x Additional resources: Resources > CTSU Operations Information> User 
Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
x 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeg
uidelines.pdf. 
 
PRO-CTCAE is not intended for expedited reporting, real time review, or safety 
reporting.  PRO-CTCAE data are exploratory and not currently intended for use in data 
safety monitoring or adverse event stopping rules. 
 
13.5 
Global Reporting/Monitoring 
 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via 
the DMU.  DMU Light reporting consists of Patient Demographics, On/Off Treatment 

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Status, Abbreviated Treatment and Course information, and Adverse Events as 
applicable.  Instructions for setting up and submitting data via DMU are available on the 
CTEP Website: https://ctep.cancer.gov/protocolDevelopment/dmu.htm.   
 
Note:  All adverse events (both routine and serious) that meet the protocol mandatory 
reporting requirements must be reported via DMU in addition to expedited reporting of 
serious adverse events via CTEP-AERS.   
 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
NRG-BN007 is a randomized phase II/III trial. The randomized phase II/III trial design 
will provide the opportunity to discontinue further enrollment (if applicable) and follow-
up for the definitive endpoint (overall survival) in the event that there appears to be no 
benefit from the experimental regimen. 
14.1.1 Stratification 
Upon entry for randomization, patients will be stratified by 1) RPA class (III vs. IV vs. 
V), and 2) Intent to use the Optune device. 
14.1.2 Randomization 
Patients will enter Step 1 to undergo central pathology review of tumors to establish 
histology and MGMT status. Permuted-block randomization based on above stratification 
factors will allocate patients meeting histology, MGMT status, and other eligibility 
criteria to one of two treatment arms in a 1:1 ratio. 
14.1.3 Sample Size Overview 
The total sample size (phase II and III combined), as described and justified in Section 
14.3.2 below, is 485 randomized patients with follow-up information. The accrual rate for 
newly diagnosed GBM patients with unmethylated MGMT for this study is expected to 
be 15 eligible and randomized patients per month after a 6-month ramp-up period. 
Therefore, it is projected that the target total accrual will be met approximately 39 
months after study activation. Further details are provided in Section 14.5. 
 
The phase II portion of the trial will enroll 150 randomized patients. Accrual will be 
suspended at that time and these patients will be followed until a total of 100 PFS events 
have been observed. The primary analysis for the phase II portion of the trial will be 
performed to determine if the trial should proceed to phase III. This analysis is projected 
to take place around 23 months after study activation. If there is sufficient evidence based 
on the phase II endpoint (progression-free survival, PFS) for potential superiority for the 
experimental treatment, the study will then continue and complete accrual for the phase 
III portion of the study. If the PFS null hypothesis is not rejected, then the trial will 
discontinue at the end of phase II. Thus, if the study ultimately ends at Phase II, a 
decrease in sample size of approximately 350 patients will result, providing efficiency in 
the case of lack of apparent benefit. 
 
If the study continues to Phase III, the required number of deaths for the final analysis for 
the phase III portion of the study is expected to be reached approximately 18 months after 
phase III accrual completion.  

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Patients who participate in phase II will contribute to phase III accrual and efficacy goals 
and analyses, including PFS, OS, PROs, and Neurocognitive Function. 
 
14.2 
Study Endpoints 
14.2.1 Primary Hypothesis Endpoints 
 Phase II:  Progression-free survival (PFS), defined as time from randomization to 
disease progress or death.  
 Phase III:  Overall survival (OS), defined as time from randomization to death from 
any cause. 
14.2.2 Secondary Endpoints 
 PFS for the entire cohort (phase II/III) 
 Two-year OS proportion 
 Comparative frequency of specific adverse events of interest; frequency summaries 
for all adverse event types 
 Patient Reported Outcomes (MDASI) 
 Neurocognitive function (NCF) 
 Selected PRO-CTCAE items (abdominal pain, rash, itching, muscle pain, joint pain, 
pain and swelling at injection site, headache, chills, mouth/throat sores, skin dryness, 
hair loss, cough, taste changes, dizziness, swelling, and hot flashes) 
14.2.3 Exploratory Endpoints 
 OS (if the study discontinues in phase II) 
 Tumor biomarker analyses, specifically but not limited to 
o PDL-1 expression 
o Mutational burden 
 MGMT protein expression  
 
14.3 
Primary Objectives Study Design (09-FEB-2021) 
14.3.1 Primary Hypothesis and Endpoints 
The primary endpoint for the randomized phase II portion of the study is PFS. As it can 
be complex to distinguish true disease progression from treatment effects (e.g., 
pseudoprogression) by conventional MRI scans, this trial will utilize the “PFS resolution” 
guidance provided in the ALLIANCE A071102 study, the updated RANO criteria (Wen, 
Macdonald et al. 2010) and additional recent efforts (Ellingson, Wen et al. 2017) to help 
distinguish between progression and pseudoprogression.  In addition, the investigators 
will have access to an online module that will be accessible from the protocol page to 
help guide in making the determination of true progression versus pseudoprogression. 
 
Based on observations from prior NRG Oncology/RTOG GBM trials among patients 
with MGMT unmethylated tumors, it is assumed that the median time to PFS failure is 
5.7 months from randomization for the control group (Arm 1 – TMZ). It is projected that 
the experimental treatment with the combination of ipilimumab and nivolumab (Arm 2 – 
ipi + nivo) will increase the median PFS time to 9.7 months, corresponding to a 42% 
relative hazard reduction (HR of 0.58) in favor of the experimental arm.  
 
The primary endpoint for the phase III study is OS. The control group median survival 

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time is expected to be about 14.5 months, based on prior NRG Oncology/RTOG 
experience in MGMT unmethylated tumors. The alternative hypothesis is that patients 
receiving the experimental treatment (ipi + nivo) will have a median survival time of at 
least 20.0 months, corresponding to a 28.0% relative hazard reduction (HR of 0.72) in 
favor of the experimental arm 
14.3.2 How Primary Endpoints Will Be Analyzed 
The phase II portion of this trial will enroll 150 randomized patients. Accrual will be 
suspended at that time. The definitive analyses for the phase II trial will be conducted 
after 100 PFS events (among both treatment arms) have been observed and central 
reviews of progression are completed, which is projected to take place around 23 months 
after study activation. The analysis will be performed on the intent-to-treat basis, 
including all randomized patients with follow-up information. PFS distributions for each 
treatment group will be estimated via the Kaplan-Meier survival function. If the stratified 
analogue of the log-rank (Mantel 1966) statistic has associated one-sided p-value is 0.15 
or less, then the trial will conclude that continuation to the phase III portion of the trial is 
warranted. Detailed information on censoring rules for PFS evaluation is given in 
Appendix VI, in accordance with the FDA Guidance for Industry: Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ance/ UCM071590.pdf). 
 
The definitive primary endpoint analyses for the phase III trial will be conducted after 
363 deaths (among both treatment arms) have been recorded, and will be performed on 
the intent-to-treat basis, including all randomized patients with follow-up information. 
Overall survival distributions for each treatment group will be estimated via the Kaplan-
Meier survival function. If the stratified log-rank statistic has associated one-sided p-
value is 0.024 or less, then the trial will conclude that the experimental arm results in 
improved OS over the control arm. 
 
Additional analyses will involve statistical models to evaluate factors related to the 
hazard of failure for PFS and OS. These models will be used to estimate treatment effects 
adjusting for patient and tumor characteristics that may be imbalanced by arm, or suggest 
a differential treatment effect by characteristic (e.g., treatment-covariate interactions). 
The Cox proportional hazards regression model will be the principal approach, however, 
in the case that the proportional hazards assumption is inadequately met, other modeling 
approaches will be applied as appropriate. 
14.3.3 Sample Size and Power Calculations:  
This trial will provide for a reliable evaluation of whether radiation therapy in 
combination with ipilimumab and nivolumab will improve outcomes in newly diagnosed 
MGMT unmethylated GBM relative to treatment with radiation therapy and 
temozolomide.  
 
For the phase II endpoint, observation of 100 PFS events among the 150  randomized 
patients (from both arms) provides 95% statistical power to detect an improvement in 
median PFS from 5.7 months in the control arm to 9.7 months in the experimental arm, 
corresponding to a hazard reduction of 42% (hazard ratio 0.58) at one-sided significance 

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level of 0.15 (and 87% power for HR of 0.65 at this same alpha). It is anticipated that at 
the expected accrual and control group PFS failure rate, this analysis will occur when the 
first 100 patients have been followed for approximately 7 months after phase II accrual 
completion. 
 
For the Phase III evaluation, a total of 363 deaths are required to detect the hypothesized 
survival benefit of a 28% reduction in hazard of death with 85% statistical power at 
significance level is 0.024 (one-sided). If the study continues to Phase III, the required 
number of deaths for the final analysis for the phase III portion of the study is expected to 
be reached within approximately 18 months after phase III accrual completion (58 
months from study initiation).  
 
With regard to number of patients required and the accrual rate, given that MGMT is 
unmethylated in about 65% of all newly diagnosed GBMs, it is estimated that 
approximately 750 patients need to be screened for MGMT methylation status to obtain 
the targeted 485 randomized patients for the phase III trial. All patients included in the 
phase II PFS evaluation will be included in the primary endpoint analysis of OS for the 
phase III portion of the trial. Total accrual time (phase II and III combined) is anticipated 
to require up to 39 months (10 months phase II accrual + 7 months accrual suspension 
and follow-up for required PFS events + 22 months phase III accrual). 
 
14.4 
Study Monitoring of Primary Objectives (17-JAN-2023) 
 
The trial is monitored on a continuous basis during conduct, including a monthly tally of 
accrual, real-time oversight of serious adverse events as required, and regular meeting of 
the study team to track progress and identify problems. 
 
Interim Reports to Monitor Study Progress  
Reports will be prepared twice per year and provided to the NRG Oncology external Data 
Monitoring Committee (DMC) until the initial treatment results have been 
presented/published. The interim reports will contain at a minimum the following 
information: 
 Total patients accrued, patient accrual rate and projected accrual completion date 
(while the study is still accruing), and information on trial eligibility of patients 
enrolled 
 Frequency distributions of important patient and disease characteristics by treatment 
arm 
 Frequencies and severity of adverse events by treatment arm 
 Information on timeliness of data reporting 
 
The DMC will review the scheduled interim efficacy/futility analyses to be carried   
out during the Phase III portion of the trial. The DMC will also review the trial on an ‘as           
needed’ basis at any time between regularly scheduled meetings. 
 
14.4.1 Interim Efficacy/Futility Monitoring 
 
 
Phase II Monitoring 

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The phase II portion of the trial will enroll 150 randomized patients. Accrual will be 
suspended at that time and these patients will be followed until 100 PFS events have 
been observed (expected to be reached approximately 23 months (= 6 months ramp-
up period + 10 months accrual + 7 months follow-up) from trial activation. The PFS 
(experimental/control) hazard ratio will be estimated. A 1-sided 0.15 level stratified 
log-rank test will be employed to determine if the trial should proceed to the phase III 
portion of the study. The trial will proceed to phase III accrual if the 1-sided p-value 
from the stratified log-rank test is less than 0.15; otherwise, the trial will discontinue 
early (at the end of phase II).  
 
If the study continues to phase III based on either the PFS analyses above, patients 
on active treatment will remain on their assigned treatment arm. All patients accrued 
to phase II are included in the phase III accrual cohort and will be included in all 
further analyses. 
 
Phase III Monitoring 
Interim analyses for the OS endpoint are planned after observing approximately 50% 
and 75% of the required number of deaths. The futility boundary is based on the 
method of Freidlin, Korn, and Gray (2010) (using the 20% of target efficacy 
criterion) for early determination of treatment inefficacy. The efficacy boundary is 
derived from the method by Fleming, Harrington, and O’Brien (1984), and provides a 
boundary that requires a less extreme boundary for early looks than the traditional 
O’Brien Fleming method, at the cost of a slightly more conservative boundary for 
later looks.  This table summarized the analyses to be conducted and the criteria for 
possible early determination of efficacy or futility for the primary endpoint. 
 
 
Analysis 
Time (mos) 
(from Ph II 
accrual 
inception) 
Prop.  
Total 
Events 
Cumulative 
Events  
(Both Arms) 
Efficacy 
Boundary 
Futility 
Boundary 
Z< 
P< 
 Z> 
P> 
Interim 1 
33 
0.50 
181 
3.03 
0.001 
0.059 
0.477 
Interim 2 
42 
0.75 
272 
2.97 
0.002 
0.298 
0.383 
Final 
54 
1.00 
363 
1.98 
0.024 
- 
- 
p-values one-sided 
 
The results of the interim analyses will be reported to the NRG Oncology DMC, 
along with all other information described earlier. The NRG Oncology statistician 
will provide a provisional recommendation to the DMC, who will deliberate and 
ultimately render a recommendation regarding actions on the trial to the NRG 
Oncology Group leadership. 
 
14.5 
Accrual/Study Duration Considerations 
Previously conducted trials in GBM by RTOG/NRG Oncology have achieved and 
sustained accrual of 39 patients/month. Screening for histology and sufficient tissue 
reduces the available patients by about 32%, resulting in 26 patients/month. Of these, 
about 65% are anticipated to be MGMT unmethylated, yielding 17 patients/month. 

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Monthly accrual is expected to be negligible for the first 6 months after study activation 
while sites obtain IRB approval and activate the trial. We conservatively assume 15 
patients/month accrual. Thus, total time required to reach the accrual goal (phase II and 
III combined) is anticipated to be about 39 months (10 months phase II accrual + 7 
months accrual suspension and follow-up for required PFS events + 22 months phase III 
accrual). 
 
If at any point accrual is terminated for lack of efficacy in the treatment arm, patients 
remaining on study treatment who are felt to be benefiting may continue at the discretion 
of the treating investigator in discussion with the patient and a revised written informed 
consent form that will be generated as needed. 
 
14.6 
Secondary Objectives Study Design  
14.6.1 Secondary Hypotheses and Endpoints 
 
Endpoints for the secondary objectives of this trial include PFS in the entire cohort (phase 
II and III combined), the OS proportion (% alive) at 2 years, summary statistics on 
adverse event frequencies, the MDASI-BT patient-reported outcome (PRO) measure, 
neurocognitive function (NCF) measures, and evaluation of a novel method to detect 
disease progression. The following hypotheses will be evaluated: 
x To determine if adding ipilimumab and nivolumab to radiotherapy significantly 
prolongs PFS versus adding temozolomide to radiotherapy in patients with newly 
diagnosed GBM without MGMT promoter methylation for the phase III part of the 
study 
x To determine if adding ipilimumab and nivolumab to radiotherapy significantly 
increases the 2-year OS rate versus adding temozolomide to radiotherapy in patients 
with newly diagnosed GBM without MGMT promoter methylation 
x To evaluate the safety of adding ipilimumab and nivolumab to radiotherapy via 
comparative frequency between arms of specific adverse events of interest and 
frequency summaries for all adverse event types 
x To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus 
adding temozolomide to radiotherapy on patient reported outcomes (PROs), as 
measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in 
patients with newly diagnosed GBM without MGMT promoter methylation 
x To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus 
adding temozolomide to radiotherapy on selected PRO-CTCAE items (abdominal 
pain, rash, itching, muscle pain, joint pain, pain and swelling at injection site, 
headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, 
dizziness, swelling, and hot flashes) in patients with newly diagnosed GBM without 
MGMT promoter methylation 
x To evaluate the impact of adding ipilimumab and nivolumab to radiotherapy versus 
adding temozolomide to radiotherapy on neurocognitive function (NCF) in patients 
with newly diagnosed GBM without MGMT promoter methylation 

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14.6.2 Definition of Secondary Endpoints and How These will be Analyzed 
Progression-Free Survival, as defined in 14.3.1, will be evaluated among all trial 
participants in the event that the trial proceeds to phase III (485 patients). Analysis for 
this endpoint will consist of estimation of the PFS curves via the Kaplan-Meier method 
and a stratified log-rank test. Statistical power will depend on the total PFS events 
accumulated at trial end, as well as any convergence of PFS curves that may occur late in 
follow-up, as is frequently observed in GBM trials. As it is anticipated that PFS events 
will exceed 375, there will be approximately 90% power to detect the 33% failure rate 
reduction specified for the phase II portion at one-sided alpha of 0.005. 
 
Additional analyses may consist of estimating the hazard ratio via the Cox proportional 
hazards model, accounting for other prognostic covariates (and evaluating whether the 
proportional hazards assumption holds or whether any treatment effect is notably time-
varying), and evaluating for potential treatment by prognostic covariate interactions. 
 
Overall Survival at 2 Years 
Because of concerns about a possible ‘late emerging’ effect of immunotherapy, estimates 
of 2-year OS will be compared between treatment arms, to determine whether the 
proportion surviving to this landmark is increased in the experimental (ipi + nivo) arm. 
Estimates will be obtained from the Kaplan Meier curves, and a test comparing the 
proportion surviving with an appropriate variance term that accounts for censoring 
(Greenwood’s formula) will be used. The current hypothesized 2-year survival estimates 
based on the assumed failure rates are 30.4% in the standard arm and 42.5% in the 
experimental arm. These estimates depend on time-independent treatment benefit (i.e., 
proportional hazards) and exponential hazards, and thus realized estimates may differ. 
 
Adverse Events 
Adverse events (AEs) will be graded according to CTCAE v5.0 and PRO-CTCAE. 
Comprehensive summaries of all AEs by treatment arm will be generated and examined. 
Counts and frequencies of worst (highest score) AE per patient will be presented overall 
and by AE type category, separately by assigned treatment group. Complementing 
physician-assessed AEs will be selected PRO-CTCAE symptom items that have 
demonstrated sensitivity to immunotherapy-related toxicities (Tolstrup 2019) but do not 
overlap with MDASI-BT. The following PRO-CTCAE symptom items will be monitored: 
rash, itching, muscle pain, joint pain, headache, chills, mouth/throat sores, skin dryness, 
hair loss, cough, taste changes, dizziness, swelling, hot flashes. The PRO-CTCAE will be 
administered according to the schedule described in Section 4.  

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The proportion of patients with at least one grade 3 or higher AE will be compared 
between treatment arm. Similarly, frequencies for specific potentially treatment related 
AEs where grade 3 or higher events are noted may be compared. Any frequencies to be 
tested will be evaluated using the chi-square or exact test as appropriate, with two-sided 
significance level 0.05. It noted that no hypotheses are specified regarding expected 
differences in AE frequency, and that given that power can be high for frequency tables 
with large sample size, only clinically material differences that represent potential patient 
risk will be of interest. 
 
Patient-Reported Symptom Burden 
As described in (11.2), symptom burden will be assessed using the MDASI-BT-modified 
(Armstrong 2006). The MDASI-BT consists of 23 symptoms rated on an 11-point ordinal 
scale (0 to 10) to indicate the presence and severity of the symptom in the last 24 hours, 
with 0 being “not present” and 10 being “as bad as you can imagine.” Symptoms included 
on the instrument are those commonly associated with cancer therapies and those 
associated with neurologic and cognitive symptoms associated with the tumor itself.  The 
MDASI-BT also includes ratings of how symptoms (on 0-10 scale) have interfered with 
different aspects of the patient’s life in the last 24 hours. These interference items include: 
general activity, mood, work (includes both work outside the home and housework), 
relations with other people, walking, and enjoyment of life. Complementing MDASI-BT 
will be selected PRO-CTCAE symptom items that have demonstrated sensitivity to 
immunotherapy-related toxicities (Tolstrup 2019) but do not overlap with MDASI-BT. 
This is referenced under Adverse Events. The MDASI-BT will be administered according 
to the schedule described in Section 4.  
 
The expected difference in symptom burden between treatment arms will partly depend on 
relative disease control benefit as well as the different adverse events associated with 
temozolomide versus the immunotherapy combination. Of primary interest is the 
difference in change in symptom burden from baseline to 6 months (from the start of 
treatment) between the two treatment arms. While scales for the individual instrument 
questions are quantitative, they represent ordinal values on a bounded range rather than 
continuous quantities. Nonetheless, in aggregate these scores approximate continuous 
distributions, and appropriate transforms will be applied to improve consistency with 
model assumptions for the outcome measure. The mean score changes from baseline to 6 
months and standard deviations will be calculated for the two treatment arms. A two-
sample t-test will be used to evaluate the difference between two arms. Note that the 
meaningful effect size for these tools is still in debate. Cohen’s widely used rules of thumb 
for interpreting the magnitude of difference define 0.8 standard deviation (SD) as a “large” 
effect size, 0.5 SD as a “medium” effect size, and 0.2 SD as a “ small” effect size (Cohen 
1988). Effect size below 0.5 SD, supported by data regarding the specific characteristics of 
a particular quality of life assessment or application, may also be clinically meaningful 
(Sloan 2005). Assuming 390 patients (~80% of the patients enrolled in the treatment trial) 
will participate in the QOL study and have both baseline and 6-month follow-up data, the 
study will have over 80% statistical power to detect effect sizes (mean difference between 
arms / standard deviation) of 0.30 or greater. 

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In addition to investigating the difference in score change from baseline to 6-months 
between two arms, we will also conduct a longitudinal analysis that will focus on patterns 
of score change over time points (baseline, t1, t2,) in MDASI-BT.  It is posited that 
patients undergoing immunotherapy may experience fewer of the traditional ‘side-
effects’ associated with cytotoxic cancer therapies, but may have greater neurologic and 
cognitive effects during active treatment. Over the longer period, greater disease control 
due to immunotherapy may lead to more favorable outcomes with respect to symptoms 
burden. This trial is uniquely positioned to evaluate this experience. To this end, we will 
implement mixed effects models for repeated measures to evaluate the MDASI-BT 
scores longitudinally. Mixed effects models describe the rate of change in scores over 
time for each treatment arm (fixed effect), taking into account the between-patient 
variability by incorporating each patient’s individual starting point and individual rate of 
change (random effect) into the model. The MDASI-BT scores will be the dependent 
variables in these models. Independent variables will include time, study arm, baseline 
stratification factors, and the interaction between time and study arm. An unstructured 
correlation matrix will be used to model the correlation between repeated observations. 
Of particular interest is the treatment group by time interaction effect, representing a 
difference in symptom burden experience over time among patients in the two groups. To 
control for multiple comparisons among time points and treatment groups, a hierarchical 
analytic approach described below will be undertaken: 
a) Perform an overall (omnibus) test of the treatment group by timepoint interaction 
effect. Prior to this test, model characteristics, including trajectories of scores may be 
examined via regression diagnostics within treatment arm, and appropriate functional 
form for the models then specified. 
b) If an overall difference in score trajectories by arm is confirmed, then 
a. test timepoint-specific differences between arms 
b. characterize treatment-arm specific patterns over time within the group 
treatment groups (changes from baseline, shape of the trajectory, etc.) 
c) If overall differences by arm cannot be established, then further characterization of 
the symptoms experience within the immunotherapy arm may be undertaken, to 
provide a detailed history of the experience. 
 
 
Neurocognitive Function 
As described in (11.1), neurocognitive function (NCF) will be assessed using the Hopkins 
Verbal Learning Test – Revised (Benedict 1998), Trail Making Test (Tombaugh 2004), 
and the Controlled Oral Word Association test (Ruff 1996).  These widely used and 
standardized psychometric instruments have been shown to be sensitive to the impact of 
cancer and the neurotoxic effects of cancer treatment in other clinical trials (Gilbert 2014; 
Meyers 2004; Wefel 2011). The tests have published normative data that account for age 
and, where appropriate, education and gender. The NCF assessments will be administered 
according to the schedule described in Section 4.  
 
The established metric for clinically significant change is the Reliable Change Index (RCI; 
Jacobson 1991). The RCI is derived from the standard error of measurement of each test 

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and represents the 90% confidence interval for the difference in raw score from baseline to 
the next assessment that would be expected if no real change occurred: 
 
RCI = 1.64(standard error of difference), where standard error of difference  
 
 
  = [2(standard error of measure2)]1/2,  and standard error of measure  
 
 
  = standard deviation1[(1 − rxy)1/2] 
 
 
 
This yields the following RCI values for each test in the Clinical Trial Battery: 
NCF Test 
RCI Value 
HVLT-R Total Recall 
5 
HVLT-R Delayed Recall 
3 
HVLT-R Delayed Recognition 
2 
TMT Part A 
12 
TMT Part B 
26 
COWA 
12 
 
At each assessment, change in raw test score relative to baseline are calculated, and 
declines in a score that meets or exceeds the RCI value is categorized as a failure. Cognitive 
failure (CF) is defined as a decline on at least one of the Clinical trial Battery tests (HVLT-
R, TMT, COWA) that meets or exceeds the RCI value.  
 
The key objective for the NCF analysis is to compare the cognition failure free (CFF) 
rate between the two treatment arms. The primary comparison of treatment effect on CFF 
rates will be based on a 2-sided 0.05-level test for cause-specific hazard ratio (CHR) in a 
Cox proportional hazards model. A 2-sided test is selected because the impact of the 
experimental ICI on neurocognitive function in comparison to the control arm is uncertain 
(Section 11.1.1).  
 
Participation in the neurocognitive function study is mandatory for all patients that are 
proficient in English and French-Canadian, given that the psychometric properties for 
translated tests are either not known or not as robust. Thus, we very conservatively estimate 
at least 70% of patients will be eligible and evaluable for the primary analysis of CFF rate 
(with exception of patients who are not English or French-Canadian speaking (~2-5%), 
early withdrawal of consent, lack of follow-up, or refusal to participate, etc.) but there 
could be as high as 90% of the full trial population. We assume that 6-month CF rate in the 
experimental ICI arm is 30%, which translates to 12-months CF rate of 51% assuming 
exponential distribution. We expect that the control arm will improve 12-month CFF by 
11% (i.e. from 49% to 60%). This difference translates to a hazard ratio (TMZ vs. ICI) of 
0.72. Assuming uniform accrual of 32 months with an additional follow-up of 18 months 
after accrual completion, the following table describes the percentage of patients evaluable 
for CFF, the effective sample size, expected number of CFF events by the end of the trial, 
and statistical power to detect the hypothesized effect size, using a 2-sided 0.05 level test, 
assuming the percentage of patients evaluable for the CFF endpoint ranges between 70% 
and 90%. Note that the timing of this analysis will be based on the timing for primary 
analysis of NRG-BN007. 
 

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Percentage of patients 
evaluable for CFF 
endpoint 
Effective sample 
size evaluable for 
CFF endpoint 
Estimated number of 
CFF events by the end 
of the trial 
Power to detect 
hypothesized effect 
in CFF (HR = 0.72) 
70% 
340 
271 
80% 
80% 
388 
310 
84% 
90% 
437 
348 
88% 
 
As a secondary analysis, the cumulative incidence function estimator will be used to 
estimate the median time to cognitive failure in the presence of precluding disease 
progression or death (Korn and Dorey 1992). Gray’s test will be used to test for a 
statistically significant difference in the distribution of CFF (Gray 1988). Results will be 
interpreted in light of competing disease progression and death, which may be frequent.  
 
Additional exploratory analysis will involve assessing the change in cognitive failure over 
time. For each NCF test, patients will be categorized as deteriorated (decline per the reliable 
change index [RCI]) or not deteriorated at each assessment. A generalized estimating 
equations (GEE) model with a binary response will be used to assess if there is difference 
between the experimental and control arms in terms of RCI-determined NCF decline over 
time. The GEE model will include fixed effects for treatment, assessment time point, and 
the treatment-by-time interaction, controlling for baseline score stratification variables and 
other covariates of interest. 
 
Missing Data Considerations for PRO and NCF Studies 
A certain degree of attrition from the PRO and NCF studies, due to both patient refusal or 
other reasons for missed assessments, and deterioration/mortality due to disease, is 
expected. Characteristics of patients with missing data will be evaluated to identify 
imbalance in factors such as treatment, baseline scores, and other clinical and demographic 
features. Prior to performing analyses, an evaluation of the amount, reasons and patterns 
of missing data will be performed, using the well-known categories of missing completely 
at random (MCAR), missing at random (MAR) and missing not at random (MNAR) 
(Fairclough 2010, Verbeke 2000. If missing data are MCAR or MAR, then a mixed model 
using maximum likelihood is sufficient because all available data can be used. A joint 
model that allows a shared parameter between the repeated measurements and time to death 
or drop out can be used if considered MNAR due to the high number of patient deaths or 
dropouts (Rizopoulos 2012). Other options for MNAR data are pattern mixture and 
selection models (Fairclough 2010, Little 1995).  Sensitivity analyses will be performed to 
compare the results of different analytic strategies (Fairclough 1998). 
 
 
 
 
14.7 
Gender/Ethnicity/Race Distribution 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 

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Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
1 
2 
0 
0 
3 
Asian 
3 
5 
0 
0 
8 
Native Hawaiian or Other 
Pacific Islander 
1 
1 
0 
0 
2 
Black or African American 
6 
9 
0 
0 
15 
White  
156 
231 
9 
15 
412 
More Than One Race 
2 
5 
0 
0 
5 
Total 
169 
253 
9 
15 
445 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
 
Asian 
0 
0 
0 
0 
 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
 
Black or African American 
0 
0 
0 
0 
 
White  
15 
22 
1 
2 
40 
More Than One Race 
0 
0 
0 
0 
 
Total 
15 
22 
1 
2 
40 
 
 

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REFERENCES (09-FEB-2021) 
 
Armstrong TS, Wefel JS, Wang M, et al (2013). Net clinical benefit analysis of radiation therapy 
oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with 
dose-intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol 
31(32):4076-4084.  
 
Bady P, Delorenzi M, Hegi ME, et al (2016).  Sensitivity analysis of the MGMT-STP27 model 
and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas 
and other tumors. J Mol Diagn. 18(3):350-361.  
 
Bartels F, Strönisch T, Farmer K, et al (2019). Neuronal autoantibodies associated with cognitive 
impairment in melanoma patients. Ann Oncol 30(5):823–829. 
 
Cloughesy TF, Lassman AB (2017). NovoTTF: where to go from here? Neuro-Oncology 19(5): 
605-608. 
Cox DR (1972). Regression models and life tables. J R Stat Soc 34:187-202.  
Cuzzubbo S, Javeri F, Tissier M, et al (2017). Neurological adverse events associated with 
immune checkpoint inhibitors: Review of the literature. Eur J Cancer 73:1-8 
 
Ellingson BM, Wen PY, Cloughesy TF (2017). Modified criteria for radiographic response 
assessment in glioblastoma clinical trials. Neurotherapeutics 14(2): 307-320. 
 
Fleming T, Harrington D, O’Brien PC (1984). Designs for group sequential tests. Cont Clin 
Trials 5(4): 348-361. 
 
Gray RJ (1988). A class of K-sample tests for comparing the cumulative incidence of a 
competing risk, Annals of Statistics 16:1141-1154.  
 
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of  
Cancer Drugs and Biologics: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/ 
UCM071590.pdf  
 
Freidlin B, Korn E, Gray R (2010). A generaly inefficacy interim monitoring rule for 
randomized clinical trials. Clin Trials 7(3): 197-208  
 
Gilbert M, Dignam JJ, Armstrong TS, et al (2014). A randomized clinical trial of bevacizumab 
for newly diagnosed glioblastoma. N Engl J Med 370:699-708 
 
Giles AJ, Hutchinson MND, Sonnemann HM, et al (2018). Dexamethasone-induced 
immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 
6(1): 51. 
 

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Hegi ME, Diserens AC, Gorlia T, et al (2005). MGMT gene silencing and benefit from 
temozolomide in glioblastoma. N Engl J Med 352(10): 997-1003. 
 
Jacobson NS, Truax P (1991). Clinical significance: a statistical approach to defining meaningful 
change in psychotherapy research. J Consult Clin Psychol. 59(1):12-19. 
 
Kaplan EL, Meier P (1958). Nonparametric estimation from incomplete observations. J Am Stat 
Assoc 53 (282): 457–481. 
 
Keskin DB, Anandappa AJ, Sun J, et al (2019). Neoantigen vaccine generates intratumoral T cell 
responses in phase Ib glioblastoma trial. Nature 565(7738): 234-239. 
 
King-Kallimanis BL, Howie LJ, Roydhouse JK, et al (2019). Patient reported outcomes in anti-
PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and 
future directions. Clin Trials 16(3):322-326.  
 
Korn EL, Dorey FJ (1992). Applications of crude incidence curves. Stat Med 11:813-829. 
 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al (2019). Five-year survival with combined 
nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535-1546. 
 
Lassman AB, Dimino C, Mansukhani M, et al (2017). Concordance of EGFR and MGMT 
analyses between local and central laboratories: implications for clinical trial design and 
precision medicine for depatuxizumab-mafodotin (ABT-414) in glioblastoma (GBM) [Abstract 
ACTR-68]. Neuro Oncol 19(suppl 6, 6): vi15. 
 
Little RJA (1992). Regression with missing x’s: A review. J Am Stat Assoc. 87:1227-1237. 
 
Mantel N. (1966). Evaluation of survival data and two new rank order statis-tics arising in its 
consideration. Cancer Chemotherapy Reports, 50:163-170. 
 
McGinnis G J, Friedman D, Young KH, et al (2016). Neuroinflammatory and cognitive 
consequences of combined radiation and immunotherapy in a novel preclinical 
model. Oncotarget 8:9155-9173. 
 
Okada H, Weller M, Huang R, et al (2015). Immunotherapy response assessment in neuro-
oncology: a report of the RANO working group. Lancet Oncol 16(15): e534-542. 
 
Ranjan S, Quezado M, Garren N, et al (2018). Clinical decision making in the era of 
immunotherapy for high grade-glioma: report of four cases. BMC Cancer 18(1): 239. 
 
Schadendorf D, Larkin J, Wolchok J, et al (2017). Health-related quality of life results from the 
phase III CheckMate 067 study. Eur J Cancer 82:80-91. 
 
Sloan AE, Gilbert MR, Zhang P, et al (2018). NRG BN002: Phase I study of checkpoint 
inhibitors anti-CTLA-4, anti-PD-1, the combination in patients with newly diagnosed 
glioblastoma. J Clin Oncol 36(Suppl): Abstract 2053. 

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Stupp R, Mason WP, van den Bent MJ, et al (2005). Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. N Engl J Med 352(10): 987-996. 
 
Stupp R, Taillibert S, Kanner AA, et al (2015). Maintenance therapy with tumor-treating fields 
plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 
314(23): 2535-2543. 
 
Stupp R, Wong ET, Kanner AA, et al (2012). NovoTTF-100A versus physician's choice 
chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment 
modality. Eur J Cancer 48(14): 2192-2202. 
 
Tolstrup LK, Bastholt L, Zwisler AD, et al (2019). Selection of patient reported outcomes 
questions reflecting symptoms for patients with metastatic melanoma receiving immunotherapy. 
J Patient Rep Outcomes 3(1):19 
 
Vatner RE, Cooper BT, Vanpouille-Box C, et al (2014). Combinations of immunotherapy and 
radiation in cancer therapy. Front Oncol 4: 325. 
 
Wen PY, Macdonald DR, Reardon DA, et al (2010). Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11): 
1963-1972. 
 
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al (2017). Overall survival with combined 
nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14): 1345-1356. 
 
Wu MC, Bailey K (1988). Analyzing changes in the presence of informative right censoring 
caused by death and withdrawal. Stat Med. 7:337-346. 
 
Yung WK, Albright RE, Olson J, et al (2000). A phase II study of temozolomide vs. 
procarbazine in patients with glioblastoma multiforme at first relapse." Br J Cancer 83(5): 588-
593. 
 
 

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APPENDIX I: CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 

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Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information.  
 
 

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APPENDIX II: NIVOLUMAB/IPILIMUMAB MANAGEMENT ALGORITHMS 
(INVESTIGATOR BROCHURE V. 20) (08-APR-2022) 
 
Note that the algorithms below are to help guide therapy. If the algorithms recommend 
management that conflicts with other sections of the protocol, follow the directives in the 
other sections of the protocol.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID ____________ 
 
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APPENDIX III: TEMOZOLONIDE PILL DIARIES 
 
 
TEMOZOLOMIDE PILL DIARY 
 
 
NRG-BN007 
 
 
A RANDOMIZED PHASE II/III OPEN-LABEL STUDY OF IPILIMUMAB AND NIVOLUMAB 
VERSUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED MGMT (TUMOR O-
6-METHYLGUANINE DNA METHYLTRANSFERASE) UNMETHYLATED GLIOBLASTOMA 
 
Concurrent Treatment Phase 
 
 
 
 
 
 
 
 
   
     INSTRUCTIONS TO THE PATIENT: 
 
 
x 
Complete one form during the radiation treatment phase and bring to your clinic visits. 
 
x 
Take Temozolomide each day starting on the first day of radiation until the last day of radiation 
 
x 
Your dose is ______ mg.  You will take _______ capsules daily: 
 
 ____ 5 mg _____ 20 mg _____100 mg  _____140 mg _____180 mg _____250 mg 
. 
 
x 
Record the date, the number of pills you took, and the time you took them. 
 
x 
If you have any comments or notice any side effects, please record them in the Comments column. 
 
 
 

Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID ____________ 
 
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Day 
Date 
# Pills Taken 
Time 
Comment 
 
 
5mg 
20mg 100mg 140mg 180mg 250mg  
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
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Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID ____________ 
 
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27 
 
 
 
 
 
 
 
 
 
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Patient’s Signature: __________________________________ Date: __________________________ 
 
 

Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID ____________ 
 
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TEMOZOLOMIDE PILL DIARY 
 
 
NRG-BN007 
 
 
 
A RANDOMIZED PHASE II/III OPEN-LABEL STUDY OF IPILIMUMAB AND NIVOLUMAB 
VERSUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED MGMT (TUMOR O-
6-METHYLGUANINE DNA METHYLTRANSFERASE) UNMETHYLATED GLIOBLASTOMA 
 
 
 
Adjuvant Treatment Phase 
 
 
 
 
 
 
 
 
   
     INSTRUCTIONS TO THE PATIENT: 
 
x Complete one form for each cycle (28 days) and bring to your next clinic visit. 
 
x Take Temozolomide on day 1-5 every 28 days for 6-12 cycles. 
 
x 
Your dose is ______ mg.  You will take _______ capsules daily: 
 
 ____ 5 mg _____ 20 mg _____100 mg  _____140 mg _____180 mg _____250 mg 
x Record the date, the number of pills you took, and the time you took them. 
 
x 
If you have any comments or notice any side effects, please record them in the Comments column. 
 

Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID ____________ 
 
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Day 
Date 
# Pills Taken 
Time 
Comment 
 
 
5mg 
20mg 100mg 140mg 180mg 250mg  
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
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25 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient’s Signature: __________________________________ Date: __________________________ 

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APPENDIX IV:  PATIENT CLINICAL TRIAL WALLET CARD
CLINICAL TRIAL WALLET CARD
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room.
Patient Name:  
Diagnosis:  
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #:  
Study Drug(S):  
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov

 
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APPENDIX V 
 
RECURSIVE PARTITIONING ANALYSIS (RPA) CLASSIFICATION  
 
 
Class III 
Age < 50 and KPS 90-100 
 
Class IV 
Age < 50 and KPS < 90; OR age t 50 and KPS 70-100 and partially 
or total resected with no worse than minor neurologic function 
impairment 
 
Class V 
Age ≥ 50 and KPS 70-100 and underwent prior partial or total tumor 
resection with worse than minor neurologic function impairment  
 
 
 

 
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APPENDIX VI (09-FEB-2021) 
 
CENSORING RULES FOR PROGRESSION-FREE SURVIVAL (PFS) ENDPOINT 
 
Situation  
Date of Progression or Censoring  
Outcome  
Incomplete or no baseline tumor 
assessments  
Randomization  
Censored  
Progression documented between 
scheduled visits  
Earliest of:  
x Date of progression assessment 
showing new lesion (if progression is 
based on new lesion); or  
x Date of last progression assessment  
Progressed  
No progression  
Date of last progression assessment with 
no documented progression  
Censored  
Treatment discontinuation for 
undocumented progression  
Date of last progression assessment with 
no documented progression  
Censored  
Treatment discontinuation for 
toxicity or other reason  
Date of documented progression with 
protocol specified continued follow-up in 
all treatment arms  
Progressed  
New anticancer treatment started  
Date of documented progression with 
protocol specified continued follow-up in 
all treatment arms  
Progressed  
Death before first PD assessment  
Date of death  
Progressed  
Death between adequate assessment 
visits  
Date of death  
Progressed  
Death or progression after more than 
one missed visit  
Date of documented progression, or if this 
date is unknown, date of death 
Progressed  
 
 
 
 

 
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APPENDIX VII (08-APR-2022) 
 
MEDIDATA PATIENT CLOUD EPRO OPERATIONAL INSTRUCTIONS 
 
Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata’s Patient Cloud 
application is preferred but not mandatory.  Patients who will be submitting PRO data via the 
Patient Cloud mobile ePRO app must be registered to the ePRO application by an authorized site 
staff after the patient has been registered to the study. Patients may use their own mobile device 
or one provisioned by the site.  
 
Sites can use a site-specific tablet for multiple study participants.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study 
participants log in to the ePRO mobile app with their passwords or their PIN codes on the same 
device.  
  
Patient Cloud Mobile ePRO Application Download 
Note that there are multiple versions of the Patient Cloud mobile ePRO app.  Patients should be 
instructed to download the version chosen by the study team for the protocol.  The patient will 
receive an error upon logging into the ePRO mobile app if the wrong version is downloaded. 
This protocol is using the current version with the following logo: 
 
Search “Patient Cloud”  in the app store  
and select the app with this icon 
 
 
 
 
CRA Site Users 
Site staff require access to the ePRO application.  This access is granted through iMedidata, and 
is similar to the process of obtaining access to Rave studies. Site staff will receive an invitation 
to the ePRO application which they must accept in order to begin registering patients. Staff that 
have not previously activated their iMedidata/Rave account at the time of initial approval of site 
registration will also receive a separate invitation from iMedidata to activate their account. 
Medidata Account Activation and Study Invitation Acceptance instructions are located on the 
CTSU members’ website under Data Management > Rave Resource Materials. Site staff will not 
be able to access the study in the ePRO application until all required Rave and study specific 
trainings (eLearnings assigned in iMedidata) are completed. 
 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Data Management tab and further under the Rave subtab or by contacting the CTSU Help Desk 
at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
 

 
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CRA Instructions for Preparing a Site Device 
Sites conducting studies entirely on-premises, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode. Multi-user mode lets multiple study participants log in 
to the Patient Cloud mobile ePRO app with their passwords or their PIN codes on the same 
device.  If patients will be using devices supplied by the institution, site staff will need to help 
the patient to access the device if the device is locked.  
 
The study provider will download the Patient Cloud mobile ePRO app to the device and set the 
mobile app to multi-user mode if applicable. **Verify that the correct ePRO mobile app (Patient 
Cloud OR Patient Cloud ePRO) is downloaded by verifying the correct version with the study 
team.  Note only one version of the mobile app is active per protocol.  This protocol is using the 
current version with the cloud and dot logo.  It is named simply “Patient Cloud” in the app 
stores.  
 
 To switch from personal mode (default setting) to multi-user mode: 
 
1. Tap About at the bottom of the log in screen. 
2. Scroll to the bottom and tap Advanced User. 
3. Tap Mode, then select Multi-User. 
4. Tap Yes to confirm. 
5. Tap the back arrows to return to the log in screen. 
 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. 
 
PATIENT USERS 
To use the Patient Cloud mobile ePRO app, patients will need to use their own device (IOS, 
Android phone or tablet) or one provided by the site.   
 
In both cases, short term data will only appear on the device until responses are completed and 
submitted.  The patient data will import directly into the database once the patient selects the 
“Submit” button and data will no longer be visible on the device.  
 
Quick Reference Cards (QRCs) are available to download and print for use by the site, and to 
hand out to the patient if desired.  The QRCs can be found here and include: Patient Cloud, iOS 
App Download, Account Activation with Email and Password, Account Activation with 
Multiple Studies Using Existing Email Address, and Troubleshooting.  A Medidata login is 
required to access the Quick Reference Cards so sites must provide them to study 
participants, if desired. 
 
PATIENT INSTRUCTIONS FOR ACCESSING PATIENT CLOUD USING YOUR 
PERSONAL DEVICE 
 
Downloading the Patient Cloud ePRO App 
If you are using your personal device, and you do not have the Patient Cloud mobile ePRO app, 
use the following instructions. When downloading the app, you must use the Apple ID or Google 

 
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account associated with the device. If the Patient Cloud mobile app is already on the device, or if 
you are using a provider's device, you can skip this section.  There are multiple versions of the 
mobile app available.  Ensure that the correct version of the ePRO mobile app is downloaded 
(see below). 
 
You will need an email address that you agree to use for this purpose. The e-mail address is 
needed to uniquely identify you on the ePRO Application, and to reset your password if needed. 
Your e-mail address will only be used for this survey study, and will not be used for mail or 
marketing purposes. 
 
If you decide to use the electronic method to complete the questionnaires, and do not have an e-
mail address, you may sign up for one at no charge at many different websites.  A few sites that 
are commonly used and will allow you to create an email address very easily are Yahoo, Gmail, 
and Outlook. 
 
For iOS (Apple mobile devices):  
 
1. An Apple ID is required for downloading the Patient Cloud mobile ePRO app. 
2. Tap the App Store icon. 
3. Search for the appropriate mobile app (named “Patient Cloud” and using the following 
ico) and follow the installation instructions.  
 
   
For Android: 
1. A Google account is required for downloading the Patient Cloud mobile ePRO app 
2. Tap the Play Store icon. 
3. Search for the appropriate mobile app (named “Patient Cloud” and using the following  
icon) and follow the installation instructions.  
 
 
 
Registering 
You must register in order to complete and submit your study forms. When you register, you will 
create a username, which is your email address, and a password that allows you to log in to the 
Patient Cloud mobile ePRO app. 
 
Note: You must have an activation code to begin this process. If you do not have an activation 
code, please contact your provider.  
There are two possible ways to register. Your provider may have sent you a link to a web address 
where you may register from any web browser, including the one on your device. The other way 
to register is on the Patient Cloud mobile app. 
1. If registering from the Patient Cloud mobile app, tap Register on the 
bottom of the log in page. If registering on the web, open the URL 
shield.imedidata.com on a web browser. 

 
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2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. Enter and confirm your email address. Tap Next. 
6. Enter and confirm your password. Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to 
display the question of your choice. 
8. Enter your security question response. 
9. Tap Create my account to complete your registration.  
If you registered on the Patient Cloud mobile ePRO app, it automatically logs you out. If you 
registered on the web, you are presented with the option to download the Patient Cloud mobile 
ePRO app. You can then proceed to log in with the credentials you created. 
 
Logging in to the App 
1. Enter your Email and Password that you created during the registration 
process. (If you previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow 
the instructions provided. 
 
Setting a PIN Code 
The first time you log in to the Patient Cloud mobile ePRO app, you are given the option to 
create a PIN code. A PIN code allows you to bypass the step of entering your email and 
password every time you need to log in to the Patient Cloud mobile ePRO app. Instead, you can 
enter a four-digit PIN. 
1. If you wish to set a PIN code the first time you log in, tap Yes when 
prompted. 
2. Note: You can also set your PIN at a later time by tapping the options 
menu (three vertical dots) on the top right corner of most pages and 
selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
If you forget your PIN code, tap Forgot PIN and you can access the app using your email and 
password. If you are logged in to the app you may reset your PIN by tapping the options menu 
(three vertical dots) in the top right corner of most pages and selecting Set PIN. 
 
Resetting Your Password 
If you are logged on to the mobile app you can reset your password by using the options menu at 
the top right of most pages. 
1. Tap the options menu icon (three vertical dots) in the top right corner of 
most pages. 
2. Tap Reset Password. 

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3. Follow the instructions to reset your password.
If you are not logged on to the mobile app you can reset your password by selecting Forgot 
Password? on the app’s home screen. 
Completing and Submitting Forms
Once logged in, forms related to your study display on the Tasks page. If you are enrolled in 
multiple studies, select the appropriate study first, and then select a form. New forms can appear 
on the Tasks page at any time, depending on how the study is designed.
There are two types of forms displayed on the Task List page:
x
Scheduled Forms (with a 
icon): These forms have a "Due Date" indicator 
in them so you are aware of the last day by which you will need to complete 
the form. If the form is due in less than one day, you will see the due time in 
hours.
x
Anytime Forms (with a
icon): These forms have "Last Completed Time" 
indicator on them which tells the most recent date or time when you 
completed the form. If you start a form, but do not complete it, you will see an 
'Incomplete" status beneath the form name, along with a half-moon icon. 
To complete and submit form(s):
1. Select the appropriate form.
2. Follow the on-screen instructions until you reach the end of the form 
where you are given the opportunity to review and change your responses 
prior to submitting.
3. If given the opportunity to review and update, review your responses by 
scrolling down the list; if you need to change an answer, tap the 
question to go back and change the answer.
4. When you are ready to submit, tap Submit Your Data.
Note: Once a form is submitted, you will be unable to edit any of your responses. In some cases, 
you may be asked to acknowledge your submission by entering your password. 
PATIENT COMPLIANCE
The patient data imports directly from a device into the Rave database.  There are no documents 
to audit.  The patient-submitted electronic responses are the source documentation.
You can determine if a patient has already submitted an assessment via ePRO by looking in the 
patient’s chart in Rave for the folder labelled “ePRO…” followed by the appropriate assessment 
time.  If there is a completed icon ( 
) the assessment was completed via ePRO.

 
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Security 
All data is encrypted on the device (256 bit encryption and Hyper Text Transfer Protocol Secure 
[https]) and the app requires each user to have a unique username and password for access.  If 
the user is idle for too long (5 minutes inactivity time), the app will time out and the user will 
need to log in again. 
 
The data will only reside on the device for a short period of time.  Once the user clicks “Submit,” 
the data is securely transferred over HTTPS between the device and internal relay to the Rave 
database.  Except for the patient's email address, no identifying information is stored in 
iMedidata. The email address is stored for what purpose?  The patient’s email links the device 
used and ePRO account to where the data is stored.  The patient’s email is not visible to anyone 
in the system. 
 
The Patient information (email/password) does not reside in Medidata Rave EDC and the patient 
accounts are hidden in iMedidata from sites and LPOs. 
 
The Patient Cloud ePRO application is 21 CFR Part 11 compliant and acts as a gateway between 
the device and Medidata Clinical Cloud (MCC).   
 
Messages and information communicated to and from the Patient Cloud ePRO are encrypted and 
therefore this information cannot be read if intercepted while in transit. 
 
Site checklist for activities prior to consenting a patient 
 Accept study invitation at iMedidata.com 
o Site staff must be rostered in RSS and have received an invitation to 
the ePRO application 
 Site staff must have already completed required eLearning assigned in 
iMedidata for the ePRO application before gaining access to the study in 
Rave.  Contact the LPO to request appropriate Rave access to register patients 
in the ePRO application. 
 Verify the iOS or Android operating system is using the most current version 
 Verify that the correct ePRO mobile app is being used. Note only 1 version of 
the ePRO mobile app is active per protocol.  This protocol uses the current 
version named “Patient Cloud” with the cloud and dot icon .   
 
 If using institutional shared devices, for the first patient only: Verify the ePRO 
mobile app is in Multi-User mode.  
Note: Sites should consider copying this site checklist and placing it in the clinic or area where 
site is consenting patients to ePRO and also copy the correct image and name of the ePRO 
mobile app version with it to help remind staff and patients of the correct version being used in 
the protocol. Sites should also inform patients that short term data will only appear on the device 
until responses are completed and submitted.  The patient data will import directly into the 
database once the patient selects the “Submit” button and data will no longer be visible on the 

 
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device. 
 
 
 
Patient withdraws study consent or withdraws consent from participating on ePRO  
CRA must instruct the patients that are participating on ePRO who decide to withdraw  
consent to delete the App from their smart phones. This will prevent QOL reminders from  
being sent to the patient.