Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Lung Non-Small Cell Carcinoma Metastatic Lung Small Cell Carcinoma Metastatic Malignant Breast Neoplasm Metastatic Malignant Digestive System Neoplasm Metastatic Malignant Neoplasm in the Brain Metastatic Malignant Solid Neoplasm Metastatic Melanoma Metastatic Renal Cell Carcinoma Recurrent Brain Neoplasm Stage IV Lung Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 19
Healthy volunteers: no

Brief summary:
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS).

SECONDARY OBJECTIVES:

I. To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs overall survival as compared to SRS.

II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS.

III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS.

IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

V. To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

VI. To tabulate and descriptively compare the adverse events associated with the interventions.

VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.

EXPLORATORY OBJECTIVES:

I. To collect serum, plasma, and whole blood for translational research analyses.

II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.

III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.

IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.

V. To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS.

VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity \>= 4 new brain metastases/year.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial.

ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.

Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.

Arms:
arm 1: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. arm 2: Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.

Interventions: intervention 1: Biospecimen Collection intervention 2: Computed Tomography intervention 3: Magnetic Resonance Imaging intervention 4: Memantine intervention 5: Quality-of-Life Assessment intervention 6: Questionnaire Administration intervention 7: Stereotactic Radiosurgery intervention 8: Whole-Brain Radiotherapy
Intervention descriptions: intervention 1: Undergo blood sample collection intervention 2: Undergo CT intervention 3: Undergo MRI intervention 4: Given PO intervention 5: Ancillary studies intervention 6: Ancillary studies intervention 7: Undergo SRS/fSRS intervention 8: Undergo HA-WBRT

Protocol document:
Prot_SAP_000.pdf: 
NRG ONCOLOGY 
 
NRG-BN009 
 
(ClinicalTrials.gov Identifier NCT #04588246) 
 
PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY (SRS) OR 
HIPPOCAMPAL-AVOIDANT WHOLE BRAIN RADIOTHERAPY (HA-
WBRT) FOR DISTANT BRAIN RELAPSE WITH 
BRAIN METASTASIS VELOCITY ≥4 BRAIN METASTASES/YEAR 
 
 


 
 
 
NRG-BN009 
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Version Date:  April 06, 2023 
NRG Oncology  
Four Penn Center 
1600 JFK BLVD Suite 1020  
Philadelphia, PA 19103 
Nrgoncology.org  
 
NRG-BN009: PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY 
(SRS) OR HIPPOCAMPAL-AVOIDANT WHOLE BRAIN RADIOTHERAPY 
(HA-WBRT) FOR DISTANT BRAIN RELAPSE WITH  
BRAIN METASTASIS VELOCITY ≥4 BRAIN METASTASES/YEAR 
 
ClinicalTrials.gov Identifier NCT04588246  
NCI Version Date: April 06, 2023  
 
Principal Investigator  
Vinai Gondi, MD 
Northwestern Medicine Cancer Center 
Warrenville 
4405 Weaver Parkway 
Warrenville, IL 60555 
630-352-5350 
 
vinai.gondi@nm.org 
Co-Principal Investigator  
Michael Chan, MD 
Wake Forest University Health Sciences 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
336-713-3600 
mchan@wakehealth.edu 
 
Participating Organizations 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
 
Participating Sites 
 U.S. 
 Canada  
 Approved International Member Sites 
 
Protocol Agents:  
Agent 
Supply 
NSC# 
IND# 
IND Sponsor 
Memantine 
Commercial 
102290 
Exempt 
N/A 


 
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Version Date:  April 06, 2023 
 
Document History 
Amendment 1 
April 06, 2023 
Initial  
November 11, 2020 
 
This protocol was designed and developed by NRG Oncology. It is intended to be used only in 
conjunction with 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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STUDY TEAM (06-APR-2023) 
 
PRINCIPAL INVESTIGATOR 
STATISTICIAN 
Principal Investigator/Radiation Oncology 
Vinai Gondi, MD 
Northwestern Medicine Cancer Center 
Warrenville 
Warrenville, IL 
630-352-5350 
vinai.gondi@nm.org 
Co-Principal Investigator/Radiation Oncology 
Michael Chan, MD  
Wake Forest University Health Sciences 
Winston-Salem, NC  
336-713-3600 
mchan@wakehealth.edu 
Mei Polley, PhD 
NRG Oncology Statistics and Data Management Center 
and University of Chicago 
Philadelphia, PA  
773-834-2215 
polleym@nrgoncology.org  
MODALITY CHAIRS 
Neuro-Oncology Chair 
Rimas Lukas, MD  
Northwestern University 
Chicago, IL   
312-695-0990 
rimas.lukas@nm.org  
 
NCORP Community Chair 
Emory McTyre, MD  
NCORP of the Carolinas (Greenville Health System 
NCORP) 
Greenville, SC  
864-455-7070 
emctyre@ghs.org  
Neurosurgery Chair 
Osaama Khan MD  
Northwestern Medicine Cancer Center 
Warrenville 
Warrenville, IL 
630-352-5450 
osaama.khan@nm.org  
Neuroradiology Chair 
Tammie Benzinger, MD, PhD  
Washington University School of Medicine  
St. Louis, MO  
Clinical: 314- 362-5950; Research: 314- 362-1558 
benzingert@wustl.edu  
Medical Physics Chairs 
Wolfgang A. Tomé, PhD 
Albert Einstein College of Medicine 
Bronx, NY  
718-430-3188 
wolfgang.tome@einsteinmed.org 
 
Yunfeng Cui, PhD 
Duke University Medical Center 
Durham, NC  
919-681-2169 
yunfeng.cui@duke.edu 
Comparative Effectiveness Chair 
Mark Mishra, MD  
University of Maryland School of Medicine 
Baltimore, MD  
410-369-5237 
mmishra@umm.edu  
 
 
 


 
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MODALITY CHAIRS Con’t 
Patient Reported Outcomes Chair 
Terri S. Armstrong, PhD, ANP-BC, FAANP 
NCI Center for Cancer Research 
Bethesda, MD  
240-760-6003 
Terri.Armstrong@nih.gov   
 
Neurocognitive Chair 
Jeffrey S. Wefel, PhD, ABPP 
MD Anderson Cancer Center  
Houston, TX  
713-563-0514 
jwefel@mdanderson.org   
 
Imaging Chairs 
Joseph Bovi, MD  
Medical College of Wisconsin 
Milwaukee, WI  
414-805-4474 
JBovi@mcw.edu  
 
Joshua Palmer, MD 
Ohio State University Comprehensive Cancer Center 
Columbus, OH  
614-293-8415 
joshua.palmer@osumc.edu 
 
Translational Science Chair 
Kounosuke Watabe, PhD 
Wake Forest University School of Medicine 
Winston Salem, NC  
336-716-0231 
kwatabe@wakehealth.edu  
 
 
STUDY CHAMPIONS 
Alliance Champion 
Daniel M. Trifiletti, MD 
Mayo Clinic 
Jacksonville, FL 
904-953-1003 
trifiletti.daniel@mayo.edu 
SWOG Champion 
Chad George Rusthoven, MD 
University of Colorado Hospital 
Aurora CO 
720-848-5376 
chad.rusthoven@ucdenver.edu 
 
 
 
 


 
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STUDY-SPECIFIC CONTACTS AND RESOURCES 
For questions/comments related to:                               Contact:  
Protocol Document, IRB review, informed 
consent documents and amendments 
 
Kathryn Okrent, Protocol Coordinator 
NRG Oncology  
215-717-0856 
okrentk@nrgoncology.org  
 
Data Management 
Including submission, eligibility  
 
 
NRG Statistics and Data Management Center Philadelphia 
Micheala (Liz) Wise, CCRC 
215-574-3221 
wisel@nrgoncology.org 
 
Sherrell Carter 
215-574-3213 
carters@nrgoncology.org   
   
 
RTQA – questions related to RT data 
submission 
Denise Manfredi, BS, RT(T) 
NRG Oncology 
215-717-2755 
dmanfredi@acr.org  
 
George Ballinger, RT (R)(T) 
NRG Oncology 
215-574-3163 
gballinger@acr.org 
RT Credentialing 
 
http://irochouston.mdanderson.org  
OR 
IROC-Credentialing@mdanderson.org 
TRIAD Support  – issues pertaining to 
installation, performance, login access, or other 
technical issues 
 
 
 
Diagnostic imaging protocol-related matters or 
issues involving crediting in Rave or receipt of 
diagnostic images 
 
Triad-Support@acr.org 
Additional installation and user guidance is available 
at https://triadhelp.acr.org 
 
 
 
IROCImagearchive@acr.org 
For a timely response, please reference the study/trial 
number in the subject line. 
 
 
Biospecimen Collection 
 
NRG Oncology Biospecimen Bank San Francisco 
415-476-7864 
NRGBB@ucsf.edu 
NRG Oncology Brain Chair 
 
Minesh Mehta, MD 
Miami Cancer Institute 
Miami, FL  


 
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786-527-8014/  
MineshM@baptisthealth.net 
 
 


 
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CONTACT INFORMATION (06-APR-2023) 
 
For regulatory 
requirements: 
For patient enrollments: 
For study 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) for 
regulatory assistance, or 
CTSURegHelp@coccg.org. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
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.  
 
 
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 on with 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. 


 
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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 e-mail:  
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 ................................................................................................................................... 11 
1. OBJECTIVES ........................................................................................................................ 12 
1.1 Primary Objective ................................................................................................................ 12 
1.2 Secondary Objectives........................................................................................................... 12 
1.3 Exploratory Objectives ........................................................................................................ 12 
2. BACKGROUND ................................................................................................................... 13 
2.1 Choice of Salvage Therapy: Whole-Brain Radiotherapy versus Stereotactic Radiosurgery 13 
2.2 Brain Metastasis Velocity .................................................................................................... 13 
2.3 Neuroprotective Strategies During WBRT .......................................................................... 15 
2.4 Neurocognitive Function and Patient Reported Outcomes .................................................. 16 
2.5 Economic and Comparative Effectiveness Analysis ........................................................... 17 
2.6 MR Imaging Analyses ......................................................................................................... 17 
2.7 Summary ............................................................................................................................ 18 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA .............................................................. 19 
3.1 Eligibility Criteria ................................................................................................................ 20 
3.2 Ineligibility Criteria .............................................................................................................. 21 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP .............. 23 
5. TREATMENT PLAN/REGIMEN DESCRIPTION.............................................................. 28 
5.1 Arm 1: Memantine  .............................................................................................................. 28 
5.2 Radiation Therapy ................................................................................................................ 29 
5.3 General Concomitant Medication and Supportive Care Guidelines .................................... 41 
5.4 Duration of Therapy ............................................................................................................. 41 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT ......................................................... 41 
6.1  Memantine .......................................................................................................................... 42 
7. ADVERSE EVENTS REPORTING REQUIREMENTS ...................................................... 43 
7.1 Protocol Agents .................................................................................................................... 43 
7.2 Adverse Events and Serious Adverse Events ...................................................................... 43 
7.3 Adverse Events for Commercial Study Agent: Memantine ................................................. 43 
7.4 Expedited Reporting of Adverse Events .............................................................................. 43 
7.5 Routine Reporting Requirements for Adverse Events 
 
 
     45 
7.6 Pregnancy  
                                                                                                    46 
8. REGISTRATION AND STUDY ENTRY PROCEDURES  ................................................ 46 
8.1 Cancer Trials Support Unit Registration Procedures ........................................................... 47 
8.2 RT-Specific Pre-Registration Requirements........................................................................ 52 
8.3 Patient Enrollment ............................................................................................................... 54 


 
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8.4 Medidata Patient Cloud ePRO Registration ........................................................................ 55 
9. DRUG INFORMATION ....................................................................................................... 56 
9.1 Commercial Agent: Memantine ........................................................................................... 56 
10. PATHOLOGY/BIOSPECIMEN ......................................................................................... 57 
10.1 Biospecimen Submission Tables ....................................................................................... 57 
11. SPECIAL STUDIES (NON-TISSUE) ................................................................................. 58 
11.1 Patient-Reported Quality of Life (QOL) and Neurocognitive Function (NCF) ................ 58 
12. MODALITY REVIEWS ..................................................................................................... 60 
12.1 Radiation Therapy Quality Assurance Reviews ................................................................ 60 
12.2 Drug Quality Assurance Reviews ...................................................................................... 61 
13. DATA AND RECORDS ..................................................................................................... 61 
13.1 Data Management/Collection ............................................................................................ 61 
13.2 Summary of Data Submission ........................................................................................... 62 
13.3 Data Quality Portal ............................................................................................................ 65 
13.4 Global Reporting/Monitoring ............................................................................................ 65 
14. STATISTICAL CONSIDERATIONS ................................................................................ 65 
14.1 Study Design  ..................................................................................................................... 65 
14.2 Study Endpoints ................................................................................................................. 66 
14.3 Primary Objectives Study Design ...................................................................................... 66 
14.4 Study Monitoring of Primary Objectives ........................................................................... 67 
14.5 Accrual/Study Duration Considerations ............................................................................ 71 
14.6 Secondary Objectives Study Endpoints ............................................................................. 71 
14.7 Exploratory Hypothesis and Endpoints .............................................................................. 77 
14.8 Gender/Ethnicity/Race Distribution ................................................................................... 78 
REFERENCES .......................................................................................................................... 80 
APPENDIX I ............................................................................................................................. 86 
APPENDIX II ............................................................................................................................ 92 
APPENDIX III ........................................................................................................................... 97 
APPENDIX IV........................................................................................................................... 98 
APPENDIX V .......................................................................................................................... 104 
 
 
 


 
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NRG-BN009 
SCHEMA (06-APR-2023) 
 
Distant brain relapse with brain metastasis velocity ≥4 brain metastases/year since last SRS*   
(see Section 3.1.2 for BMV Calculation) 
 
STRATIFY 
 
BMV Cohort 
1. >13 brain metastases/year 
2. 4-13 brain metastases/year 
 
Receiving immunotherapy 
1. Yes 
2. No 
 
DS-GPA  
1. ≤2  
2. >2 
 
RANDOMIZE (1:1) 
↓ 
↓ 
Arm 1 
HA-WBRT +  
Memantine 
 
 
Arm 2 
SRS/fSRS 
 
BMV = brain metastasis velocity; DS-GPA = diagnosis-specific graded prognostic assessment; 
fSRS = fractionated stereotactic radiosurgery; HA-WBRT = whole brain radiotherapy with 
hippocampal avoidance; SRS = stereotactic radiosurgery. 
 
*See Appendix V.  “Last SRS” refers to the most recent SRS procedure that the patient 
received prior to enrollment on this study. 
 
 


 
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1. OBJECTIVES 
1.1 Primary Objective (06-APR-2023) 
To determine if hippocampal-avoidant whole brain radiotherapy (HA-WBRT) in 
patients with distant brain failure with brain metastasis velocity ≥4 new brain 
metastases/year prolongs time to neurologic death as compared to stereotactic 
radiosurgery (SRS). 
 
1.2 Secondary Objectives (06-APR-2023) 
1.2.1 To determine if HA-WBRT in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year prolongs overall survival as compared to SRS. 
1.2.2 To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year prolongs intracranial progression-free survival as 
compared to SRS. 
1.2.31.1.3 To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year improves brain metastasis velocity at subsequent 
relapse as compared to SRS. 
1.2.4 To assess perceived difficulties in cognitive abilities, symptom burden and health status 
after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain 
metastasis velocity ≥4 new brain metastases/year. 
1.2.5  To compare neurocognitive function outcomes following HA-WBRT, as compared to 
SRS, in patients with distant brain failure with brain metastasis velocity ≥4 new brain 
metastases/year.  
1.2.6  To tabulate and descriptively compare the adverse events associated with the 
interventions 
1.2.7  To tabulate and descriptively compare the number of salvage procedures used to manage 
recurrent intracranial disease following the interventions 
 
1.3 Exploratory Objectives (06-APR-2023) 
1.3.1 To collect serum, plasma, and whole blood for translational research analyses. 
1.3.2 To collect baseline and all follow-up MR imaging for hippocampal volume, memory 
center substructures, Axial T2 volumes, and quantitative texture analysis. 
1.3.3 To collect baseline and follow-up MR imaging to extract whole brain volume, white 
matter volume and volume of metastatic disease to correlate with cognitive change at 4 
months. 
1.3.4  To evaluate dose-volume histogram parameters to correlate with radiation toxicity. 
1.3.5 To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in 
patients with distant brain failure with brain metastasis velocity ≥4 new brain 
metastases/year at time improves brain metastasis velocity and/or overall survival at 
subsequent relapse as compared to SRS. 
1.3.6 To compare the estimated cost of brain-related therapies and quality-adjusted life years 
in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain 
failure with metastasis velocity ≥4 new brain metastases/year. 
 


 
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2. BACKGROUND 
2.1 
Choice of Salvage Therapy: Whole-Brain Radiotherapy versus Stereotactic 
Radiosurgery  (06-APR-2023) 
The development of brain metastases is an unfortunate and common complication in 
oncology patients and can occur in 10% to 30% of cancer patients (Brown 2018).  
Stereotactic radiosurgery (SRS) has replaced WBRT as standard upfront therapy for 
patients with four or fewer brain metastases due to improved cognitive and patient-
reported outcomes (Brown 2016; Chang 2009; Soffietti 2013).  Multiple phase III 
randomized trials have now shown that WBRT does not improve survival compared to 
SRS alone in patients with 4 or fewer brain metastases (Kocher 2010; Aoyama 2006; 
Churilla 2017). Results from a recent Japanese phase II study suggest that SRS is also 
feasible in patients with up to 10 brain metastases (Yamamoto 2014), and the 
application of SRS in the setting of multiple (>4) brain metastases continues to 
increase.   
 
The expanding application of SRS has led to an increasing incidence of distant brain 
relapses that represent untreated micro-metastatic disease, which would have been 
traditionally treated with upfront WBRT. In the setting of 1-4 newly diagnosed brain 
metastases, this inferior intracranial control of SRS has not translated into decrements 
in survival, cognition or patient-reported outcomes.  However, recent evidence suggests 
that the cognitive decline seen in patients with SRS, while less than with WBRT, can 
still be significant (Brown 2016).  What is not known is whether multiple serial salvage 
SRS procedures may collectively worsen cognition or quality of life.  This question has 
not been studied in the setting of distant brain relapse after SRS, where there exists a 
paucity of data to guide salvage therapy decisions.  
 
The use of WBRT has shown superior intracranial control over SRS monotherapy in 
published randomized trials (Brown 2016, Kocher 2011, Aoyama 2006, Andrews 
2004), given the higher distant brain failure following SRS (Brown 2016, Kocher 2011, 
Aoyama 2006).  Given that the cumulative effects of distant brain failures can lead to 
neurologic deterioration, a WBRT approach is the modality likely best able to mitigate 
neurologic deterioration in the setting of more extensive brain metastasis relapse.  
 
2.2 
Brain Metastasis Velocity (06-APR-2023) 
The research team at Wake Forest University published on the concept of brain 
metastasis velocity (BMV) at the time of distant brain relapse after SRS. This metric 
has the capacity to predict the risk of developing serial distant brain relapses after 
salvage SRS and is strongly associated with survival and neurologic death (Farris 
2017). BMV is defined as:   
 
Brain metastasis 
velocity (BMV) 
 
 
 
= 
 
[Total number of new brain metastases since last SRS] 
[Time interval (in years) since upfront SRS] 
 
 
 
In a cohort of 737 brain metastasis patients from a single institution, Farris et al. 
observed that BMV at first or second distant brain relapse after SRS predicted for 


 
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overall survival (Figure 1a) (Farris 2017). In a larger validation dataset of >2000 brain 
metastasis patients from 9 other institutions, BMV remained prognostic with nearly 
identical median survival outcomes (Figure 1b) (McTyre 2017).  Specifically, patients 
who had a BMV≥4 brain metastases/year had a 7-month shortening in median survival 
as compared to patients with BMV<4 brain metastases/year (p<0.0001). Interestingly, 
the prognostic capacity of BMV remained significant over multiple different systemic 
therapy eras (i.e., before or after 2007, roughly correlating with the emergence of 
multiple targeted therapies with brain penetration). BMV at first distant brain relapse 
was also predictive of BMV at second distant brain relapse, highlighting the ability of 
BMV to serve as a surrogate marker for intracranial control.  The prognostic value of 
BMV has since been validated in two additional published series (Figure 1c) 
(Yamamoto 2019, Fritz 2018). 
 
Importantly, using a centralized definition of neurologic death, BMV at first or second 
distant brain relapse after SRS predicted for neurologic death following salvage SRS 
(Figure 2) (Fritz 2018).  In this study, neurologic death was defined as progressive 
neurologic decline at time of death irrespective of status of extracranial disease or 
death from inter-current disease in patients with severe neurologic dysfunction (Table 
1). Patients with BMV≥4 brain metastases/year were nearly 2-fold more likely to 
suffer neurologic death than patients with BMV<4 brain metastases/year.  A recent 
analysis of brain metastasis patients treated with SRS in the immunotherapy era 
confirmed that BMV remained prognostic for both overall survival and neurologic 
death, with >7-fold increased risk of neurologic death in patients with BMV≥4 brain 
metastases/year (p=0.005) (Figure 2b) (LeCompte 2019). 
 
The summation of these findings underscores the capacity of BMV following SRS to 
distinguish a subset of patients (BMV≥4 brain metastases/year) whose inferior 
intracranial control with salvage SRS significantly raises the risk of neurologic death 
as a primary contributor to inferior survival.  Thus, prevention of neurologic death in 
this high-risk population is an important treatment goal that may impact overall 
survival, especially as systemic therapies continue to improve control of extracranial 
disease. 
 
Figure 1 
 
 
 
 
    
 
 
Figure 2 
A  
 
 
B 


 
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2.3 
Neuroprotective Strategies During WBRT (06-APR-2023) 
Studies demonstrating inferior cognitive outcomes following WBRT relative to SRS for 
1-4 brain metastases were largely conducted prior to the publication of large brain 
metastasis trials testing pharmacologic and technologic neuroprotective strategies 
during WBRT.  These trials were conducted through the legacy RTOG/NRG Oncology 
cooperative groups and have significantly advanced our approach to safer delivery of 
WBRT.   
 
RTOG 0614 was a phase III trial of prophylactic memantine versus placebo during 
WBRT for patients with brain metastases (Brown 2013).  In this trial of 554 patients, 
the addition of memantine to WBRT significantly prevented cognitive decline (HR 
0.78; 95% CI, 0.62 to 0.99; p=0.02) (Figure 3A).  These practice-changing results led 
to the establishment of prophylactic memantine as standard of care during WBRT. 
 
RTOG 0933 was a phase II trial of conformal avoidance of the hippocampus during 
WBRT using intensity-modulated radiotherapy for patients with brain metastases 
(Gondi 2015).  This trial demonstrated highly promising cognitive outcomes relative to 
historical controls and served as the basis for NRG-CC001, a phase III trial of WBRT 
with memantine with or without hippocampal avoidance during WBRT for patients 
with brain metastases.  NRG-CC001 reached its target accrual in March 2018 with 518 
patients randomized. There was no difference in grade 3 or higher toxicity between the 
treatment arms.  The median follow-up for alive patients was 7.8 months.  There was 
no difference between arms in terms of baseline cognitive function, overall survival 
(HR=1.13, 95% CI: 0.89-1.44, p=0.31) or intracranial progression (HR 1.12, 95% CI 
0.90-1.39, p=0.33).   
 
The addition of hippocampal avoidance to WBRT plus memantine significantly 
prevented cognitive decline (Figure 3B; adjusted HR=0.74, 95% confidence interval 
(CI):  0.58-0.95, p=0.02) (18).  The difference was first seen at 4 months and 
maintained throughout the follow-up period, and was attributable to improvements in 
executive function at 4 months (p=0.01) and learning (p=0.049) and memory (p=0.02) 
at 6 months. While age also predicted for prevention of cognitive function failure, test 
for interaction between treatment arm and age was non-significant (p=0.67), indicating 
that the cognitive benefit of hippocampal avoidance does not differ by age.   
 
Importantly, the addition of hippocampal avoidance to WBRT+memantine preserved 
patient-reported symptom burden, as assessed by the M.D. Anderson Symptom 


 
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Inventory Brain Tumor Module (MDASI-BT).  Patients on the HA-WBRT+memantine 
arm experienced less symptom interference and less cognitive symptoms at 6 months 
(estimate=-1.02, p=0.008 and estimate=-0.63, p=0.011, respectively, Table 5) 
compared to the WBRT+memantine arm.  Cognitive symptom differences were driven 
primarily by 2 items: problems with remembering things and difficulty speaking. At 6 
months, patients on the HA-WBRT+memantine arm had less difficulty remembering 
things (mean 0.16 vs. 1.29, p=0.013) and less difficulty speaking (mean -0.20 vs. 0.45, 
p=0.049) as compared to the WBRT+memantine arm.   Greater improvement in fatigue 
at 6 months was reported in the HA-WBRT+memantine arm as compared to the 
WBRT+memantine arm (mean 0.93 vs. -0.16, p=0.036).  Analyses with longer follow-
up (median follow-up of 12.1 months) additionally demonstrated better preservation of 
overall symptom burden (p<0.0001) at 6 months on the HA-WBRT+memantine arm 
compared to the WBRT+memantine arm, while continuing to show similar benefits in 
cognitive function and patient-reported quality of life with hippocampal avoidance. 
 
Based on these practice-changing results, the WBRT arm on this proposed phase III 
trial will include both neuroprotective strategies of prophylactic memantine and 
hippocampal avoidance using intensity-modulated radiotherapy.  Importantly, this trial 
will be one of a few ongoing studies of SRS versus WBRT to incorporate both highly 
effective neuroprotective strategies on the WBRT arm in a manner that will compare 
the neurocognitive and patient-reported cognitive and quality of life effects of greater 
intracranial control versus more targeted intracranial treatment in the modern 
management of brain metastases.  Thus, for this trial, neurocognitive function (NCF) 
and patient-reported outcomes (PRO) will be included as important secondary 
endpoints to compare both neurocognitive outcomes, as well as the perceived impact of 
cognitive symptoms on function, overall symptom burden and general health status.   
 
Figure 3 
A 
 
 
 
B 
 
 
 
2.4 
Neurocognitive Function and Patient Reported Outcomes 
The current trial will build on the successes of RTOG 0614 and NRG-CC001 in 
utilizing the same NCF and PRO measures with the addition of the PROMIS Cognitive 
Function Short Form 4a self-report assessment. There are a number of advantages of 
such an approach including familiarity and acceptance of these measures by clinical 
Cognitive Function Failure (%)
0
25
50
75
100
Months from Randomization
0
3
6
9
12
15
Patients at Risk
Memantine
Placebo
Patients at Risk
75
66
Patients at Risk
33
25
Patients at Risk
27
19
Patients at Risk
15
12
Patients at Risk
9
9
Failures
219
219
Total
256
252
p (one-sided) =
0.01
HR=
0.784 (0.621, 0.988)
Memantine
Placebo


 
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research staff, the well-established use and validation of these measures in brain 
metastasis research, and the possibility of future post-hoc analyses between studies.   
 
The neurocognitive tests to be used in this study (the Hopkins Verbal Learning Test – 
Revised (Benedict 1998), Trail Making Test (Tombaugh 2004), and the Controlled Oral 
Word Association (Ruff 1996) are the same tests as were used in RTOG 0614, NRG-
CC001, NCCTG/Alliance N0574, and NCCTG/Alliance N107C, and that are being 
used in numerous ongoing brain met trials (e.g., NRG-CC003, SWOG S1827).   
 
While NCF outcomes have been recognized as being crucial in the brain metastasis 
population (Lin 2013), there is also interest in evaluating the impact of treatment arm 
on patient-reported outcomes. PROMIS Cognitive Function Short Form 4a measures 
perceived cognitive abilities (e.g., memory, attention, and decision making) and the 
application of such abilities to everyday tasks (e.g., planning, organizing, calculating, 
remembering and learning).  Symptom assessment measures such as the MDASI-BT 
have been specifically developed in patients with brain tumors to capture patient self-
reports of symptom severity and the patient's perception of the impact or interference 
with daily activities.  The MDASI-BT has demonstrated reliability and validity in the 
brain tumor patient population, including predictive validity for tumor recurrence 
(Armstrong 2006, Armstrong 2011) and sensitivity to cognitive preservation strategies 
(Brown in press).  Health-related general health status will also be measured using the 
EQ-5D-5L, an established, validated measure that has been used in brain metastasis 
populations (Takura 2010, Langley 2013). Combined, the PROMIS, MDASI-BT and 
EQ-5D-5L assessments are brief and therefore not a significant burden for patients to 
complete.  
 
2.5 
Economic and Comparative Effectiveness Analysis (06-APR-2023) 
Prior cost-effectiveness analysis (CEA) studies of SRS for brain metastases have been 
focused on patients with newly diagnosed brain metastases (Lester-Coll 2016), and 
have typically not accounted for increased costs of WBRT with hippocampal avoidance 
and memantine (Savitz 2015).  This will be the first study to prospectively conduct a 
CEA of SRS and HA-WBRT with memantine for patients requiring salvage brain-
directed radiotherapy for recurrent brain metastases.     
 
2.6 
MR Imaging Analyses (06-APR-2023) 
Imaging-based predictors of neurocognitive decline are becoming increasingly 
informative for clinicians making decisions for their patients with brain metastases. 
Prior work has shown that MR T2/FLAIR volume significantly increases after WBRT 
and that the presence of pre-treatment MR T2/FLAIR abnormality is a predictor of 
white matter injury (WMI) post-treatment (Sabsevitz 2013). Furthermore, on secondary 
analysis of RTOG 0933, pre-treatment MR T2/FLAIR WMI was found to correlate 
with subsequent memory decline following HA-WBRT (Bovi 2019). This observation 
was corroborated on planned NRG CC001 secondary analysis, which demonstrated that 
pre-treatment WMI volume predicted for post-treatment neurocognitive decline at 4-
and 12-months following HA-WBRT (Bovi 2020). These findings suggest a greater 
baseline susceptibility to neurocognitive decline in patients with larger volume pre-


 
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treatment despite attention to hippocampal dosimetry. As a follow-up to these findings, 
we hypothesize that brain metastasis patients with larger MR-determined pre-treatment 
WMI develop more neurocognitive decline.  
 
In addition to WMI, WBRT can lead to atrophy of the brain and various substructures 
including the hippocampus (Hoffmann 2018, Seibert 2017).  Additional studies have 
also found a correlation with whole brain volume loss, poor cognition, and overall 
survival (Gui 2019, Hoffman 2018). Injury to the right versus left hippocampus appears 
to correlate with loss of different memory outcomes. Pediatric patients demonstrate 
worse visual and memory outcomes with radiation when there is higher dose to the left 
hippocampus (Zureick 2018). In healthy older adults, hippocampal volumes correlate 
with episodic memory (Caillaud 2019). An additional hypothesis is that the use of HA-
WBRT in lieu of SRS may lead to more atrophy of the whole brain and hippocampus, 
correlating with inferior cognitive outcomes. The volume of the whole brain and 
memory substructures will be measured in NRG-BN009 to enable future explorations 
of these objectives.  
 
2.7 
Summary (06-APR-2023) 
At the present time, no level I evidence exists on appropriate salvage therapy (SRS or 
HA-WBRT) for distant brain relapses after SRS management.  As such, there is no 
established standard of care in this important and increasingly common real-world 
scenario.  BMV following SRS distinguishes a subset of patients (BMV≥4 brain 
metastases/year) whose inferior intracranial control with salvage SRS not just portends 
poorer survival, but also significantly raises the risk of neurologic death as a primary 
contributor to that survival.  Improving intracranial control in this high-risk population 
is an important treatment goal in order to prevent neurologic death.  Given the 
predominance of neurologic causes for death in this high-risk population and ongoing 
improvements in systemic therapy for control of extracranial disease, prevention of 
neurologic death may also impact overall survival. 
 
We hypothesize that for patients with distant brain failure with BMV ≥4 brain 
metastases/year, the improved intracranial control of HA-WBRT relative to SRS will 
translate into benefits in terms of prevention of neurologic death and, as a secondary 
endpoint, prolongation of overall survival.  Given practice-changing advances in the 
use of prophylactic memantine and hippocampal avoidance as neuroprotective 
strategies to enable safer delivery of HA-WBRT, as secondary objectives, we seek to 
also compare the NCF and patient-reported outcomes of HA-WBRT relative to SRS.  
 
Demonstration of neurologic death and overall survival benefits from HA-WBRT for 
patients with distant brain failure with BMV ≥4 brain metastases/year would not only 
validate the importance of BMV as a predictor of survival outcomes, but also establish 
a role for HA-WBRT in the management of such high-risk brain metastasis patients.  
Any associated survival benefit of HA-WBRT over SRS would have to be weighed 
against any corresponding impact on patient-reported cognitive, symptom or quality of 
life outcomes, which are important patient-centered outcomes that will be prospectively 
and longitudinally collected in this proposed study.  If this proposed trial were not to 


 
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find a neurologic death or overall survival benefit from HA-WBRT, then the secondary 
endpoint of patient-reported outcomes would help define the appropriate salvage 
therapy, especially given the inclusion of practice-changing neuroprotective strategies 
of prophylactic memantine and hippocampal avoidance during WBRT.   
 
Additionally, the question of whether SRS or HA-WBRT is the optimal salvage 
modality for distant brain relapse is significant from a medical resources standpoint, 
given high costs of both treatment approaches at a time of increasing emphasis on 
value-based healthcare delivery.  Given the growing support by patients and healthcare 
providers for multiple serial SRS treatments (over an HA-WBRT approach that may 
obviate the need for subsequent SRS treatments due to improved intracranial control ) 
without well-established risk/benefit data, there is a critical need for a robust cost-
effectiveness analysis of both treatment approaches in the setting of a prospective 
multi-institutional cooperative group clinical trial.  Thus, this trial includes proposed 
comparative and cost-effectiveness secondary analyses.  
 
Finally, in the contemporary era where many patients with brain metastases receive 
treatment prior to or after their distant brain relapse with either targeted therapies or 
immunotherapies, there is a need for a clearer understanding of both the potential 
toxicities as well as potential benefits of these treatments in relation to HA-WBRT 
versus SRS.  While the advent of immunotherapies has improved survival outcomes in 
subgroups of brain metastasis patients, neurologic death remains a relevant endpoint.  
Two recent analyses have assessed the effect of immunotherapies on neurologic death 
in the brain metastasis population.  Lanier et al (2019) reported a cumulative incidence 
of neurologic death in brain metastasis patients receiving immunotherapy was only 
10%.  However, in the population with BMV ≥4 brain metastases/year, LeCompte et al 
(2019) reported cumulative incidence of neurologic death to be 38%, confirming in a 
modern immunotherapy-treated population that neurologic death rates remain 
unacceptably high in the BMV≥4 cohort.  This prospective study with pre-specified 
endpoints addressing these issues and including immunotherapy usage as a 
stratification factor will provide additional insight. 
 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
 
Notes: 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 


 
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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 
 
 
3.1. 
Eligibility Criteria (06-APR-2023) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
3.1.1 Patients must have developed their distant brain relapse(s) at least 8 weeks after last 
SRS and within 21 days prior to randomization 
• Distant brain relapse lesions to be treated must measure <3.0 cm in maximal extent 
and total volume of distant brain relapses to be treated must measure <30 mL on the 
contrast-enhanced diagnostic MRI brain scan obtained within 21 days prior to 
randomization.   
• “last SRS” refers to the most recent SRS procedure that the patient received prior to 
enrollment on this study. 
• Distant brain relapse lesions must be diagnosed on MRI, which will include the 
following elements: 
REQUIRED MRI ELEMENTS 
• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled 
gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 
3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo 
(TFE) MRI, BRAVO (Brain Volume Imaging) or 3D Fast FE (field echo).  The T1-
weighted 3D scan should use the smallest possible axial slice thickness, not to 
exceed 1.5 mm. 
• Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged).  
• A minimum of one axial T2 FLAIR (preferred) or T2 sequence is required.  This 
can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the 
axial plane. 
 
ADDITIONAL RECOMMENDATIONS 
• Recommendation is that an axial T2 FLAIR (preferred) sequence be performed 
instead of a T2 sequence. 
• Recommendation is that that pre-contrast 3D T1 be performed with the same 
parameters as the post-contrast 3D T1. 
• Recommendation is that imaging be performed on a 3 Tesla (3T) MRI. 
• Recommendation is that the study participants be scanned on the same MRI 
instrument at each time point. 
• Recommendation is that if additional sequences are obtained, these should meet the 
criteria outlined in Kaufmann et al., 2020. 
• If additional sequences are obtained, total imaging time should not exceed 60 
minutes.   


 
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See Appendix IV for a summary of key imaging requirements, and contact the 
Neuroradiology and Imaging Co-Chairs for further information or assistance if 
needed. 
 
3.1.2 Brain metastasis velocity (BMV) since last SRS must be ≥4 brain metastases/year.  
 
Use the following equation to calculate BMV  
 
           BMV 
 
= 
 
[Total number of new brain metastases since last SRS] 
[Time interval (in years) since last SRS] 
 
 
“last SRS” refers to the most recent SRS procedure that the patient received prior to 
enrollment on this study. 
 
BMV calculations should be rounded down to integers. For example, a patient 
who had the last SRS 2.6 years ago and had 10 (cumulative) new brain metastases 
since then would have BMV = 10/2.6 = 3.85. This patient would be assigned to the 
BMV < 4 category, and hence is NOT eligible for this trial. 
 
3.1.3  The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
3.1.4 Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, 
non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or 
gastrointestinal cancer within 10 years prior to randomization. If the original histologic 
proof of malignancy is greater than 10 years, then pathological (i.e., more recent) 
confirmation is required (e.g., from a systemic metastasis or brain metastasis). 
• Other histologies are not permitted. 
3.1.5 History and physical examination within 28 days prior to randomization 
3.1.6 Age ≥ 18 
3.1.7 Karnofsky Performance Status of ≥70 within 28 days prior to randomization; 
3.1.8 Adequate renal function within 28 days prior to randomization defined as follows: 
• Calculated creatinine clearance (CrCl) ≥30 ml/min 
For males: CrCl = [140-age (years)] · *Weight (kg)/[72 · serum creatinine (mg/dL)] 
For females: CrCl = 0.85 · [140-age (years)] · *Weight (kg)/[72 · serum creatinine 
(mg/dL)] 
*Actual weight should be used unless patient is greater than 30% above 
IBW, then used Adjusted BW (= IBW + 0.4*actual BW) in the Cockcroft 
Gault equation. 
• BUN within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN 
is 20 mg/dL, then BUN up to 30 mg/dL is permitted). 
3.1.9 Negative urine or serum pregnancy test (in women of childbearing potential) within 14 
days prior to randomization.  
 
 
3.2 
Ineligibility Criteria (06-APR-2023) 
Patients with any of the following conditions are NOT eligible for this study. 
 


 
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3.2.1 BMV ≥4 brain metastases/year at time of any SRS prior to enrollment. 
• Patients are permitted to have undergone multiple SRS treatments to different brain 
metastases so long as prior BMV has been less than 4 brain metastases/year.  
3.2.2 Prior WBRT or prophylactic cranial irradiation. 
3.2.3 Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside 
previously SRS-treated metastases is allowed) 
3.2.4 Brain metastases from primary germ cell tumor or lymphoma. 
3.2.5 Definitive leptomeningeal metastasis. 
3.2.6 Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; Concurrent 
immunotherapy is permitted. 
3.2.7 Radiographic evidence of enlargement or other architectural distortion of the lateral 
ventricles, including placement of external ventricular drain or ventriculoperitoneal 
shunt. 
3.2.8 Known history of demyelinating disease such as multiple sclerosis 
3.2.9  Inability to swallow pills 
3.2.10 Contraindication to MR imaging such as non-MR conditional implanted metal devices 
or unknown metallic foreign bodies, or contraindication to gadolinium contrast 
administration during MR imaging, such as anaphylactic allergy that cannot be 
adequately addressed with pre-contrast medications or acute kidney injury 
3.2.11 Contraindications to memantine, including: 
• Allergy, including prior allergic reaction to memantine 
• Intractable seizures on adequate anticonvulsive therapy—more than 1 seizure per 
month for the past 2 months 
• Current use of NMDA agonist 
• Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with 
memantine 
3.2.12 Severe, active co-morbidity defined as follows: 
• Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months  
• Transmural myocardial infarction within the last 6 months  
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
randomization  
• Chronic obstructive pulmonary disease exacerbation or other acute respiratory 
illness precluding study therapy at the time of randomization  
• Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic 
disease 
• Renal tubular acidosis or metabolic acidosis 
• HIV positive with CD4 count < 200 cells/microliter. Note that patients who are 
HIV positive are eligible, provided they are under treatment with highly active 
antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 
30 days prior to randomization. Note also that HIV testing is not required for 
eligibility for this protocol. 
3.2.13 
Pregnant or lactating women, or women of childbearing potential and men who are 
sexually active and not willing/able to use medically acceptable forms of 
contraception; this exclusion is necessary because the medication and radiation 
involved in this study has unknown effects on the unborn fetus. 


 
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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
(06-APR-2023) 
 
PRE-TREATMENT ASSESSMENTS 
Assessment 
Prior to Randomization 
Prior to Treatment  
Brain MRI w/wo contrast (See 
Section 3.1.1 and Appendix IV) 
demonstrating BMV≥4 brain 
metastases/year since last distant 
brain relapse 
Within 21 days 
 
Neurocognitive: HVLT-R, TMT, 
COWA (upload in RAVE 
required) 
 
X 
QOL: MDASI-BT, EQ-5D-5L, 
PROMIS cognitive function* 
 
X 
Histological/cytological 
evaluation 
X  
 
Neurologic exam* 
Within 28 days 
 
History/physical exam* 
Within 28 days 
 
Karnofsky performance status* 
Within 28 days 
 
Calculated creatinine clearance, 
BUN 
Within 28 days 
 
Urine or serum pregnancy test  
(if applicable) 
Within 14 days 
 
Serum for banking and laboratory 
correlative studies (for consenting 
patients; see Section 10 for 
details) 
 
X 
*In person preferred; may be conducted by telehealth visit at the discretion of the site-
identified qualified healthcare professional. 
 
 


 
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ASSESSMENTS DURING TREATMENT AND IN FOLLOW-UP 
 
Assessments  
From start of 
SRS/fSRS or  
HA-WBRT:  
at months 2, 4, 
6, 9 and 12 
(+/- 2 weeks) 
Every 6 months after 
month 12 
(+/- 4 weeks) 
Within 21 days after 
patient death 
Physical exam* 
X 
X 
 
Neurologic exam* 
X 
X 
 
Karnofsky performance 
status* 
X 
X 
 
Adverse event 
evaluation 
X 
X 
 
Calculated creatinine 
clearance (Arm 1 
patients) 
At each visit 
while on 
memantine, or as 
clinically 
indicated. 
 
 
Brain MRI w/wo 
contrast (See Section 
3.1.1 and Appendix IV) 
X 
As clinically indicated 
 
Neurocognitive: HVLT-
R, COWA, TMT 
(upload in RAVE 
required) 
X 
 
 
QOL: MDASI-BT, EQ-
5D-5L, PROMIS 
cognitive function* 
X 
 
 
Serum for banking and 
laboratory correlative 
studies (for consenting 
patients; see Section 10 
for details) 
Within 2 months 
of start of 
SRS/fSRS or 
HA-WBRT 
 
 
Assessment of 
neurologic death (for 
details, see Definition of 
Disease Assessments/ 
Neurologic Death) 
below 
 
 
X 
*In person preferred; may be conducted by telehealth visit at the discretion of the site-
identified qualified healthcare professional. 
Definition of Disease Assessments 
 
Neurologic death: 
Within 21 days of patient death, the Neurologic Death Form should be completed by the 


 
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treating physician to determine if death was due to neurologic causes and submitted via 
Medidata Rave.  In addition, any medical record documentation that supports this 
assessment should be submitted via Medidata Rave to facilitate central review of 
neurologic death assessment.  All submitted medical record documentation should have all 
Protected Health Information (PHI) blacked out.  
 
Each Neurologic Death Form will undergo real-time central review by the trial’s Co-
Principal Investigators Dr. Gondi and Dr. Chan and Neuro-Oncology Co-Chair Dr. Lukas, 
all of whom will be blinded to the treatment arm of the enrolled patient.  
 
Definition of neurologic death (death due to neurologic causes):  
1) Progressive neurologic decline or new neurologic symptoms/signs at time of death 
irrespective of status of extracranial disease OR  
2) Death from inter-current disease in patients with severe neurologic dysfunction. 
 
 
 


 
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Sample of Case Report Form for Neurologic Death determination: 
(Please note this is only a sample, is subject to change, and should be used only as a guide 
with precise details/information provided on the Case Report Form.) 
 
Date of death: 
 
1. Prior to death, was the patient experiencing progressive neurologic decline? (Y/N) 
If Y, were they experiencing progressive 
... motor weakness? (Y/N) 
... difficulty with ambulation? (Y/N) 
... vision changes? (Y/N) 
... difficulty understanding? (Y/N) 
... difficulty speaking? (Y/N) 
... seizures? (Y/N) 
... confusion? (Y/N) 
... episodes of mental status changes? (Y/N) 
... cognitive slowing? (Y/N) 
…cranial nerve palsies? (Y/N) 
... other neurologic symptoms (Y/N).  If Y, please define. 
 
2. One month prior to death, was the patient experiencing any new neurologic 
symptoms/signs? (Y/N) 
If Y, were they experiencing new 
... motor weakness? (Y/N) 
... difficulty with ambulation? (Y/N) 
... vision changes? (Y/N) 
... difficulty understanding? (Y/N) 
... difficulty speaking? (Y/N) 
... seizures? (Y/N) 
... confusion? (Y/N) 
... episodes of mental status changes? (Y/N) 
... cognitive slowing? (Y/N) 
…cranial nerve palsies? (Y/N) 
... other neurologic symptoms (Y/N).  If Y, please define. 
 
3. If Y to (1) or (2), did the patient develop other progressive medical conditions (e.g., 
hepatic encephalopathy) that could explain the progressive neurologic decline or new 
neurologic symptoms/signs? (Y/N) 
If such a progressive medical condition existed, please define and explain the progressive 
medical condition and please provide information on the status of intracranial metastatic 
disease on last brain MRI before death. 
  
4. If N to (1) or (2) and death is due to inter-current disease, did the patient have severe 
neurologic dysfunction at time of death? (Y/N).  If Y, please define. 
 
 


 
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Intracranial progression 
Target lesions: 
Contrast-enhancing lesions that can be accurately measured in at least 
one dimension with a minimum diameter being double the slice thickness 
of the MRI scan (0mm skip) and is visible on two or more axial slices 
(e.g.., the minimal lesion diameter can be 4mm if the slice thickness is 
2mm with 0mm skip). 
 
The diameter perpendicular to the longest diameter in the plane of 
measurement should be at least 2mm for the lesion. 
 
Lesions around a cyst or surgical cavity should not be considered a target 
lesion unless there is a nodular component that measures 5mm or more in 
longest diameter and 2mm or more in perpendicular plane.  The cystic or 
surgical cavity should not be measured for the determination of a 
response. 
 
As per RANO-BM criteria (Lin 2015), intracranial progression will be defined as: 
1) Local progression of lesions treated with prior radiation  
a. At least a 20% increase in the sum of longest diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study) and 
b. At least a 5mm or more increase in one target lesion, or 
 
2) Distant Progression/development of new brain lesion 
a. A new lesion is one that was not present on prior scans and is visible in 
minimum two projections.  If a new lesion is equivocal, for example 
because of its small size, continued therapy can be considered, and 
follow up assessment will determine if the new lesion is new disease. If 
repeat scans confirm there is definitely a new lesion, progression should 
be declared using the date of initial scan showing the new lesion. 
 
Note: Intracranial leptomeningeal progression is a subtype of distant progression characterized 
by linear, curvilinear, or nodular contrast enhancement along the leptomeningeal surfaces 
including, but not limited, cortical sulci, cranial nerves, cerebellar folia, and ventricular 
ependymal surfaces. Cytological evaluation of cerebrospinal fluid (CSF) can offer 
confirmatory data on suspected leptomeningeal progression, but is not required for diagnosis. 
Questions regarding leptomeningeal progression in an individual case should be reviewed with 
the local Radiologist.   
 
Brain metastasis velocity at subsequent distant brain relapse 
Brain metastasis velocity at subsequent distant brain relapse (BMVs) is defined as follows: 
 
Brain metastasis 
velocity (BMVs) 
 
 
 
= 
 
[Total number of new brain metastases since on-study SRS/HA-WBRT] 
[Time interval (in years) since on-study SRS/HA-WBRT] 
 
 
 


 
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5. TREATMENT PLAN/REGIMEN DESCRIPTION (06-APR-2023) 
 
Protocol treatment must begin within 21 calendar days after randomization and within 
42 days of diagnostic MRI used for eligibility.   
 
 
Protocol 
Treatment 
Arm 1* 
Arm 2 
Dose 
SRS/fSRS 
 
X 
See Section 5.2. 
HA-WBRT 
X 
  
30 Gy in 10 fractions over 2 weeks 
Memantine 
X 
  
Target BID dose 20 mg/day OR target extended-
release dose 28 mg/day (refer to tables in 5.1.2) 
*Arm 1: At the treating physician’s discretion, consolidative SRS boost to selected brain 
metastases following HA-WBRT is permitted during the follow-up period before radiographic 
progression of those brain metastases.  There are no protocol specifications regarding this 
consolidative SRS boost. 
 
5.1 
Arm 1: Memantine  (06-APR-2023) 
5.1.1 Memantine should preferably start prior to HA-WBRT as soon as possible after 
randomization but must start no later than before the fourth HA-WBRT 
treatment. 
 
If a patient is enrolled on the study and is unable to acquire memantine, the 
patient should remain on the study and otherwise proceed per the assigned 
treatment per study guidelines and be followed per protocol.  This should be 
documented in the memantine pill diary. 
 
5.1.2 Both extended release memantine and twice daily memantine dosing will be allowed. 
Patients continue on memantine for 24 weeks. The dosing and schedule will be outlined 
separately for each. See Section 6 for dose modifications in the setting of abnormal 
renal function. 
 
 
Twice Daily Dosing Memantine 
 
The target dose for memantine is 20 mg (10 mg divided twice daily). Dose is escalated 
by 5 mg per week to target of 10 mg twice daily (i.e., 5 mg a day for week 1, then 5 mg 
BID for week 2, then 10 mg in AM and 5 mg in PM for week 3, then 10 mg in AM and 
10 mg in PM by week 4). 
 
 
Daily AM Dose 
Daily PM Dose 
Week 1 
5 mg 
None 
Week 2 
5 mg 
5 mg 
Week 3 
10 mg 
5 mg 
Weeks 4-24 
10 mg 
10 mg 
 
Extended Release Memantine 
The target dose for extended release memantine is 28 mg. Dose is escalated by 7 mg 


 
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per week to target of 28 mg daily (i.e., 7 mg a day for week 1, then 14 mg a day for 
week 2, then 21 mg a day for week 3, then 28 mg a day for by week 4). 
 
 
Daily Dose Extended Release Memantine 
Week 1 
7 mg 
Week 2 
14 mg 
Week 3 
21 mg 
Weeks 4-24 
28 mg 
 
 
 
Administration 
Memantine is administered by mouth taken with full glass of water (>8 oz). Memantine 
is well absorbed after oral administration and absorption is not affected by food and 
therefore can be taken with or without food. Doses should be taken within 2 hours of 
scheduled time.  For the twice daily dosing memantine, outside the 2 hours, patient 
should skip the dose.  Missed doses should be documented but patients should not try to 
make up missed doses. If treatment is interrupted for longer than several days, dosing 
may need to be resumed at lower doses and retitrated. Memantine should be continued 
through the duration of 24 weeks regardless of disease status (i.e., if a patient 
progresses in the brain as long as study drug is tolerated study drug should be 
continued). 
 
Memantine Pill Diary 
Prior to starting treatment, the patient will be provided with and instructed in the proper 
use of a pill diary (See Appendix II) to record daily pill consumption. This record will be 
checked for compliance by the study nurse. The diary will be retained in the patient’s 
record for submission to NRG ONLY upon request; i.e., diaries are not to be submitted 
but will be retained at the site as source documents. Compliance will be assessed by the 
study nurse at each study visit during treatment (at months 2, 4, and 6) and is defined as 
>85% of doses accurately taken, but for any noncompliance patients must be re-
instructed.    If treatment is interrupted for longer than several days, dosing may need to 
be resumed at lower doses and retitrated. 
 
5.2 
Radiation Therapy (06-APR-2023) 
 
5.2.1 Arm 1: HA-WBRT  
 
Pre-treatment reviews are required for both credentialed and non-credentialed 
physicians.  The Pre-Treatment Review process requires 3 business days from the receipt of 
complete data.   
 
PHYSICIANS/INSTITUTIONS PREVIOUSLY CREDENTIALED FOR HA-WBRT:  
Patients can be enrolled by treating physicians and institutions that have passed pre-enrollment 
benchmark cases for hippocampal contouring and HA-WBRT treatment planning from prior or 
ongoing trials NRG-CC009, NRG-CC003, NRG-CC001, RTOG 0933, or CCTG CE.7.   
 
The first patient enrolled from each credentialed treating physician and institution in Arm 1 


 
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will require a Pre-Treatment Review of hippocampal contouring and HA-WBRT treatment 
plan.  Credentialed physicians and institutions and that have passed one (1) pre-treatment 
review of a patient enrolled on the HA-WBRT arm of NRG-CC009, NRG-CC003, NRG-
CC001, or CCTG CE7 will be permitted to enroll patients on NRG-BN009 without pre-
treatment case review.  
 
The patient cannot start treatment until they have received approval from the Imaging and 
Radiation Oncology Core (IROC)-Philadelphia RT.  The Pre-Treatment Review process 
requires 3 business days from the receipt of complete data.  For each credentialed treating 
physician and institution, if an unacceptable deviation occurs the next case may require a Pre-
Treatment review.  
 
PHYSICIANS/INSTITUTIONS NOT PREVIOUSLY CREDENTIALED FOR HA-WBRT :  
A non-credentialed physician may enroll to this trial but will be required to pass successfully 2 
pre-treatment reviews on NRG-BN009. Once this requirement has been met the credentialing 
requirement will have been met in lieu of completing a benchmark case. If the first 2 pre-
treatment cases are not acceptable, then the physician/institution will be required to continue 
with pre-treatment reviews until 2 pre-treatment reviews are successfully passed.  
Alternatively, if the institution has a previously credentialed physician then that physician will 
need to review the contours for any future cases until the credentialing requirement has been 
met.  The patient cannot start treatment until they have received approval from the Imaging and 
Radiation Oncology Core (IROC)-Philadelphia RT.   
 
See Section 13.2 for specifics on submission requirements 
 
At the treating physician’s discretion, consolidative SRS boost to selected brain 
metastases following HA-WBRT is permitted during the follow-up period before 
radiographic progression of those brain metastases.  There are no protocol specifications 
regarding this consolidative SRS boost. 
 
Treatment Technology 
 
IMRT is required for HA-WBRT on Arm 1.  Fixed-gantry IMRT, helical tomotherapy or 
VMAT can be used.  All participating sites must be credentialed for IMRT.  Megavoltage 
beam of 6MV or greater must be used with a minimum source-axis distance of 100cm.  The 
exception is the use of the helical tomotherapy unit that has a source-axis distance of 85cm.   
 
 
 
Immobilization and Simulation 
 
Immobilization 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be 
achieved using appropriate clinical devices.   
 
For HA-WBRT with or without optional simultaneous integrated boost, patients must be 
immobilized in the supine position using an immobilization device such as an Aquaplast mask 


 
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over the head.  Patients must be treated in the immobilization device. 
 
Simulation Imaging For HA-WBRT planning with or without optional simultaneous integrated 
boost, a non-contrast treatment-planning CT scan of the entire head region using the smallest 
possible axial slice thickness not exceeding 2.5 mm will be required. The axial slice thickness 
of the treatment-planning CT scan should match the MRI axial slice thickness as much as 
possible.  The treatment-planning CT scan must be acquired with the patient in the same 
position and immobilization device as for treatment.  This should be obtained within 21 days 
prior to initiating treatment. 
 
 
 
Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
 
To yield acceptable image quality, the pre (if performed) and post gadolinium contrast-
enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest 
possible axial slice thickness not exceeding 1.5 mm. These imaging sequences should be 
obtained with the patient in the supine position 
 
 
See Appendix IV for a summary of key imaging requirements. 
 
Downloading MRI Protocol Documents:   
If you don't currently have a three-dimensional SPGR, MP-RAGE, or TFE sequence on 
your scanner, many acceptable examples are available for download from the 
Alzheimer's Disease Neuroimaging Initiative (ADNI) 
http://adni.loni.usc.edu/methods/documents/mri-protocols. 
 
Sites should contact the Neuroradiology or Imaging Co-Chairs for further information 
or assistance if needed. 
 
Note: The MRI study is mandatory irrespective of randomization to Arms 1 or 2 of this 
study. 
 
For Arm 1 HA-WBRT planning, the MRI and treatment-planning CT should be fused 
semi-automatically for hippocampal contouring. 
 
 
 
Image fusion between CT and MRI must be performed by a medical physicist and/or 
treating physician.   
 
Definition of Target Volumes and Margins 
 
For HA-WBRT on Arm 1, the following structures are required and must be named for 
digital RT data submission as listed in the table below.  These structures must be contoured 
and submitted with the treatment plan. Resubmission of data may be required if labeling of 
structures does not conform to the standard DICOM name listed.  Capital letters, spacing and 


 
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use of underscores must be applied exactly as indicated.  
 
Standard Name 
Description 
Detailed Specification 
CTV_3000 
CTV to receive 30 Gy 
 
 
The whole-brain parenchyma to 
the foramen magnum. 
PTV_3000 
PTV to receive 30 Gy 
 
 
The CTV_3000 excluding the 
hippocampal avoidance region. 
No set-up margin is added. 
 
 
 
Definition of Critical Structures and Margins 
 
For HA-WBRT on Arm 1, all structures listed in the table below must be contoured and 
labeled for digital RT data submission as listed. 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.  All structures should be 
contoured on the planning CT, using the fused MRI for guidance as described below.  Due to 
variance in eye position between the CT and MRI, the lenses and optic nerves should be 
contoured using the CT dataset only. 
 
Standard Name 
Description 
Descriptive Details 
Hippocampi 
Bilateral 
hippocampal 
contours  
 
Bilateral hippocampal contours will be manually generated on 
the fused planning MRI/CT image set by the treating physician 
according to contouring instructions specified on 
http://www.rtog.org//corelab/contouringatlases/hippocampalsp
aring.aspx. 
Hippocampi_05 
Hippocampal 
avoidance 
region 
Generated by three-dimensionally expanding the hippocampal 
contours by 5 mm.   
Hippo_L  
Left 
hippocampus 
Bilateral hippocampal contours will be subdivided into Left 
and Right hippocampi. 
Hippo_R  
Right 
hippocampus 
Bilateral hippocampal contours will be subdivided into Left 
and Right hippocampi. 
Lens_L 
Left lens 
Due to variance in eye position between the CT and MRI, if 
possible, the left lens should be contoured using the CT dataset 
only. 
Lens_R 
Right lens 
Due to variance in eye position between the CT and MRI, if 
possible, the right lens should be contoured using the CT 
dataset only. 
OpticNrv_L 
Left optic 
nerve 
Due to variance in eye position between the CT and MRI, if 
possible, the left optic nerve should be contoured using the CT 
dataset only. 
OpticNrv_R 
Right optic 
nerve 
Due to variance in eye position between the CT and MRI, if 
possible, the right optic nerve should be contoured using the 
CT dataset only. 
OpticChiasm 
Optic chiasm 
Located above the pituitary fossa, the optic chiasm includes 
both anterior and posterior limbs.  It is best visualized on 
SPGR/MPR/TFE T1 MRI sequence, but should be confirmed 
on CT dataset due to potential variation in CT/MRI fusion. 
 


 
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Dose Prescription 
 
For HA-WBRT on Arm 1, one treatment of 3.0 Gy will be given daily over approximately 2 
weeks for a total of 30.0 Gy (10 fractions). Treatment does not necessarily need to start on a 
Monday and it is acceptable for treatment to start later in the work week.  IMRT plan should be 
normalized such that 95% of the PTV_3000 volume receives prescription dose of 30 Gy in 10 
fractions of 3.0 Gy per fraction. If ≥ 90% of the PTV_3000 volume receives prescription dose 
of 30 Gy, it will be considered Variation Acceptable . 
 
 
 
Compliance Criteria 
 
For HA-WBRT on Arm 1: 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 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 required. 
 
Accuracy of MRI/CT fusion and hippocampal contouring will be assessed subjectively by 
central physician reviewer.    If MRI/CT fusion or hippocampal contouring is not considered 
acceptable, this will be scored as a Deviation Unacceptable. 
 
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 
Notes 
PTV_3000 
 
D2%[Gy] 
<= 37.5Gy 
>37.5Gy to 40Gy  
Dose to hottest 2% 
of PTV_3000 
D98%[Gy] 
>=25Gy 
22.5Gy to <25Gy 
Dose to 98% of 
PTV_3000 
V30Gy [%] 
>=95% 
90% to <95% 
Volume receiving 
prescription dose 
of 30 Gy 
 
 
Normal Structure Constraints and Compliance Criteria 
 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Notes 
Hippocampi 
D100%[Gy] 
<=9Gy 
>9Gy to 10Gy  
Dose to 100% of 
Hippocampus 
D0.03cc[Gy] 
<= 16Gy 
>16Gy to 17Gy  
Dose to hottest 


 
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0.03 cc volume 
of Hippocampus 
OpticNrv_L 
D0.03cc[Gy] 
<=30Gy 
>30Gy to 37.5Gy 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_L 
OpticNrv_R 
D0.03cc[Gy] 
<=30Gy 
>30Gy to 37.5Gy 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_R 
OpticChiasm 
D0.03cc[Gy] 
<=30Gy 
>30Gy to 37.5Gy 
Dose to hottest 
0.03 cc volume 
of OpticChiasm 
 
Delivery Compliance Criteria 
 
 
Per Protocol 
Variation 
Acceptable 
Notes 
Interruptions 
0 break days 
1-3 break days 
Unscheduled break 
days 
 
Treatment Planning Procedures and Priorities 
 
For HA-WBRT on Arm 1:  Intensity-modulated radiotherapy will be used for patients 
enrolled in the WBRT with hippocampal avoidance arm.  In optimizing planning, the 
following treatment-planning priorities should be followed: 
 
 
1. OpticChiasm  
 
2. OpticNrv_L or OpticNrv_R 
 
3. Hippocampus 
 
4. PTV_3000 
 
5. Lens_L or Lens_R 
 
In the event that an OAR with higher priority than PTV_3000 cannot be constrained 
within Unacceptable Deviation limits, then D98% and/or V30Gy for PTV_3000 should 
be lowered to Variation Acceptable range to ensure that the OAR with higher priority 
does not exceed Unacceptable Deviation limits. 
 
 
 
Dose Calculations 
 
For HA-WBRT with or without optional simultaneous integrated boost on Arm 1: 
Primary dataset for dose calculation should be non-contrast treatment-planning CT scan of the 
entire head region using the smallest possible axial slice thickness not exceeding 2.5 mm.  
Dose matrix grid size must be ≤ 3 mm in sagittal and coronal directions.  
 
 


 
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Patient-Specific QA 
 
For HA-WBRT on Arm 1: Patient-specific QA is strongly 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. Measured dose distribution will be compared to planned dose distribution 
using a Gamma criterion of 4% dose difference and 3 mm distance to agreement. The pass rate 
should be at least 90% measured for the entire plan. These QA data will not be collected but 
should be held by the institution and available for review if requested. 
 
Daily Treatment Localization/IGRT 
 
Verification orthogonal films or images that localize the isocenter placement shall be obtained.  
The length of the treatment field shall be indicated on these films.  These films will not be 
collected but should be held by the institution and available for review if requested. 
 
5.2.2 Arm 2: SRS/fractionated SRS (fSRS)  
 
Treatment Technology 
 
This protocol requires photon treatment. GammaKnife or linear accelerator-based treatments 
with nominal x-ray energy of 6MV or greater (including isocentric conical collimators, MLC, 
or linear accelerators mounted on robotic arms) are allowed. The treatment machines must be 
commissioned for small field sizes. Credentialing for SRS head phantom irradiation from 
IROC Houston is mandatory. 3D-CRT (including static and dynamic MLC arcs), IMRT 
techniques (including Tomotherapy and VMAT) are allowed.  
 
Immobilization 
 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be 
achieved using appropriate clinical devices.  Both invasive frame-based immobilization and 
non-invasive thermoplastic mask-based immobilization are allowed. 
 
 
Simulation Imaging  
 
Contiguous CT slices of 1.25 mm slice thickness or less should be obtained. CT scan should 
cover from top of head to bottom of skull. Post gadolinium contrast-enhanced three-
dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-
RAGE), or turbo field echo (TFE) MRI scan (as defined in Section 3.2) is required for target 
delineation.  
 
Downloading MRI Protocol Documents:   
If you don't currently have a three-dimensional SPGR, MP-RAGE, or TFE sequence on 
your scanner, many acceptable examples are available for download from the 
Alzheimer's Disease Neuroimaging Initiative (ADNI) 
http://adni.loni.usc.edu/methods/documents/mri-protocols. 


 
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Sites should contact the Neuroradiology or Imaging Co-Chairs for further information 
or assistance if needed. 
 
See Appendix IV for a summary of key imaging requirements. 
 
Image fusion between CT and MRI must be performed by a medical physicist and/or treating 
physician.   
 
For radiosurgical modalities (e.g., GammaKnife) where MRI can be used for treatment 
planning, CT is not required. 
 
Definition of Target Volumes and Margins 
Target names: 
GTV(1-9)_ 
Frontal_ 
L_ or R_ 
XXXX (cGy) 
 
CTV(1-9)_ 
Parietal_ 
L_ or_R_ 
XXXX (cGy) 
 
PTV(1-9)_ 
Cerebellum_ 
L_ or R_ 
XXXX (cGy) 
 
 
 
Temporal_ 
L_ or R_ 
XXXX (cGy) 
 
 
Occipital_ 
L_ or R_ 
XXXX (cGy) 
 
 
Brainstem_ 
(No Lateral) 
XXXX (cGy)  
 
 
Detailed Specifications 
GTV: The GTV is defined as the enhancing metastasis on a gadolinium-enhanced 3D SPGR 
MRI scan. 
CTV: CTV is defined as identical to GTV. 
PTV: The PTV is defined as identical to CTV or as the CTV plus an optional volumetric 
1.0mm margin. 
If GTV=CTV=PTV (i.e., no PTV margin utilized), then only the PTV target needs to be 
generated for SRS planning and submitted for central review. 
For cases using single isocenter multitarget, the 1.0mm PTV margin is recommended.  
 
 
 
Definition of Critical Structures 
 
Note: All structures must be named for digital RT data submission as listed in the table below. 
Structures marked as “Required when applicable” must be contoured and submitted when 
applicable (e.g., metastasis close to structure) 


 
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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 
 
Importance 
(Required/Required when applicable/Optional) 
BrainStem 
 
Brainstem 
Required when applicable 
OpticChiasm 
 
Chiasm 
Required when applicable 
OpticNrv_L 
 
Left optical nerve 
Required when applicable 
OpticNrv_R 
 
Right optical nerve 
Required when applicable 
 
Dose/Volume Prescription 
 
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.  Cases will be scored using the Compliance Criteria table. 
 
Single fraction SRS: 
 
Arm 2: SRS.   
PTVs with maximum dimension <1.0 cm receive 24 Gy 
PTVs with maximum dimension ≥1.0 cm to <2.0 cm receive 22 Gy 
PTVs with maximum dimension ≥2.0 cm to <3.0 cm receive 18 Gy 
 
For brain stem lesions, peripheral doses of 18-20 Gy, 16-18 Gy, and 14-16 Gy should be used 
for tumor volumes of less than 1 cm3, 1-4 cm3, and 4-10 cm3, respectively. 
 
The dose is prescribed to the isodose line encompassing at least 99% of the PTV. 
 
Fractionated SRS (fSRS):  
 
Note: At the physician discretion, fractionated SRS may be used. In patients where single-
fraction SRS planning leads to a per-lesion brain (normal brain plus target volume) V12 >10cc, 
fractionated SRS is encouraged to lower risk of radiation necrosis. Please contact study PIs for 
questions. 
 
Arm 2: fSRS.   


 
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PTVs with maximum dimension <3.0 cm receive 27 Gy/ 3 fractions 
 
For brain stem lesions, peripheral doses of 21 Gy should be used for tumor volumes of ≤10 
cm3, respectively. 
 
The dose is prescribed to the isodose line encompassing at least 99% of the PTV. 
 
 
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. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
Target Volume Constraints and Compliance Criteria for SRS and fSRS 
 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol Variation 
Acceptable 
Notes 
PTV 
 
D99%[%] 
100% 
95% to 
105% 
Dose (%) to 99% of PTV 
D0.03cc[%] 
<=120% 
>120% to 
<=125% 
Maximal dose (%) to 
0.03cc 
Conformity Index <=1.5* 
> 1.5 to 
<=2.0* 
Ratio of prescription 
isodose volume over the 
PTV volume 
*Does not apply to lesions having a volume of less or equal than 0.1 cm3. 
 
Normal Structure Constraints and Compliance Criteria 
 
Single fraction SRS: 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
BrainStem 
 
D0.03cc[Gy] 
<=12Gy 
>12Gy to < 14Gy 
D1%[Gy] 
<=10Gy 
>10Gy to < 12Gy 


 
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OpticChiasm, 
OpticNrv 
D0.03cc[Gy] 
<=8Gy 
>8Gy to < 10Gy 
 
Fractionated SRS: 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation Acceptable 
BrainStem 
 
D0.03cc[Gy] 
<=23.1Gy 
>23.1Gy to < 24.1 Gy 
D0.5cc[Gy] 
<=18Gy 
   >18Gy to < 20Gy 
OpticChiasm, 
OpticNrv 
D0.03cc[Gy] 
<=17.4Gy 
  >17.4Gy to < 19.5 Gy 
OpticChiasm, 
OpticNrv 
D0.2cc[Gy] 
<=13.8Gy 
   >13.8Gy to < 15.3Gy 
 
Delivery Compliance Criteria 
 
 
Per Protocol 
Unacceptable Deviation 
Start date 
 
<= 21days 
days after 
randomization 
>21 days after 
randomization  
 
Treatment Planning Priorities and Instructions 
 
For SRS/fSRS on Arm 2: In optimizing planning, the following treatment-planning priorities 
should be followed: 
 
1. 
BrainStem*  
2. 
OpticChiasm, OpticNrv_L, OpticNrv _R 
3. 
PTV1, PTV2, … 
*For brainstem metastases, PTV exceeds brainstem in treatment planning priorities.   
 
In the event that an OAR with higher priority than a PTV cannot be constrained within 
Unacceptable Deviation limits, then D99% and/or D0.03cc and/or Conformity Index for that 
PTV should be lowered to Variation Acceptable range to ensure that the OAR with higher 
priority does not exceed Unacceptable Deviation limits. 
 
- Required algorithms  
Acceptable choices of algorithm are listed at 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf.  Besides the algorithms listed, the pencil beam 
algorithm is also allowed in this protocol. Any algorithm used for this study 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.  


 
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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 (e.g., conical collimators in stereotactic radiosurgery). 
 
- Primary dataset for dose calculation 
Planning CT image is the primary dataset for dose calculation. In case MR image is used for 
dose calculation, a method of correcting image distortion and tissue density has to be applied to 
get accurate body contour and heterogeneity corrections. Periodic phantom QA is a must to 
verify its linearity.  
 
-Dose matrix resolution 
Dose grid size should be ≤ 1.25 mm in all directions. 
 
-Potential radiosurgical techniques include 3D conformal beams, static MLC arcs, dynamic 
conformal MLC arcs, cone-based arcs, IMRT, VMAT, GammaKnife, CyberKnife, or 
combination of different techniques.  
 
Using single isocenter to treat multiple targets at same time is allowed with VMAT technique 
(or other published equivalent techniques). By doing so, dosimetric compliance criteria should 
be evaluated for each target individually. An end-to-end test for this type of technique is 
strongly recommended. 
 
- Take all measures to ensure a plan is deliverable including embodying collision clearance 
checks prior to treatment.   
 
 
Patient-Specific QA 
 
Any patient-specific QA that needs to be acquired should follow institutional guidelines. 
 
For photon IMRT plans, patient specific QA is mandatory. QA is performed by delivering the 
plan onto a phantom and measuring the dose using an ion chamber array or other 2D/3D 
device. Measured dose distribution will be compared to planned dose distribution using a 
Gamma criterion of 3% dose difference and 2 mm distance to agreement. The pass rate should 
be at least 90% measured for the entire plan. 
 
Daily Treatment Localization/IGRT 
 
For SRS treatment, IGRT is mandatory except for invasive frame-based setup on GammaKnife 
treatment.  The use of IGRT permits elimination of the margin of PTV. Image guidance 
methods include 2D x-ray, 3D x-ray, electromagnetic localization, optical surface imaging, and 
others.  Image registration techniques can include bone as surrogate, fiducial markers, and/or 
soft tissue.  Localization checks are per institutional guidelines but recommended after each 
patient shift.  
 
Daily treatment check sheet 
Prior to delivery of radiation, develop a verification checklist. The checklist should include 


 
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collision clearance check for each radiation delivery field, final patient position verification 
signed by physician, etc. Therapist and physicist sign off of each step. 
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 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.  
 
Herbal and Nutritional Supplement 
The concomitant use of herbal therapies is generally 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,  basic multivitamins, L-glutamine, or probiotics oral supplements will be 
permitted either at or below the recommended dosing by a healthcare provider.   Herbal-
based multivitamins are not allowed.  
 
Concomitant Medication Precautions 
The clearance of memantine is reduced with alkaline urine conditions at pH 8 or higher. 
Urine pH can be made more alkaline with chronic use of carbonic anhydrase inhibitors 
(e.g. acetazolamide, brinzolamide, methazolamide, dorzolamide, topiramate) and sodium 
bicarbonate and hence, memantine should be used with caution with these medications.  
Concurrent use of memantine with other NMDA antagonists (e.g. amantadine, ketamine, 
or dextromethorphan) is an exclusion criterion, and other medications should be 
considered. 
 
5.3.2 Participation in Other Trials  
Patients are not to participate in other radiotherapeutic trials.  Patients may participate 
in trials that do not test radiotherapy questions, including trials of novel systemic 
therapy agents.  However, the ineligibility criterion 3.2.5 should be carefully 
considered. 
 
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: 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 6 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 


 
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6.1 Memantine 
Approximately 50% of memantine is metabolized by the liver; the remaining 50% is 
excreted unchanged by the renal system. Separate tables are provided for twice daily or 
extended release dosing of memantine. 
 
6.1.1 Twice Daily Dosing 
A dosage reduction to 5 mg orally twice daily is recommended in patients with severe 
renal impairment [creatinine clearance (CrCl), 5 to 29 milliliters/minute (mL/min)]. 
Therefore the eligibility criterion for creatinine clearance is ≥ 30 mL/min and no 
dosage adjustment is needed in patients with mild (CrCl greater than 50 to 80 mL/min) 
or moderate (CrCl 30 to 49 mL/min) renal impairment. 
 
Creatinine should be evaluated at each follow-up evaluation. Memantine will be dose 
modified based on criteria outlined in the dose modification table below. 
 
% Calculated Dose  
*Creatinine Clearance (CrCl) (ml/min) 
>30 
5-29 
<5 
10 mg by mouth twice daily 
5 mg by mouth twice daily 
Recheck value weekly; 
If CrCl not > 29 (mL/min) by 3 
weeks, continue at reduced dose 
throughout protocol treatment. 
HOLD STUDY DRUG 
Recheck value weekly; 
If CrCl not > 5 (mL/min) by 3 
weeks, discontinue memantine 
* For males: CrCl = [140-age (years)] · *Weight (kg)/[72 · serum creatinine (mg/dL)] 
For females: CrCl = 0.85 · [140-age (years)] · *Weight (kg)/[72 · serum creatinine (mg/dL)] 
*Actual weight should be used unless patient is greater than 30% above IBW, then used 
Adjusted BW (= IBW + 0.4*actual BW) in the Cockcroft Gault equation. 
 
6.1.2 Extended Release Dosing 
A dosage reduction to 14 milligrams (mg) orally daily is recommended in patients 
with severe renal impairment (creatinine clearance (CrCl), 5 to 29 milliliters/minute 
(mL/min)). Therefore the eligibility criteria is for creatinine clearance ≥ 30 ml/min 
and no dosage adjustment is needed in patients with mild (CrCl greater than 50 to 
80 mL/min) or moderate (CrCl 30 to 49 mL/min) renal impairment. 
 
Creatinine should be evaluated at each follow-up evaluation. Memantine will be 
dose modified based on criteria outlined in the dose modification table. 
 
% Calculated Dose  
*Creatinine Clearance (CrCl) (ml/min) 
>30 
5-29 
<5 
28 mg by mouth daily 
14 mg by mouth daily 
Recheck value weekly; 
If CrCl not > 29 (mL/min) by 3 
weeks, continue at reduced dose 
throughout protocol treatment 
HOLD STUDY DRUG 
Recheck value weekly; 
If CrCl not > 5 (mL/min) by 3 
weeks, discontinue memantine 
* For males: CrCl = [140-age (years)] · *Weight (kg)/[72 · serum creatinine (mg/dL)] 


 
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For females: CrCl = 0.85 · [140-age (years)] · *Weight (kg)/[72 · serum creatinine (mg/dL)] 
*Actual weight should be used unless patient is greater than 30% above IBW, then used 
Adjusted BW (= IBW + 0.4*actual BW) in the Cockcroft Gault equation. 
 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  Protocol Agents 
Commercial Agents 
The commercial agent in NRG-BN009 is memantine. 
 
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. 
 
 
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. 
 
 
7.3 
Adverse Events for Commercial Study Agent: Memantine  
Refer to the package insert for detailed pharmacologic and safety information 
 
7.4 
Expedited Reporting of Adverse Events (06-APR-2023) 
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 CTEP web site,  
https://ctepcore.nci.nih.gov/ctepaers/security/login 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
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adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Oncology by phone at 1-215-574-3191. An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
7.4.1 Expedited Reporting Methods 
• 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.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Deidentified supporting source documentation should be 
uploaded to the Source Document Portal via the CTEP-AERS integration.    
• 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.  
 
7.4.2 Expedited Reporting Requirements for Adverse Events  
 
Any Phase Study Utilizing Standard of Care Treatment1 
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 


 
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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: 
• 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 
None 
 
7.4.3 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. 
7.4.4 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: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
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. 
 
7.5 
Routine Reporting Requirements for Adverse Events 


 
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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. 
 
7.6 
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 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 (06-APR-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 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. 
• Investigator (IVR)— MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) 
or graduate level researchers (e.g., PhD); 
• Associate Plus (AP)— clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 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 new CTEP-IAM accounts, and  by July 1, 2023 for all users) is required to  
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: 
• Addition to a site roster; 
• Selection as the treating, credit, or drug shipment  investigator or consenting person in 
OPEN; 
• Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
 
In addition, all investigators acting as the Site-Protocol PI, consenting/treating/drug shipment, 
or as the CI must be rostered at the enrolling site with a participating organization (i.e., 
Alliance). 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 (06-APR-2023) 
 
Permission to view and download this protocol and its supporting documents is 
restricted and is based on the 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 Cancer Trials Support System  Unit 
(CTSU) members’ website. 
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 
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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 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 emailing the email address above 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: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• 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 to have an 
Approved status following processing of the IRB/REB approval record: 
• Have an active status at the site(s) on the IRB/REB approval on at least one 
participating organization’s roster; 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile;  
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 
in the RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
 
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  


 
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• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); 
• Compliance with all applicable protocol-specific requirements (PSRs) 
 
Protocol-Specific Requirements for Protocol NRG-BN009 Site Registration  
• IRB/REB approved consent (International and Canadian sites only: English and 
native language versions) English version must be submitted to NRG Regulatory 
(Regulatory-PHL@nrgoncology.org) for review prior to IRB/REB/IEC  
submission. Note: International and Canadian Institutions must provide 
certification/verification of IRB/REB/IEC consent translation to NRG Oncology 
(described below).  
 
Translation of documents is critical. The institution is responsible for all 
translation costs. All regulatory documents, including the IRB/REB/IEC  
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. 
 
 
• This is a study with a radiation and/or imaging (RTI) component and the 
enrolling site must be aligned to an RTI provider for SRS and IMRT. To manage 
provider associations or to add or remove associated providers, access the 
Provider Association page from the Regulatory section of the CTSU members’ 
website at https://www.ctsu.org/RSS/RTFProviderAssociation.  Site 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 members’ 
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 


 
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should follow instructions in the protocol 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, IROC will 
automatically send the approval 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, the enrolling site 
may access Oncology Patient Enrollment Network (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..   
 
• Neurocognitive Function Testing Certification  
Institutions must meet certification requirements for administering 
neurocognitive assessments. Upon review and successful completion of the 
Neurocognitive Certification, Dr. Jeffrey Wefel will notify both the certified 
examiner and NRG Headquarters that the examiner has successfully completed 
this requirement. See protocol-specific material on CTSU website for 
certification requirements 
 
 
 
Additional Requirements for sites in Canada  
 
All institutions in Canada must conduct this trial in accordance with International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per 
section 6.2.5 of ICH E6(R2)]. This trial is being conducted under a Clinical Trial 
Application (CTA) with Health Canada. As a result essential documents must be retained 
for 15 years following the completion of the trial at the participating site (15 years post 
final analysis, last data collected, or closure notification to REB, whichever is later), or 
until notified by the sponsor, NRG Oncology, that documents no longer need to be 
retained [per C.05.012 (4) of the FDR].  In addition, upon request by the auditor, REB or 
regulatory authority, the investigator/institution must make all required trial-related 
records available for direct access [per section 4.9.7 of ICH]. Prior to clinical trial 
commencement, sites in Canada must also complete and submit to NRG Regulatory 
(Regulatory-PHL@nrgoncology.org): 
• Clinical Trial Site Information Form,  
• Qualified Investigator Undertaking Form  
• Research Ethics Board Attestation Form 
• Protocol Signature Page  
• Delegation of Tasks (DTL) Log  
• List of Laboratories  
• SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  


 
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• 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). 
 
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 log 
Record Retention: The sponsor, NRG Oncology, shall maintain records identified in 
Health Canada guidelines Part C, Division 5, section C.05.012 for a period of  at least 
15 years. 
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: 
• Log on 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); 
• Click on Protocols in the upper left of your screen 
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 
Oncology and protocol number NRG-BN009; 
• 
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 initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log on 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. 


 
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Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• 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. 
 
 
8.2  
RT-Specific Pre-Registration Requirements (06-APR-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   The credentialing notification document (email) must be uploaded by the 
site to the CTSU Regulatory Submission Portal for RSS to be updated.   
 
RT   
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment 
Modality 
 
photons 
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 
A SRS phantom study and IMRT HN phantom study provided by 
the IROC Houston QA Center must be successfully completed. 
Instructions for requesting and irradiating the phantoms are found 
on the IROC Houston web site 
(http://irochouston.mdanderson.org).  
Pre-treatment 
X 
A non-credentialed physician may enroll to this trial but will be 
required to pass successfully 2 pre-treatment reviews on NRG-
BN009. Once this requirement has been met the credentialing 
requirement will have been met in lieu of completing a benchmark 
case and the site can request a credentialing letter by completing a 
CSI form. If the first 2 pre-treatment cases are not acceptable, a 
credentialed physician from your site will need to review the 
contours for any future cases. See 5.2.2 for more details  
 
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 Radiation Therapy Data Submission Using Transfer of Images and Data 
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: 
• 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);  
• 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; and 
• TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
ETCTN roster.  
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access to TRIAD and may submit images for credentialing purposes, or for enrollments 
to which the provider is linked in OPEN. 
 
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 
username and password 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 (06-APR-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 Lead Protocol Organization (LPOs) registration/randomization systems or 
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:   
• 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); 
• To perform enrollments or request slot reservations:  Be on a LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar. Registrars 
must hold a minimum of an AP registration type; 
• Have an approved site registration for a 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.  
Prior to accessing OPEN, site staff should verify the following: 


 
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• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 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. Please 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. 
 
8.4 Medidata Patient Cloud ePRO Registration (06-APR-2023)  
This study includes the use of Medidata’s Patient Cloud ePRO (electronic patient-
reported outcomes) application. The Patient Cloud mobile ePRO application allows 
patients to report clinical trial information (patient reported outcomes (PRO)) 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 
ePRO 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 Appendix I. 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 (Apple), 
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 ePRO mobile app available.  Ensure that the correct 
version of the Patient Cloud mobile ePRO app is downloaded by the patient. Note only 
1 version of the app is active per protocol and this protocol is using: 
The mobile app named simply “Patient Cloud” that has this icon in the app stores: 
 
 
 
 
 
 
 
 
 
 
For sites providing a shared institutional device for use by multiple patients on site: The 
site staff should assist the patient with registration to the ePRO application and access 
to the Patient Cloud mobile ePRO 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.  
 


 
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8.4.1 CRA Patient Registration Instructions for Patient Cloud 
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 (iMedidata login is 
required); the landing page contains general information as well as links to additional 
resources on the left side of the screen: 
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". 
 
Reminder- site staff must have already completed the Medidata Patient Cloud training 
in order to register study participants. Please visit the CTSU website for reference 
information.  
 
 
9. DRUG INFORMATION  
9.1 
Commercial Agent: Memantine 
 
 
Sites are permitted to prescribe and dispense either memantine immediate release or 
extended release tablets. Sites must refer to the package insert for detailed 
pharmacologic and safety information.  
 
9.1.1 Adverse Events 
 
Please refer to the package insert. 
 
9.1.2 Availability/Supply  
 
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 preparation, handling, and storage. 
 
The use of drug(s) or combination of drugs in this protocol meet the criteria described 
under Title 21 CFR 312.2(b) for IND exemption.) 
 


 
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10. PATHOLOGY/BIOSPECIMEN 
10.1 
Biospecimen Submission Tables (06-APR-2023) 
 
10.1.1 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.) 
 
A detailed description of biospecimen collection and submission procedures can be found in 
the Biospecimen Collection and Submission Manual (found on the CTSU protocol page under 
the Protocol Related Documents tab).  
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. 
 
Optional Study Description #1: Serum Analysis for Exosomal MicroRNA and Cytokine 
Profiling 
 
Specimen Type  
Collection Time Points 
 
Collection Information and  
Requirements/Instructions for 
Site 
Shipping 
 
Serum- Red top tube 
Pre-treatment  
Within 21 days before 
SRS/fSRS or HA-WBRT  
 
Post-treatment 
Within 2 months of start 
of SRS/fSRS or  
HA-WBRT 
Storage:  -80°C and ship frozen 
Forms: ST form 
Kits: request from NRGBB-SF. 
Shipping: Prepaid label provided 
 
 
Batch Ship frozen on dry 
ice by overnight courier to 
NRGBB-SF. 
 
 


 
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Optional Study Description #2: 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-
BN009 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 
Email: NRGBB@ucsf.edu 
Specimen Type  
Collection Time Points 
 
Collection Information and  
Requirements/Instructions for 
Site 
Shipping 
 
Serum- Red top tube 
Pre-treatment  
Within 21 days before 
SRS/fSRS or HA-WBRT  
 
Post-treatment 
Within 2 months of start 
of SRS/fSRS or  
HA-WBRT 
May be residual from Optional 
Study Description #2 above 
 
Storage:  -80°C and ship frozen 
Forms: ST form 
Kits: request from NRGBB-SF. 
Shipping: Prepaid label provided 
 
Batch Ship frozen on dry 
ice by overnight courier to 
NRGBB-SF. 
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
 
11.1 Patient-Reported Quality of Life (QOL) and Neurocognitive Function (NCF)  
(06-APR-2023)  
 
11.1.1 QOL Background and 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 2006, 
Armstrong 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, 


 
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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.  
 
Health-related quality of life will be assessed using the EQ-5D-5L and PROMIS 
Cognitive Function Short Form 4a v2.0. The EQ-5D-5L is a standardized self-report 
measure of health status developed by the EuroQOL Group in order to provide a 
simple, descriptive profile and a single index value for clinical and economic appraisal 
(Oemar 2013). The initial EQ-5D was adapted to include a 5-level measure of severity 
to improve reliability and sensitivity and reduce ceiling effects. It consists of 2 pages, 
the EQ-5D-5L descriptive (mobility, self care, usual activities, pain/discomfort, 
anxiety/depression) using 5 levels (no problems, slight problems, moderate problems, 
severe problems, and extreme problems) and the EQ Visual Analogue scale (EQ VAS).  
The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, visual 
analogue scale with endpoints labeled ‘the best health you can imagine’ and ‘the worst 
health you can imagine’, with respondents marking an X on the scale to indicate health 
today and then writing the number marked on the scale in a box below. The digits for 5 
dimensions can be combined in a 5-digit number describing the respondent’s health 
state. The 4-item PROMIS form was found to be highly correlated with the 8-item 
measure and has demonstrated excellent internal consistency and reliability (Safer 
2015, Cella 2015), and has criterion validity related evidence for measuring cognitive 
concerns (Valentine  2019). 
 
11.1.2 NCF Background and Assessments 
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 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 (Wefel 
2011, Gilbert 2014, Meyers 2004). 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 Administration of NRG-BN009 Patient-Completed Questionnaires and NCF 
Assessments 
Patient Population 
All patients enrolled in NRG-BN009 who speak English or live in Canada and speak 
French will be required to participate in the QOL/NCF study.   Speakers of other 
languages are not permitted to participate in the QOL/NCF study. 
 
Time Points for Administration 
See Section 4. 
 
Administration Instructions  
After the baseline, QOL questionnaires may be completed using the Patient Cloud 
mobile ePRO application (discussed in Section 8) or on paper at the visit.  If the patient 


 
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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 Principal/Co-Principal Investigators/Radiation Oncology Co-Chairs (Vinai Gondi, 
MD; Michael Chan, MD) and/or NRG Oncology Headquarters–approved designees 
will perform an RT Quality Assurance Review after IROC Philadelphia-RT has 
received complete data in TRIAD. Pre-treatment reviews for HA-WBRT will be 
reviewed within 3 business days of submission of complete data. Reviews for all other 
cases (SRS and post-hoc HA-WBRT) will be ongoing and performed remotely. The 
final cases will be reviewed within 6 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. 
 


 
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12.2 
Drug Quality Assurance Reviews 
 
The Neuro-Oncology Co-Chair (Rimas Lukas, MD) or NRG Oncology Headquarters–
approved designee will perform a Quality Assurance Review to evaluate memantine 
protocol compliance.  The review process is contingent on timely submission of 
treatment data. The scoring mechanism is: 1) Per Protocol, 2) Acceptable Variation, 
3) Unacceptable Deviation, and 4) Not Evaluable.   
 
 
Dr. Lukas/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 (06-APR-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: 
• 
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); and  
• 
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: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
• Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
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 


 
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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 (06-APR-2023) 
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. 
 
ARM 1 HA-WBRT IMRT submission requirements 
DICOM Items 
DICOM CT Image 
Due Within 1 week of start 
 
 
of RT. 
 
For Pre-treatment reviews 
submit for review prior to 
RT; 3 Business days 
required from submission 
of complete data.  
 
Triad Time Point: 
  DICOM Structure 
 
       RT Digital Plan 
 
DICOM Dose  
 
 
DICOM Plan  
 


 
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All required structures must be labeled per the tables in Sections 
5.2.1 
 
5.2.2 
 
Imaging needed for RT review: 
 
Entire MRI used with Planning CT must be submitted with RT 
 
data. Pre-treatment reviews cannot be completed without 
submission of the MRI. MRI sequences to be submitted are: MP-
RAGE, TSE, axial T2 or axial T2 FLAIR (PREFERRED) 
sequences, and gadolinium contrast-enhanced three-dimensional 
SPGR. Please submit ADC, DWI, pre-contrast axial T1 (3D 
strongly encouraged) imaging if available.  
 
  
Triad Time Point: Baseline  
 
 
 
 
 
 
 
 
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. 
 
ARM 2 SRS submission requirements 
DICOM Items 
DICOM CT/MR Image 
Due Within 1 week of start 
 
 
of RT.   
 
  DICOM Structure 
 
      TRIAD Time point:    
RT Digital Plan Modified 
 
DICOM Dose  
 
 
DICOM Plan  
 
All required structures must be labeled per the tables in Sections 
5.2.4 
 
5.2.5 
 
Submit a redacted PDF of the treatment plan via TRIAD 
 
Imaging needed for RT review: 
 
Post gadolinium contrast-enhanced three-dimensional spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo 
(MP-RAGE), or turbo field echo (TFE) MRI scan  
 
Post gadolinium contrast-enhanced three-dimensional spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo 
Triad Time Point: Other  


 
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(MP-RAGE), or turbo field echo (TFE) MRI scan  
               . 
 
For radiosurgical modalities (e.g., GammaKnife) where MRI can be used 
for treatment planning, CT is not required. 
 
 
 
 
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 MRI 
sequences. Please still submit ENTIRE MRI Brain exam. 
 
• MRI with Axial T2 FLAIR (preferred) or axial T2 
TSE/FSE images required. 
• Pre and Post Gadolinium contrast-enhanced three-dimensional (3D) images required. 
 
Baseline 
Follow-up 
  
Please reference appendix IV for specific MRI imaging parameter guidelines for 3D sequences. 
Please also submit ADC and DWI imaging if available. 
Please ensure selection of the correct imaging time point in TRIAD. 
To ensure anonymity of our trial patients, TRIAD is uniquely configured to remove and/or re-identify 
Protected Health Information (PHI) from image metadata during the image submission process.  
Do not apply any further anonymization to any exam prior to uploading into the TRIAD application.  
Essential data which must be preserved includes the study date, scanner station name, scanner serial 
number and scan acquisition parameters. Any further anonymization prior to submission via TRIAD 
may  exclude an exam from final analysis due to the omission of these important technical elements.  
While TRIAD can de-identify all PHI within DICOM image metadata, some files stored in imaging 
PACS systems may include data that TRIAD cannot anonymize automatically (including patient 
questionnaires, dose reports, and other electronic records). For these file types:  
• 
Expand all series within the TRIAD Preview Window  
• 
Deselect files which may contain PHI before moving them to the submission queue (these 
include files such as protocol pages, patient reports, questionnaires, and study orders)  
• 
Prior to submitting, you may also utilize the Clean Pixel Tool within TRIAD to redact any 
PHI that has been “burned into” images 


 
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Consult with your PACS administrator or contact the IROC Philadelphia Core Laboratory for further 
information.  
*Only submit diagnostic imaging specified in the protocol (Required assessments can be located in 
section 4). 
 
13.3 Data Quality Portal (06-APR-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 Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms. DQP 
Form Status, and DQP Reports modules. 
 
 
 
13.4 Global Reporting/Monitoring 
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   
Note: Serious adverse events must be submitted via CTEP-AERS per protocol 
guidelines. 
 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design (06-APR-2023) 
NRG-BN009 is a randomized phase III trial to determine if hippocampal-avoidant 
whole brain radiotherapy (HA-WBRT) with memantine in patients with distant brain 
failure with brain metastasis velocity ≥4 new brain metastases/year prolongs time to 


 
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neurologic death as compared to stereotactic radiosurgery (SRS). 
14.1.1 Randomization 
 
Patients who meet the eligibility criteria will be randomized using permuted block 
randomization in a 1:1 randomization ratio to SRS arm (control arm) or HA-WBRT 
arm (experimental arm). Randomization will be stratified by: BMV (>13 vs. 4-13), DS-
GPA at time of last SRS (≤2 vs. >2) and receiving immunotherapy at time of 
enrollment (yes vs. no). 
14.1.2 Total Accrual 
This trial will enroll a total of 350 patients. 
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint 
The primary endpoint is time to neurologic death defined as time from randomization 
until progressive neurologic decline at time of death, irrespective of status of 
extracranial disease, or death from inter-current disease in patients with severe 
neurologic dysfunction. 
14.2.2 Secondary Endpoints 
• Overall survival, defined as time from randomization to death from any cause 
• Intracranial progression-free survival, defined as time from randomization to 
intracranial progression or death from any cause 
• Brain metastasis velocity at subsequent relapse 
• Neurocognitive function outcomes 
• Cognitive abilities, symptom burden and health status, as measured by MDASI-BT, 
PROMIS cognitive function, and EQ-5D-5L  
• Adverse events associated with the interventions 
• Number of salvage procedures and estimated cost of brain-related therapies 
 
14.3 
Primary Objectives Study Design (06-APR-2023) 
14.3.1 Primary Hypothesis and Endpoints 
The primary endpoint for this randomized phase III study is time to neurologic death. 
Detailed definition of this endpoint is given in Section 4. The null hypothesis is that 
HA-WBRT in patients with brain metastasis velocity ≥4 new brain metastases per year 
since last SRS will be equivalent in terms of time to neurologic death as compared to 
salvage SRS alone. The alternative hypothesis is that HA-WBRT in patients with brain 
metastasis velocity ≥4 new brain metastases per year will decrease the 12-month 
neurologic death rate to 24%, as compared to 34% in the SRS arm.  This improvement 
corresponds to a 38% relative hazard reduction (HR of 0.621) in favor of the HA-
WBRT arm, assuming exponential distribution. 
14.3.2 How Primary Endpoints Will Be Analyzed 
The definitive primary endpoint analysis for this phase III trial will be conducted after 
127 neurologic death events (among both treatment arms) have been recorded. The 
primary analysis will be done on an intent-to-treat basis, such that all eligible and 
randomized cases on the study will be included in the arm to which they are 
randomized regardless of what treatment the patients actually received. The primary 
comparison of treatment effect on neurologic deaths will be based a one-sided 0.05-
level (score) test for cause-specific hazard ratio (CHR) in a Cox proportional hazards 


 
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model. If the associated one-sided p-value is 0.05 or less, then the trial will conclude 
that HA-WBRT prolongs time to neurologic death over SRS. 
 
Additional analyses will involve estimating the median time to neurologic death using 
the cumulative incidence function estimator in the presence of precluding events such 
as non-neurologic deaths in the two arms, separately (Korn 1992). The Gray’s test will 
be used to evaluate the difference in the distribution of neurologic deaths (Gray 1988). 
These results will be interpreted in light of the competing non-neurologic deaths, which 
may be frequent. 
14.3.3 Sample Size and Power Calculations 
Due to the competing risk of non-neurologic death, the method described by Pintilie is 
used for the sample size estimation. It is assumed that the 12-month neurologic death 
rate is 34.0% in the SRS group based on results from Farris et al (2017), and that the 
12-month rate for non-neurologic death is the same for both arms, at 38.9%.  It is 
projected that HA-WBRT would reduce the 12-month neurologic death rate by 10%, 
which corresponds to a hazard ratio (HR) of 0.621 for HA-WBRT with respect to SRS. 
Assuming uniform accrual of 333 patient over 33 months (at 10 pts/month accrual rate) 
with an additional 12 months follow-up after accrual completion, this design will give 
85% statistical power to detect the targeted HR of 0.62 (experimental vs. control) using 
a 1-sided 0.05-level (score) test for cause-specific hazard ratio (CHR) in a Cox 
proportional hazards model, based on the assumed incidence rates for neurologic deaths 
and non-neurologic deaths (competing risk) above (Pintilie). The primary analysis will 
be event-driven and will be conducted when a total of 127 events (neurologic deaths) 
have been observed. The trial will over-accrue by 5% (i.e. for a total of 350 patients) to 
account for ineligibility, early consent withdrawal, lack of follow-up, etc. 
 
 
14.4 
Study Monitoring of Primary Objectives (06-APR-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 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 
 
DMC Reviews 
The NRG Oncology Data Monitoring Committee (DMC) will review the trial twice a 
year, with respect to patient accrual, morbidity, and timeliness of data reporting. The 


 
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DMC also will review the study for the protocol-specified primary endpoint interim 
analysis, as well as on an “as needed” basis if the need arises.  
 
14.4.1 Interim Futility Monitoring 
One interim futility analysis for the primary endpoint of neurologic death will be 
performed when about 50% of the expected number of events (i.e. 64 neurologic 
deaths) have occurred. The futility analysis will be based on testing treatment effect on 
neurologic deaths using a 1-sided 0.4 level (score) test for cause-specific hazard ratio 
(CHR) in a Cox proportional hazards model. The analysis will be done on an intent-to-
treat basis.  
To evaluate the operating characteristics of the proposed futility monitoring rule in the 
context of this trial, we conducted 5,000 Monte-Carlo simulations for a number of 
significance levels for the futility test (namely, 0.30, 0.40, 0.50). In each simulated trial, 
we assumed that time to event of interest (neurologic death) and time to competing 
risks (non-neurologic death) were independently and exponentially distributed 
according to the true hazard rates specified in Section 14.3.3. We assumed that 333 
patients (based on the Pintilie formula) were accrued uniformly over 33 months with 12 
months of additional follow-up after accrual completion. An interim futility test was 
performed at the designated 1-sided significance level when 64 events of interest have 
occurred. If the simulated trial did not stop early due to futility, then the trial proceeded 
to full accrual and a final efficacy analysis was conducted when 127 events of interest 
has been reached based on a 1-sided 0.05 level test. Under the null hypothesis (when 
HA-WBRT does not prolong time to neurologic death as compared to SRS), we 
recorded the following design characteristics: (i) the probability of early stopping due 
to futility, (ii) timing of futility analysis (since trial activation), (iii) number of patients 
enrolled by the time of interim analysis, (iv) estimated cause-specific hazard ratio and 
95% CI at time of interim analysis based on Cox proportional hazards model, and (v) 
the probability that the trial continues to full accrual and rejects the null hypothesis (this 
is the overall type I error). Under the alternative hypothesis (when HA-WBRT prolongs 
time to neurologic death as compared to SRS), we recorded the following design 
characteristics: (i) the probability of early stopping due to futility, (ii) timing of final 
efficacy analysis since study activation (among trials that proceed to full accrual), (iii) 
the estimated cause-specific hazard ratio and 95% CI based on Cox proportional 
hazards model (among trials that proceed to full accrual), and (iv) the probability that 
the trial continues to full accrual and rejects the null hypothesis (this is the power of the 
design). 
The table below displays the operating characteristics of the study design incorporating 
the proposed futility monitoring rule in the context of this trial. Balancing the desire 
between maximizing the probability of stopping the trial early under the null and 
minimizing the power loss, we selected the 1-sided significance level of 0.40 for the 
interim futility test. With this rule, the trial will have on average 60% of the chance to 
stop at interim under the null hypothesis. At the same time, there is approximately 33% 
(median 111 patients) saving in sample size if the trial stops early. This design is only 
associated with a negligible power loss (~2%) as a result of the futility test. Based on 
the simulations, the median time for the futility analysis to occur would be roughly 28 
months after study activation (including the initial 6-months ramp-up). The overall type 


 
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I error is maintained at under the 5% nominal level (4.5%). As expected, the median 
estimated cause-specific HR was 1.0 (95% CI: 0.61-1.64) under the null hypothesis. 
Under the alternative hypothesis, the design will have only 5.2% of the chance to stop 
at the futility interim. The median estimated cause-specific HR was 0.61 (0.43-0.87). 
The final efficacy analysis (if the trial does not stop early at interim) will occur roughly 
51 months after study activation (again including the initial 6-months ramp-up). 
 
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. 


 
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Operating Characteristics of the Study Design 
 
1-sided 
sig. 
level at 
interim 
Under Null Hypothesis 
 
 
 
Under Alternative Hypothesis 
prob. Of 
stopping 
at 
futility 
median HR 
(95% CI) at 
interim 
analysis 
median # pts 
enrolled by 
time of interim 
(range) 
median time 
(month) of 
interim since 
study activation 
(range)  
type I 
error 
prob. Of 
stopping 
at futility 
median HR 
(95% CI) at 
final analysis 
median time 
(months) of final 
analysis since 
study activation 
(range) 
power 
0.30 
71% 
1.0 (0.61-1.64) 
221 (169-285) 
28 (23-35) 
4.5% 
9.2% 
0.60 (0.42-0.86) 
50 (39-134) 
81.4% 
0.40 
60% 
1.0 (0.61-1.64) 
221 (163-282) 
28 (22-35) 
4.5% 
5.2% 
0.61 (0.43-0.87) 
51 (39-141) 
82.7% 
0.50 
50% 
1.0 (0.61-1.64) 
220 (162-278) 
28 (22-34) 
4.8% 
3.2% 
0.62 (0.43-0.88) 
51 (39-194) 
83.7% 


 
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14.5 
Accrual/Study Duration Considerations 
For the recent NRG phase III trial (NRG-CC001) evaluating the role of WBRT for 
brain metastases, the expected accrual rate was 9 patients per month over 5 years.  In 
actuality, the trial accrued at a rate of 16.2 patients per month and completed accrual in 
32 months, 2 years sooner than expected.  Based on the historical experience of accrual 
to NRG brain metastasis trials, we anticipate negligible accrual during the first 6 
months while sites obtain IRB approval and activate the trial. Thereafter, we expect a 
uniform accrual rate of 10 patients per month. This estimate is based on observation 
that the BMV ≥ 4 cohort comprises approximately 60% of brain metastasis patients. 
The required number of neurologic death events for the primary endpoint is expected to 
be reached about 12 months after accrual completion. It is projected that the primary 
analysis will take place approximately 12 months after accrual completion or 51 
months after study activation (6 months ramp-up + 33 months accrual + 12 months 
additional follow-up).  
 
If the trial is stopped early due to futility in the experimental 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 Endpoints (06-APR-2023)  
14.6.1 Secondary Hypotheses and Endpoints:  
Endpoints for the secondary objectives of this trial include OS, intracranial progression-
free survival, brain metastasis velocity at subsequent relapse, summary statistics on 
adverse event frequencies, the MDASI-BT, EQ-5D-5L, PROMIS cognitive function 
patient-reported outcome (PRO) measures, neurocognitive function (NCF) measures, 
and number of salvage procedures and estimated cost of brain-related therapies. The 
following hypotheses will be evaluated: 
 
• To determine if HA-WBRT in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year prolongs overall survival as compared to SRS. 
• To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year prolongs intracranial progression-free survival 
as compared to SRS. 
• To evaluate if HA-WBRT in patients distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year improves brain metastasis velocity at 
subsequent relapse as compared to SRS. 
• To assess perceived difficulties in cognitive abilities, symptom burden and health 
status, as measured by the MDASI-BT, EQ-5D-5L and PROMIS cognitive function, 
after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain 
metastasis velocity ≥4 new brain metastases/year.  
• To compare neurocognitive function outcomes following HA-WBRT, as compared 
to SRS, in patients with distant brain failure with brain metastasis velocity ≥4 new 
brain metastases/year. 


 
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• To tabulate and descriptively compare the post-treatment adverse events associated 
with the interventions. 
• To compare the number of salvage procedures in patients who receive HA-WBRT, 
as compared to SRS, in patients with distant brain failure with brain metastasis 
velocity ≥4 new brain metastases/year. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Intracranial Progression-Free Survival 
Intracranial progression-free survival (IPFS), defined as time from randomization to 
intracranial progression or death from any cause, will be evaluated among all trial 
participants. Analysis for this endpoint will consist of estimation of the IPFS curves via 
the Kaplan-Meier method and a stratified log-rank test. 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 
Overall survival (OS) is defined as time from randomization to death from any cause. 
The analytical techniques for OS would be similar to those for IPFS, as described 
above. 
 
Adverse Events 
Adverse events (AEs) will be graded according to CTCAE v5.0. 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. 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 power can be high for frequency tables with large sample size; only clinically 
material differences that represent potential patient risk will be of interest. 
 
Neurocognitive Function 
As described in Sections 2.4 and 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.  
 
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(RCI; Jacobson 1991). The RCI is derived from the standard error of measurement of 
each test 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. 
 
We have chosen to prioritize the primary NCF/QOL analysis to include changes within 
the first 12-month time period because we expect to see the most meaningful effects on 
cognitive function during the first year after randomization. As such, patients will 
complete NCF testing at baseline, month 2, month 4, month 6, month 9, and month 12. 
The key objective for the NCF analysis is to compare the cognition failure neurologic 
death free survival (CFNDFS) between the two treatment arms. CFBNDFS is defined 
as the duration from randomization to time of CF or neurologic death, whichever comes 
first. Detailed definition of neurologic death, the primary efficacy endpoint of the parent 
trial, is given in Section 4. The primary comparison of treatment effect on CFNDFS will 
be based on a 1-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox 
proportional hazards model. A 1-sided test is selected because our hypothesis is that HA-
WBRT will improve cognitive outcomes as compared with SRS. 
 
Participation in the real time integrated 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 endpoint of CFNDFS (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 cognitive failure (CF) rate in the SRS arm is 30%, which 
translates to 12-months CF rate of 51% assuming exponential distribution. In BN009, we 
assume that 12-month neurologic death rate in the SRS arm is 34%. Combining CF and 
neurologic death as in the CFNDFS definition, it is estimated that about 85% of patients 


 
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in the SRS arm will have experienced a CFNDFS event by 12 months after randomization 
(corresponding to a hazard rate of 0.158 in the SRS arm). We expect that HA-WBRT 
will improve 12-month CFNDFS rate by 10% (i.e. from 15% to 25%). This difference 
translates to a hazard ratio (HA-WBRT vs. SRS) of 0.73. Assuming uniform accrual of 
33 months with an additional follow-up of 12 months after accrual completion, the 
following table describes the percentage of patients evaluable for the CFNDFS, the 
effective sample size, expected number of CFNDFS events by the end of the trial, and 
statistical power to detect the hypothesized effect size, using a 1-sided 0.05 level test, 
assuming the percentage of patients evaluable for the CFNDFS primary endpoint ranges 
between 70% and 90%. Note that the timing of this analysis will be based on the timing 
for primary analysis of BN009, and will take place roughly after all participating patients 
have at least 12 months of follow-up. 
 
Percentage of 
patients evaluable for 
CFNDFS endpoint 
Effective sample size 
evaluable for 
CFNDFS endpoint 
Estimated number of 
CFNDFS events by 
the end of the trial 
Power to detect 
hypothesized effect 
in CFNDFS (HR = 
0.73) 
70% 
233 
222 
75% 
80% 
266 
254 
80% 
90% 
300 
286 
84% 
 
As a secondary analysis, the cumulative incidence function estimator will be used to 
estimate the median time to cognitive failure or neurologic death (CFND) in the presence 
of precluding non-neurologic deaths (Korn and Dorey 1992). Gray’s test will be used to 
test for a statistically significant difference in the distribution of CFND (Gray 1988). 
Results will be interpreted in light of competing non-neurologic deaths, which may be 
frequent. Finally, as an exploratory analysis, we will assess the change in NCF scores 
over time.  Specifically, we will implement mixed effects models for repeated measures 
to evaluate NCF 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 NCF 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 cognitive function experience over time among patients in the two groups. 
 
Patient-Reported Outcomes 
MDASI-BT: As described in Section 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) 


 
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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 
MDASI-BT will be administered according to the schedule described in Section 4.  
 
We will conduct a longitudinal analysis that will focus on patterns of score change over 
time points (baseline, month 2, 4, 6, 9, and 12) in MDASI-BT. It is posited that patients 
in the HA-WBRT arm will achieve greater control of brain metastasis which may lead 
to more favorable outcomes with respect to symptoms burdens. To assess this, 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, treatment arm, 
baseline stratification factors, and the interaction between time and treatment 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, 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 exploratory 
characterizations of the symptoms experience will be undertaken within each 
treatment arm, separately.  
 
PROMIS Cognitive Function Short Form 4a v2.0: This measure is a 4-item questionnaire 
that assesses patient-perceived cognitive concerns over the past 7 days.  The 4-item short 
form was found to be highly correlated with the full 8-item measure and demonstrated 
excellent internal consistency reliability and has criterion validity related evidence for 
measuring cognitive concerns but not cognitive performance. This measure asks the 
patient to rate the frequency of the following cognitive complaints over the preceding 7 
days: (1) My thinking has been slow; (2) It has seemed like my brain was not working as 
well as usual; (3) I have had to work harder than usual to keep track of what I was doing; 
and (4) I have had trouble shifting back and forth between different activities that require 
thinking. Each question has five response options ranging in value from one to five (with 
lower scores indicating more severe cognitive concerns). The total raw score for a short 


 
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form would be the sum of the values of the response to each question (therefore, for a 
short form which all questions are answered, the lowest possible score is 4 and the highest 
possible raw score is 20). Similar longitudinal analytic strategy as outlined above for 
MDASI-BT will be adopted to analyze the PPOMIS Cognitive Function data. 
 
EQ-5D-5L: The EQ-5D-5L is a standardized self-report measure of health status. The 5-
level EQ-5D version (EQ-5D-5L) was introduced by the EuroQol Group in 2009 to 
improve the instrument’s sensitivity and to reduce ceiling effects, as compared to the EQ-
5D-3L. It consists of 2 pages, the EQ-5D-5L descriptive (mobility, self care, usual 
activities, pain/discomfort, anxiety/depression) using 5 levels (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) and the EQ 
visual analogue scale (EQ VAS). The digits for 5 dimensions can be combined in a 5-
digit number describing the respondent’s health state. We will employ similar 
longitudinal analytic strategies as delineated above for MDASI-BT to analyze EQ-5D-
5L data. 
 
Missing Data Considerations for PRO and NCF Studies 
A certain degree of attrition from the NCF/PRO studies, due to both patient refusal or 
other reasons for missed assessments, and deterioration 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). 
 
For NCF testing, all standard monitoring procedures will be applied to monitoring and 
ensuring patients complete NCF testing at the prespecified time points.  Noncompliant 
sites will be contacted and reminded that this is a mandatory component of the trial. NRG 
HQ will send reminder emails to sites for each patient a week in advance of their 
scheduled follow up tests time point to help reduce missing data. The trained and certified 
test administrator selects a test completion code for every test with every patient 
indicating the test was completed or the reason a test was not completed or was 
discontinued such as discontinued due to the severity of neurologic disability. 
 
 
Power Calculations 
In this trial, the symptom burdens and patient-perceived cognitive functions will be 
assessed with MDASI-BT, PROMIS Cognitive Function Short Form 4a v2.0, and EQ-
5D-5L instrument. The expected difference in symptom burdens and cognitive functions 
between treatment arms will partly depend on relative disease control benefit as well as 


 
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the adverse events between two treatment arms. Of key interest is the difference in change 
in symptom burden and cognitive function 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. 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 266 patients (roughly 80% of the patients enrolled in the treatment trial; 
equally split between two arms) will participate in the QOL studies and have both 
baseline and 6-month follow-up data, each study will have 80% statistical power to detect 
effect size (mean difference between arms / standard deviation) of 0.35 or greater using 
a 2-sided 0.05 level t-test. 
 
14.7 
Exploratory Hypothesis and Endpoints 
 
Brain metastasis velocity at subsequent distant brain relapse (BMVs)  
BMVs will be defined as follow: 
 
BMVs = (total number of new brain metastases since on-study SRS) / (years since 
on-study SRS),  
 
where on-study SRS refers to the SRS procedure that the patient received on this study. 
 
The Wilcoxon rank-sum test will be used to compare the distributions of BMVs 
between the two treatment arms at 2-sided 0.05 level.  
 
Radiographic endpoints 
We will collect baseline and follow-up MR imaging axial T2 FLAIR (PREFERRED) or 
T2 volumes and extract imaging data from both the SRS and HA-WBRT +SRS arms. 
The entire MRI DICOM data will be stored at baseline and month 4. We will extract 
first order geometric features. For the geometric features we will use axial T2 FLAIR 
(PREFERRED) or T2 imaging sequence. The scanning parameters are available on the 
ADNI website as described in Section 5.2. Quality control on image acquisition is to be 
provided by IROC Philadelphia imaging QA center to ensure consistent image quality 
across different scanners. The imaging sets will be standardized to account for inter-
scanner variability by using bias field correction, anisotropic diffusion noise reduction 
and signal intensity normalization. The whole brain volume, white matter volumes and 
volume of metastatic disease will be segmented by two independent investigators using 
a single software system.  
 
We will evaluate the dose to these structures and determine if pre-treatment white 


 
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matter volume may be correlated with cognitive function (HVLT-R) and patient 
reported difficulties in cognitive abilities (PROMIS-4a v2.0). Specifically, changes in 
score of cognitive assessments will be calculated by subtracting the score at the 4-
month follow-up from the baseline score. For HVLT-R, a positive change score would 
reflect a cognitive decline, whereas a negative score would indicate decline for 
PROMIS-4a v2.0. The Pearson’s correlation will be estimated to characterize the 
association between imaging features (whole brain volume, white matter volumes and 
volume of metastatic disease) and change in cognitive score, both within two treatment 
arms separately as well as combining data across arms. In the event that normality 
assumption may be violated, rank-based correlation coefficients such as Spearman or 
Kendall will be used. At the present time, there is a paucity of literature data suggesting 
that imaging biomarkers in this disease will be “predictive” of benefit from SRS alone 
in preserving cognitive function. However, the imaging data generated from this trial 
would provide an unique opportuntity to explatory this hyopthesis. Specifically, we will 
also explore via a Cox proportional hazards model the presence of a statistical 
interaction between these imaging parameters and treatment group based on 2-sided 
0.05 level test. Of note, given the limited sample size (projected to be ~100 patients 
based on RTOG 0933 experience) available for the imaging obejcteives, it is 
appreciated that statistical power for the interaction test is likely very limited (Polley 
2013). As such, these analyses will be hypothesis-generating in nature. 
 
A secondary analysis of RTOG 0933 using HA-WBRT demonstrated a correlation 
between MRI axial T2/FLAIR (PREFERRED) volume and cognitive outcomes (Bovi 
2019). In that study, about 29% of the patients (33/113) had pre-treatment postcontrast 
volumetric T1 and axial T2/fluid-attenuated inversion recovery MRI and underwent 
pre-treatment and 4-month post-treatment cognitive testing. This trial will randomize a 
total of 333 patients. Assuming the same percentage of patients evaluable for the 
imaging objective as the Bovi et al. study, the sample size for this aim would be about 
97 patients. Assuming a two-sided 0.05 level test of correlation, this sample size would 
allow us to detect a true correlation of 0.28 or larger with 80% statistical power. 
 
 
14.8 
Gender/Ethnicity/Race Distribution 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
2 
1 
0 
0 
3 
Asian 
3 
1 
0 
0 
4 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
26 
9 
0 
0 
35 
White  
157 
114 
5 
4 
280 


 
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More Than One Race 
0 
0 
0 
0 
0 
Total 
188 
125 
5 
4 
322 
 
 
 
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 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
1 
0 
0 
3 
White  
14 
10 
1 
0 
25 
More Than One Race 
0 
0 
0 
0 
0 
Total 
16 
11 
1 
0 
28 
 
 
 


 
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APPENDIX I (06-APR-2023) 
Medidata Patient Cloud ePRO Operational Instructions 
 
Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata’s Patient Cloud 
mobile ePRO application is preferred but not mandatory.  Patients who will be submitting PRO 
data via the Patient Cloud mobile 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 Patient Cloud (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 Patient Cloud mobile ePRO app if the 
wrong version is downloaded. This protocol is using the current version 
named “Patient Cloud” with the following logo: 
 
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 Resources >Frequently Asked 
Questions (FAQs)>Rave>1. How do I gain access to iMedidata and studies in Rave>Medidata 
Account Activation and Study Invitation Acceptance. 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 Help button or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
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 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.  


 
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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. Note only 1 
version of the mobile app is active per protocol.  This protocol is using the 
version named simply “Patient Cloud” with the cloud and dot logo. 
 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.     Under Mode, then select Multi-User from the drop-down menu. 
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 ePRO mobile app, patients will need to use their own device (Apple/iOS or Android 
smartphone 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.  
 
Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Quick Reference Cards (QRCs) are available to download, print for use by the site, and to hand 
out to the patient if desired.  The QRCs can be found here (staff iMedidata login is required for 
access) and include: Patient Cloud iOS App Download, Account Activation with Email and 
Password, Account Activation with Multiple Studies Using Existing Email Address, and 
Troubleshooting.   
Downloading the Patient Cloud mobile ePRO App 
If you are using your personal device, and you do not have the Patient Cloud mobile app, use 
the following instructions. When downloading the app, you must use the Apple ID or Google 
account associated with the smart phone or tablet onto which you intend to install the mobile 
app. If the correct version (see logo below) of 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 Patient Cloud mobile app available.  Ensure that the 
correct version of the Patient cloud mobile app is downloaded.  Note only 1 
version of the mobile app is active per protocol.  This protocol is using the 
version named simply “Patient Cloud” with the cloud and dot logo.   
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 iPhones and iPads):  
1. An Apple ID is required for downloading the Patient Cloud mobile ePRO app. 


 
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2. Tap the App Store icon on your mobile device. 
3. Search “Patient Cloud” for the appropriate ePRO mobile app, download the one 
with the cloud logo shown and follow the installation instructions.  
 
For Android smart phones and tablets: 
1. A Google account is required for downloading the ePRO mobile app 
2. Tap the Play Store icon on your mobile device. 
3. Search “Patient Cloud” for the appropriate ePRO mobile app, download the one 
with the logo shown 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 ePRO mobile 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 ePRO mobile app. 
1. If registering from the ePRO mobile app, tap “Have an Activation Code” near the 
bottom of the login page. If registering on the web, open the URL 
shield.imedidata.com on a web browser. 
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 response to the security questions. 
9. Tap Create my account to complete your registration.  
 
If you registered on the ePRO mobile app, it automatically logs you out. If you registered on 
the web, you are presented with the option to download the ePRO mobile app. You can then 
proceed to log in with the credentials you created. 
Logging in to the Patient Cloud (ePRO) mobile 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 ePRO mobile 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 


 
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time you need to log in to the ePRO mobile 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 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 your PIN?” and you can access the app using your 
email and password. You may reset your PIN by tapping the options menu (three vertical 
dots) on the top right of most pages (after login) and selecting Set PIN. 
Resetting Your Password 
You can reset your password by using the options menu (three vertical dots) on the top right of 
most pages (after login). 
1. 
Tap the options menu icon (three vertical dots). 
2. 
Tap Reset Password. 
3. 
Follow the instructions to reset your password. 
 
Completing and Submitting Forms 
Once logged into the Patient Cloud mobile ePRO app, forms related to your study are 
displayed on the Tasks List page. Select a form, and complete and submit the form. New forms 
can appear on the Tasks List page at any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• 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. 
• 
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.  
Follow the on-screen instructions until you reach the end of the form where you may 
be given the opportunity to review and change your responses prior to submitting. 
2. 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. 
 
3. 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.  
 


 
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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. 
 
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 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 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 are encrypted and 
therefore this information cannot be read if intercepted while in transit. 
 
Site checklist for activities prior to consenting a patient 
o Accept study invitation at iMedidata.com 
o Site staff must be rostered in RSS and have received an invitation to the ePRO 
application 
o 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. 
o Verify the IOS or Android operating system is using the most current version 
o Verify that the correct Patient Cloud mobile ePRO app is being used. Note only 1 
version of the mobile app is active per protocol.  This protocol uses the current version 
named “Patient Cloud” with the cloud and dot icon (see below).   
o 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 name (“Patient Cloud”) and image 
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 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  


 
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being sent to the patient. 
 
’’“”“”‘”’ 
 
 


 
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APPENDIX II: MEMANTINE PILL DIARIES (06-APR-2023) 
 
 


Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID  ________________ 
 
 
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MEMANTINE PILL DIARY 
 
 
NRG-BN009 
 
PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY (SRS) OR HIPPOCAMPAL-AVOIDANT WHOLE BRAIN RADIOTHERAPY 
(HA-WBRT) FOR DISTANT BRAIN RELAPSE WITH BRAIN METASTASIS VELOCITY ≥4 BRAIN METASTASES/YEAR 
 
Twice Daily Dosing 
 
 
 
   
     INSTRUCTIONS TO THE PATIENT: 
 
 
 
Dosing Schedule:  
 
 
Daily AM Dose 
Daily PM Dose 
Week 1 
5 mg 
None 
Week 2 
5 mg 
5 mg 
Week 3 
10 mg 
5 mg 
Weeks 4-24 
10 mg 
10 mg 
 
 
 
• 
Record the date, the dose and the time taken. 
 
• 
If you forget dose and it has been less than 2 hours, you can take dose and document time taken.  If 
it has been more than 2 hours please SKIP dose and note skipped dose on the diary. Resume with 
next scheduled dose.    DO NOT take a double dose or try to make up any dose.  
 
• 
 If several doses in a row are missed, dosing may need to start over at lower doses and increased to 
higher doses. Contact the study team if this happens and document it in the pill diary.   
 
 
• 
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  ________________ 
 
 
Patient’s Signature: __________________________________ Date: __________________________ 
 
 
Week____________ 
Day 
Date 
AM Dose 
AM Dose 
Time 
PM Dose  
PM Dose 
Time 
Comment 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Today’s Date  _____/______/______ Patient Initials ________________ Patient Study ID  ________________ 
 
 
Patient’s Signature: __________________________________ Date: __________________________ 
 
 
 
MEMANTINE PILL DIARY 
 
 
NRG-BN009 
 
PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY (SRS) OR HIPPOCAMPAL-AVOIDANT WHOLE BRAIN RADIOTHERAPY 
(HA-WBRT) FOR DISTANT BRAIN RELAPSE WITH BRAIN METASTASIS VELOCITY ≥4 BRAIN METASTASES/YEAR 
 
 
Extended Release Dosing 
 
 
 
 
   
     INSTRUCTIONS TO THE PATIENT: 
 
 
 
Dosing Schedule:  
 
 
Daily Dose Extended Release Memantine 
Week 1 
7 mg 
Week 2 
14 mg 
Week 3 
21 mg 
Weeks 4-24 
28 mg 
 
 
• 
Record the date, the dose and the time taken. 
 
DO NOT take a double dose or try to make up any dose.  
 
• 
If several doses in a row are missed, dosing may need to start over at lower doses and increased to 
higher doses. Contact the study team if this happens and document it in the pill diary.   
 
• 
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  ________________ 
 
 
Patient’s Signature: __________________________________ Date: __________________________ 
 
 
Week ___________ 
Day 
Date 
Dose 
Dose Time 
Comment 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 


 
 
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APPENDIX III:  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 IV:  SUMMARY OF KEY IMAGING REQUIREMENTS (06-APR-2023) 
 
 
(1) What are the minimum MRI sequence requirements for the study? 
• Axial T2 FLAIR (preferred) or T2 
• 3D T1 Post-Contrast 
• T1 Pre-Contrast 
 
NOTE: FOR THE PRE-CONTRAST T1 IMAGINNG, 3D IMAGING SEQUENCE IS 
STRONGLY ENCOURAGED   
 
(2) Regarding the 3D T1 MRI: 
a. Both pre-contrast T1 and post-contrast T1 imaging are required.  A 3-D imaging sequence 
is required for post-contrast T1 imaging and strongly encouraged for pre-contrast T1 
imaging. 
 
b. Can I use a different sequence for pre- versus post-contrast?   
It is recommended that the 3D T1 be acquired as a matched data set pre- and post-contrast.   
 
c. Can the 3D T1 be acquired in the sagittal plane?   
If you have isotropic voxels, it is acceptable to acquire the 3D sequence in any plane. 
 
(3) Regarding the axial T2 FLAIR (preferred) sequence:  
a. Is axial acquisition required?   
Yes, if 2D sequence is obtained. 
 
b. Should the axial T2 FLAIR (preferred) or axial T2 be performed at an angle or straight?   
These can be performed either straight or at a standard AC-PC clinical angle.  If the pre 
gadolinium 3D T1 is acquired in an axial plane, then the axial T2 FLAIR (preferred) or axial T2 
and post gadolinium 3D T1 sequences need to be set up the same way.  Either straight or angled 
is acceptable for the study. 
 
c. Can we use our site’s standard 2D T2 FLAIR?   
Yes, as long as the acquisition is axial. 
 
d. Can we substitute 3D T2/FLAIR?  
Yes, as long as you have isotropic voxels, it is acceptable to acquire the 3D sequence in any 
plane. 
 
(4) Is 2D Spin Echo T1 post-contrast required?   
No. 
(5) What MRI Brain imaging sequences are to be submitted through TRIAD? 
The entire Diagnostic brain MRI exam is to be submitted for all enrolled subjects. Please understand this 
means, the three required MRI brain sequences (3D post T1, pre T1 (3D imaging sequence strongly 
encouraged), and axial T2 FLAIR and/or axial T2 FSE), as well as all other sequences obtained for the 
brain MRI visit. Please also submit ADC and DWI imaging if available.  These sequences should be 
submitted under timepoint “Baseline” separately from RT “Baseline” so that they properly credit 


 
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in the Medidata Rave system. 
 
Minimum standard MR imaging protocol as per Kaufmann et al.  Please consult Kaufmann et al (2020) for 
more details. 
 
3T MRI  (Preferred) 
1.5T MRI 
 
3D T1 
Prea 
3D T1 
Postb 
Ax 2D 
T2/FLAIRc,i 
Ax 2D T2c 
3D T1 
Prea 
3D T1 
Postb 
Ax 2D 
T2/FLAIRc,i 
Ax 2D T2c 
Sequence 
IR-
GREd 
IR-GREd 
TSEe 
TSEe 
IR-
GREd 
IR-
GREd 
TSEe 
TSEe 
Plane 
Sagittal 
or Axial 
Sagittal 
or Axial 
Axial 
Axial 
Sagittal 
or Axial 
Sagittal 
or Axial 
Axial 
Axial 
Mode 
3D 
3D 
2D 
2D 
3D 
3D 
2D 
2D 
TR (ms) 
2100f 
2100f 
>6000 
>2500 
2100f 
2100f 
>6000 
>3500 
TE (ms) 
Min 
Min 
100-140 
80-120 
Min 
Min 
100-140 
80-120 
TI (ms) 
1100g 
1100g 
2000-2500h 
 
1100g 
1100g 
2000-2500h 
 
Flip angle 
10o-15o 
10o-15o 
90o/≥160o 
90o/≥160o 
10o-15o 
10o-15o 
90o/≥160o 
90o/≥160o 
Frequency 
256 
256 
≥256 
≥256 
≥172 
≥172 
≥256 
≥256 
Phase 
256 
256 
≥256 
≥256 
≥172 
≥172 
≥256 
≥256 
NEX 
≥1 
≥1 
≥1 
≥1 
≥1 
≥1 
≥1 
≥1 
FOV 
256 mm 
256 mm 
240 mm 
240 mm 
256 mm 
256 mm 
240 mm 
240 mm 
Slice 
thickness 
1 mm 
1 mm 
3mm 
3mm 
≤1.5 
mm 
≤1.5 mm ≤4 mm 
≤4 mm 
Gap/ 
spacing 
0 
0 
0 
0 
0 
0 
0 
0 
Other 
options 
 
 
 
 
 
 
 
 
Parallel 
imaging 
Up to 3x Up to 3x 
Up to 2x 
Up to 2x 
Up to 2x Up to 2x Up to 2x 
Up to 2x 
 
Abbreviations: 
TR=repetition time 
TE: echo time 
TI: inversion time 
 
NEX: number of excitations 
FOV: field of view 
aPre-contrast T1 imaging is required and strongly encouraged to be acquired as a 3D imaging sequence with 
equivalent parameters to the 3D post-contrast T1 imaging. 
b3D post-contrast T1 imaging is required. 
cAxial T2/FLAIR or T2 sequence is required.  Axial T2/FLAIR is strongly preferred. 
dIR-GRE: inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization 
prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR 
or FAST SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field 
echo (3D Fast FE; Toshiba).  A 3D acquisition without inversion preparation will result in different contrast 
compared with MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
eTSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; Hitachi, Toshiba) 
fFor Siemens and Hitachi scanners. GE, Philips and Toshiba scanners should use a TR = 5-15 ms for similar 
contrast. 
gFor Siemens and Hitachi scanners. GE, Philips and Toshiba scanners should use a TI = 400-450 ms for similar 
contrast. 
hChoice of TI should be chosen based on the magnetic field strength of the system (e.g., TI = 2000ms for 1.5T 
and TI = 2500ms for 3T). 
i3D FLAIR is an optional alternative to 2D FLAIR with sequence parameters as follows per EORTC guidelines: 


 
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3D TSE/FSE acquisition; TE = 90-140ms; TR = 6000-10,000ms; TI = 2000-2500ms (chosen based on vendor 
recommendations for optimized protocol and field strength); GRAPPA≤2; Fat Suppression; Slice thickness 
≤1.5mm; Orientation Sagittal or Axial; FOV ≤250mm x 250mm; Matrix ≥244x244. 
 
MRI Technical Contacts: 
 
Seth Cole BA AS RT (R)(CT)(ARRT)  
ACR Clinical Research Center Core Laboratory  
scole@acr.org / 215-574-3154 
 
Cyndi Price AS RT (R)(MR)(ARRT)  
ACR Clinical Research Center Core Laboratory  
cprice@acr.org / 215-940-8863 
 
 
 
 


 
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MRI: Brain 
Version 1.02, 10Jun2021 
 
Image quality in the multicenter setting can be greatly influenced by variances in acquisition protocols. These variances 
may be related not only to equipment manufacturer and model, but also technique. 
The study may permit imaging per institutional standard-of-care. However, aligning image acquisition to established 
standards is essential for robust quality data. 
The table below is provided as a guideline and overview for MRI Brain exams at either 1.5T or 3T.  Please refer to your 
site’s specific MRI manufacturer’s imaging protocols for the optimal scanning protocol.  
The Brain Tumor MRI examination should contain, at a minimum, the following sequences but not limited to:  
1. Localization scan 
2. Axial 3D T1 Pre-Contrast 
3. Axial T2 FLAIR 
4. Axial 3D T1 Post Contrast (parameters and images should match the Axial 3D T1 pre-contrast) 
Advanced imaging sequences are frequently used such DWI, post contrast Axial T2 for tissue quantification (prior 
to Axial 3D T1 post contrast), and DSC. 
 
Exam and Patient Preparation 
Magnet Strength 
1.5T or 3T 
 
Coil 
Vendor Head Coil 
 
FOV 
2D Sequences = 256 mm x 256 mm 
3D Sequences = 240 mm x 240 mm 
Adjust to patient body. 
Patient Position 
Supine 
Position head as straight as possible 
and immobilize for a good quality 
scan. 
Contrast Injection 
Dual-chamber 
power 
injector 
recommended 
 
 Contrast Bolus =  0.1 
mmol/kg 
 
   body weight 
 
 
Bolus Rate =  3-5 mL/s 
 
Saline Flush =  20 mL 
Insertion of intravenous catheter in 
upper extremity prior to the start of 
imaging. 
Slice Plane 
Axial/Coronal/Sagittal planes 
(orthogonal to area of interest) 
Scan 
direction 
based 
on 
site 
preference. 
 
 


 
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Image Acquisition 
Localization Scan 
3-plane localization scan 
 
Pre-Contrast 
Axial 3D T1w IR-
GRE 
Siemens 
 Slice thickness ≤ 1.5 mm 
 
TR =  2100 ms 
 
TE = min 
 
TI = 1100 ms 
 
Flip angle  = 10°–15° 
 
Acceleration = 2X 
 
GE and Philips 
 Slice thickness ≤ 1.5 mm 
 
TR <  15 ms 
 
TE < min 
 
TI = 400–500 ms 
 
Flip angle  = 10°–15° 
 
Acceleration = 2X 
Must match Ax 3D T1 post contrast 
parameters and locations. 
Pre-Contrast 
Axial T2 2D FLAIR 
 
Orthogonal high-resolution 
 
 Slice thickness = 3 mm 
 
Gap = 0 mm 
 
TR  ≥ 6000 ms 
 
TE = 100–140 ms 
 
TI = 2500 ms (3T) 
 
 = 1100 ms (1.5T) 
 
Flip angle =  90–160° 
 
Acceleration  up to 2X 
3D T2 FLAIR is acceptable as well. 
Post-Contrast 
Axial 3D T1w IR-
GRE 
Siemens 
 Slice thickness ≤ 1.5 mm 
 
TR =  2100 ms 
 
TE = min 
 
TI = 1100 ms 
 
Flip angle  = 10°–15° 
 
Acceleration = 2X 
 
GE and Philips 
 Slice thickness ≤ 1.5 mm 
 
TR <  15 ms 
 
TE < min 
 
TI = 400–500 ms 
 
Flip angle  = 10°–15° 
 
Acceleration = 2X 
Must match Ax 3D T1 post contrast 
parameters and locations. 
 
 


 
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Additional Image Acquisition 
Axial 2D DWI 
(SS-EPI) 
 Slice thickness ≤ 4 mm 
 
Gap = 0 mm 
 
TR ≥  5000 ms 
 
TE = min 
 
TI = 1100 ms 
 
Flip angles  = 90°/180° 
 
Acceleration = up to 2X 
 
b-values = 0, 500, 1000 
 
  s/mm2 
Diffusion directions at least 3 
 
Performed 
prior 
to 
contrast 
administration. 
Ax 2D T2w  
 
 Slice thickness ≤ 4 mm 
 
Gap = 0 mm 
 
TR ≥  2500 ms 
 
TE = 80–120 ms 
 
Flip angles  = 90°/180° 
 
Acceleration = Up to 2X 
 
 
Acquired post contrast and before 
postcontrast 
3D 
T1-weighted 
images to control timing of images 
after contrast administration. 
DSC 
 Slice thickness ≤ 3–5 mm 
 
Gap = 0–0.25 mm 
 
TR =  1000–1500 ms 
 
TE = 30–35 ms 
 
Flip angles  = 60° 
 
Acceleration = Up to 2X 
DSC is done post injection. 
 
Only the tumor needs to be covered, 
not the entire head. 
 
References 
 
1. ACR–ASNR–SPR Practice Parameter for the Performance and Interpretation of Magnetic Resonance Imaging 
(MRI) of the Brain, Res. 17 – 2019. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/MR-Brain.pdf, 
accessed February 16, 2021. 
2. Indications for MRI brain. https://mrimaster.com/index-3.html, accessed February 16, 2021. 
3. MR Brain WO [contrast] Neuro Protocol. https://www.ohsu.edu/school-of-medicine/diagnostic-radiology/mr-brain-
wo-neuro-protocol-0, accessed February 16, 2021. 
 
 
 


 
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APPENDIX V:  DISEASE-SPECIFIC GRADED PROGNOSTIC ASSESSMENT  
(DS-GPA) (06-APR-2023) 
 
For stratification, DS-GPA at time of enrollment will be used.  DS-GPA is calculated using the following 
formula (Sperduto 2012): 
 
Small Cell or Non-Small Cell Lung Cancer 
 
GPA Scoring Criteria 
 
Prognostic Factor 
0 
0.5 
1.0 
Patient Score 
Age, years 
>60 
50-60 
<50 
 
KPS 
<70 
70-80 
90-100 
 
Extra-cranial mets 
Present 
--- 
Absent 
 
No. of brain mets 
>3 
2-3 
1 
 
Sum total 
 
 
Melanoma 
 
GPA Scoring Criteria 
 
Prognostic Factor 
0 
1.0 
2.0 
Patient Score 
KPS 
<70 
70-80 
90-100 
 
No. of Brain Mets 
>3 
2-3 
1 
 
Sum total 
 
 
Breast Cancer 
 
GPA Scoring Criteria 
 
Prognostic Factor 
0 
0.5 
1.0 
1.5 
2.0 
Patient Score 
Age, years 
≥60 
<60 
n/a 
n/a 
n/a 
 
KPS 
≤50 
60 
70-80 
90-100 
n/a 
 
Subtype 
Basal 
n/a 
LumA 
HER2 
LumB 
 
Sum total 
 
 
Renal Cell Carcinoma 
 
GPA Scoring Criteria 
 
Prognostic Factor 
0 
1.0 
2.0 
Patient Score 
KPS 
<70 
70-80 
90-100 
 
No. of Brain Mets 
>3 
2-3 
1 
 
Sum total 
 
 
GI Cancers 
 
GPA Scoring Criteria 
 
Prognostic Factor 
0 
1.0 
2.0 
3.0 
4.0 
Patient Score 
KPS 
<70 
70 
80 
90 
100 
 
Sum total 
 
 
 

ICF_001.pdf: 
NRG ONCOLOGY 
 
NRG-BN009 
 
(ClinicalTrials.gov Identifier NCT #04588246) 
 
PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY (SRS) OR 
HIPPOCAMPAL-AVOIDANT WHOLE BRAIN RADIOTHERAPY (HA-
WBRT) FOR DISTANT BRAIN RELAPSE WITH 
BRAIN METASTASIS VELOCITY ≥4 BRAIN METASTASES/YEAR 
 
 


Protocol Version Date: 04/06/23 
 
 
 
 
 
 
 
NRG-BN009 
Page 1 of 22 
 
 
 
Research Study Informed Consent Document 
 
 
 
Study Title for Participants: (06-APR-2023) Comparing whole brain radiotherapy using 
a technique that avoids the hippocampus to stereotactic radiosurgery in people with cancer 
that has spread to the brain and come back in other areas of the brain after earlier 
stereotactic radiosurgery 
 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
(06-APR-2023) 
Protocol NRG-BN009, Phase III Trial of Stereotactic Radiosurgery (SRS) or 
Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Distant Brain 
Relapse With Brain Metastasis Velocity ≥4 Brain Metastases/Year (NCT 04588246) 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you received stereotactic 
radiosurgery to treat cancer that spread to your brain, and now the cancer has returned in other 
areas of the brain. 
 
Brain Metastasis Velocity (BMV) is a measure of how fast the cancer is spreading in your brain.  
If you have a BMV of four or higher, more treatment is needed to control the spread of cancer in 
your brain. 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 


Protocol Version Date: 04/06/23 
 
 
 
 
 
 
 
NRG-BN009 
Page 2 of 22 
 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
 
Why is this study being done? (06-APR-2023) 
 
This study is being done to answer the following question:  
 
Can we extend your life by using a type of radiation therapy called whole-brain radiation therapy 
that avoids the hippocampus to preserve memory plus the medication memantine that can 
decrease the risk of side effects of radiation on thinking and memory, to the usual treatment?  
 
We are doing this study because we want to find out if HA-WBRT and memantine is better or 
worse than the usual approach for your brain cancer.  The usual approach is defined as care most 
people get for cancer that has spread to the brain and returned in other areas of the brain after 
receiving SRS. 
 
 
What is the usual approach to my brain cancer? (06-APR-2023) 
 
The usual treatment for your brain cancer is stereotactic radiosurgery, or SRS, that delivers a 
high dose of radiation only to the small areas of cancer in the brain , but does not treat even 
smaller areas of cancer that cannot be seen in the brain.  
 
What are my choices if I decide not to take part in this study? 
 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
 
What will happen if I decide to take part in this study? (06-APR-2023) 
 
If you decide to take part in this study, you will either get treatment with HA-WBRT and 
memantine, or you will get treatment with SRS.  
 
The usual treatment, SRS, delivers a high dose of radiation only to the small areas of cancer in 
the brain but does not treat even smaller areas of cancer that cannot be seen in the brain.  SRS is 
a single treatment over one day (or in some cases a few days) as an outpatient procedure.  
 
If you receive HA-WBRT, you will receive it 5 days per week Monday through Friday for about 
2 weeks as an outpatient procedure. Whole brain radiation therapy delivers a low dose of 
radiation to the entire brain including the normal brain tissue. Hippocampus avoidance during 


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whole-brain radiation therapy (HA-WBRT) decreases the amount of radiation that is delivered to 
the hippocampus which is a brain structure that is important for memory.  The medicine 
memantine is also often given with whole brain radiation therapy because it may decrease the 
risk of side effects of radiation on thinking and memory.  
You will receive memantine as a tablet by mouth for 6 months. 
 
If you do not receive HA-WBRT plus memantine, you will receive the usual SRS treatment as 
described above.  
 
After you finish your treatment, your doctor and study team will watch you for side effects and 
follow your condition.  They will check you every 2 to 3 months for at least 1 year after you start 
treatment. If you are receiving memantine, your doctor will continue to see you in the clinic as 
needed. 
 
What are the risks and benefits of taking part in this study? (06-APR-2023) 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer or preventing your 
cancer from coming back. 
 
There is also a risk that you could have side effects from the study approach.  These side effects 
may be worse and may be different than you would get with the usual approach for your cancer.   
 
Some of the most common side effects that the study doctors know about are: 
 
Stereotactic radiosurgery (SRS) 
• pain or discomfort during the treatment if a head frame is used 
• 
the development of the same cancer in other areas of the brain 
 
Whole brain radiation therapy with hippocampus avoidance (HA-WBRT) 
• hair loss 
• temporary scalp redness and drying 
• tiredness  
 
Memantine 
• tiredness or drowsiness  
• indigestion 
 


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There may be some risks that the study doctors do not yet know about.   
 
 
Benefits 
There is evidence that memantine and HA-WBRT is more effective in preventing the same 
cancer from growing in other areas of the brain compared to the usual approach of SRS. It is not 
possible to know now if the study approach will extend your life compared to the usual 
approach.  This study will help the study doctors learn things that will help people in the future. 
 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  This may mean slowly stopping the study treatment so that there is not a sudden unsafe 
change, risk to your health, etc.  If you stop, you can decide if you want to keep letting the study 
doctor know how you are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the National Cancer Institute (NCI), Institutional Review Board 
(IRB), Food and Drug Administration (FDA), or study sponsor (NRG Oncology).  The 
study sponsor is the organization who oversees the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? (06-APR-2023) 
 
The usual treatment for patients with cancer that has spread to the brain is a type of combined 
radiation and surgery treatment called stereotactic radiosurgery (SRS). The purpose of this study 
is to compare the usual treatment of SRS to HA-WBRT and memantine for patients with cancer 
that has spread to the brain and come back in other areas of the brain after earlier treatment with 


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SRS.  HA-WBRT and memantine instead of the usual treatment could better control your brain 
cancer. But, it could also cause side effects, which are described in the risks section below.  
 
This study will help the study doctors find out if this different approach is better, the same, or 
worse than the usual approach.  To decide if it is better, the study doctors will be looking to see if 
the study approach extends your life by about 1 year compared to the usual approach.  
 
Memantine is FDA approved for treating dementia and is commonly used off-label (that is, for a 
purpose for which it is not FDA approved) for patients receiving whole-brain radiation therapy 
for cancer that has spread to the brain.  
 
There will be about 350 people taking part in this study. 
 
 
What are the study groups? (06-APR-2023) 
 
This study has 2 study groups.  You will be told which group you are in.  
 
• Group 1  
 
If you are in this group, you will  
receive whole brain radiation therapy with hippocampal avoidance (HA-WBRT). HA-
WBRT will be given to you as an outpatient for 5 days per week for about 2 weeks (about 
10 treatments). The treatments last about 10 to 20 minutes, including the set-up. You will 
also be given the drug memantine, which has also been shown to preserve memory 
function. Memantine will be taken by mouth once or twice daily with water, with or 
without food. Memantine will be taken for up to 6 months. You will be given a 
medication diary to complete every cycle and a clinical trial wallet card with study 
information to provide to other healthcare providers if needed. 
 
 
There will be about 175 people in this group. 
 
• Group 2  
 
If you are in this group, you will get the usual treatment of SRS. You will receive a high 
dose of radiation to the small areas of cancer in the brain. For most patients, the usual 
time on the SRS treatment machine is 30 to 90 minutes, but the entire procedure can take 
up to 4-6 hours including preparation time.  
 
There will be about 175 people in this group. 
 
We will use a computer to assign you to one of the study groups.  This process is called 
“randomization.”  It means that your doctor will not choose and you cannot choose which study 
group you are in.  You will be put into a group by chance. You will have an equal chance of 
being in Group 1 or Group 2. 


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Another way to find out what will happen to you during this study is to read the chart below. 
Start reading at the left side and read across to the right, following the lines and arrows.  
 
 
 
 
Randomize – 
The computer will 
randomly put you in a 
study group. 
Group 2 
Stereotactic 
radiosurgery (SRS) 
 
(Usual approach 
group) 
You agree to take 
part in the study 
and sign this 
consent form. 
Group 1 
Hippocampal-avoidant 
whole brain radiation 
therapy (HA-WBRT) 
+  
Memantine 
 
 
(Study group) 


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What exams, tests, and procedures are involved in this study? (06-APR-2023) 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
Neurocognitive Function Study  
If you speak and understand English or live in Canada and speak French, you will be asked to 
complete 3 thinking measures to evaluate your thinking abilities, such as memory and following 
directions; these thinking measures will be administered by a trained test administrator in the 
clinic. Researchers will use this information to better understand what effects the treatments are 
having on your ability to think.  
 
Since these thinking measures are being used for research, the responses you provide will not be 
shared with your study doctor.  If you have any serious health issues or other concerns, please 
talk with your doctor or nurse right away. 
 
You will be asked to complete the thinking measures 6 times during your regular office visits for 
the study:  
• Before starting treatment (1 time); and 
• At 2, 4, 6, 9, and 12 months after you start treatment (5 times) 
 
The three combined thinking measures will take about 20-30 minutes to complete each time.  
You don’t have to answer any question that makes you feel uncomfortable. There are no costs to 
you or your insurance. 
 
 
Patient Reported Outcome Questionnaires 
If you speak and understand English or live in Canada and speak French, you will be asked to fill 
out 3 questionnaires with questions about symptoms, your general health status, and your 
physical and emotional well-being. Researchers will use this information to better understand 
how patients feel and function during treatments and what effects the treatments are having.  
 


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Since these questionnaires are being used for research, the responses you provide will not be 
shared with your study doctor.  Please also report any symptoms or difficulty with activities 
directly to your doctor or nurse right away.  
 
You will be asked to fill out the questionnaires 6 times during your regular office visits for the 
study:  
• Before starting treatment (1 time); and 
• At 2, 4, 6, 9, and 12 months after you start treatment (5 times) 
 
Each questionnaire will take about 5-10 minutes to complete each time you fill it out.  The 
questionnaires will ask about things like your symptoms such as tiredness or weakness, your 
ability to complete physical tasks, and your emotional and social well-being.  You don’t have to 
answer any question that makes you feel uncomfortable. 
 
You will have the option of completing the questionnaires by paper or by an electronic device 
(See *Section Below).  
*Option for completing Patient Reported Outcomes Questionnaires with a personal electronic 
device 
If you speak and understand English or live in Canada and speak French you will have the option of 
completing the questionnaires on paper or by an electronic device. If you choose to complete the 
questionnaires with an electronic device, you will enter your answers to the questionnaires via a 
personal electronic device such as your smart phone or tablet. In some cases, a tablet may be 
provided to you at your health care institution. The use of your own electronic device on a 
cellular network may result in a nominal cost to your data plan.  Regardless of the device you 
use, your answers and personal information will not be stored on the device. Your answers will 
be sent to the research database and will be kept private in the same way listed in the later 
section about who will see your medical records.  Your e-mail address will only be used for this 
survey study and will not be used for mail or marketing purposes. NRG Oncology will not keep 
your e-mail address. 
 
If you need help using the questionnaire application on your phone or tablet, ask for help at your 
study site. You don’t have to answer any question that makes you feel uncomfortable.  Someone 
may help you enter your answers in the device if you need.   
 
All patients will complete the questionnaires before treatment on paper. After that, you can 
choose to complete the questionnaires for the remaining time points online or on paper. The 
choice is up to you. If you choose to complete the questionnaires using an electronic device, see 
Appendix I of this document for more information. 
 
Please circle your answer: 
I choose to use the electronic software for completing the Patient Reported Outcomes 
(PRO)  questionnaires. I agree to fill out the PRO questionnaires electronically (after 
treatment has started).  
 
YES 
 
 
NO 


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What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies.  
 
The radiation and drug treatments used in this study could be very harmful to an unborn or 
newborn baby.  There may be some risks that doctors do not yet know about.  It is very 
important that you check with your study doctor about what types of birth control or pregnancy 
prevention to use while you are receiving study treatment and, for patients receiving memantine, 
90 days after the last dose of memantine. 
 
Side Effect Risks 
 
The radiation and drug treatments used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and let 
you know if changes occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study treatments. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 


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Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Study Group 1 – Possible side effects of memantine are listed in the tables below. Memantine is 
part of the experimental approach for treating this type of cancer. 
 
Possible Side Effects of Memantine (Table Version Date: October 14, 2020) 
 
Memantine is well-tolerated and is not associated with frequently occurring side effects.  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving memantine, from 4 to 20 may have: 
• Headache 
• Constipation   
• Diarrhea 
• Pain  
• Shortness of breath 
• High blood pressure 
• Coughing  
• Nervousness 
• Changes in behavior  
• Confusion, Restlessness 
• Inability to obtain enough sleep 
• Depression 
• Tiredness, lack of energy 
• Vomiting 
 
RARE, AND SERIOUS 
In 100 people receiving memantine, 3 or fewer may have: 
• Seeing or hearing things that aren’t there 
• Damage to kidney function  
NOTE:  Stevens Johnson Syndrome (SJS) is a severe skin rash with blisters and can involve the 
inside of mouth and other parts of the body and can include fever. Stevens Johnson Syndrome is 
very rare and, at this time, it is unknown if memantine causes this skin reaction. However, there 
have been reports of SJS while taking memantine. If you notice any skin reactions during 
treatment, inform your health care provider immediately.   
 
Additional Drug Risks 
 
Memantine could interact with other drugs. Please inform your study doctor about any other 
drugs you are taking.  


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Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
 
Possible Side Effects of Radiation Therapy (06-APR-2023) 
 
Study Group 1 – Possible side effects of hippocampal-avoidant whole brain radiation therapy 
(HA-WBRT) are listed in the tables below. HA-WBRT is part of the experimental approach for 
treating this type of cancer. 
 
Possible Side Effects of Hippocampal-Avoidant Whole Brain Radiation Therapy (HA-
WBRT) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving HA-WBRT, more than 20 and up to 100 may have: 
• Hair loss 
• Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving HA-WBRT, from 4 to 20 may have: 
• Temporary scalp redness and drying 
• Nausea 
• Cataract formation  
• Dry mouth 
• Taste changes 
• Temporary ear and ear canal redness, plugging or drainage  
• Headaches 
• Memory loss, which may be permanent 
• Increased sleepiness (occurring four to ten weeks after radiation therapy is complete 
and lasting for several days up to two weeks) 
• The development of cancer in or near the hippocampus 
 
RARE, AND SERIOUS 
In 100 people receiving HA-WBRT, 3 or fewer may have: 
• Decreased brain function such as motor function (coordination/movement) 
• Severe damage to or death of normal brain tissue, which may require surgery to 
remove 
• Hardening of the arteries in the brain which rarely may lead to strokes many years after 
whole brain radiotherapy 
• A second new cancer caused by radiation, in the brain or nearby organs which rarely 
may occur many years after whole brain radiotherapy 
• Eye damage with the possibility of permanent blindness 
 
 


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Study Group 2 – Possible side effects of stereotactic radiosurgery (SRS) are listed in the tables 
below.  SRS is the usual approach for treating this type of cancer: 
 
Possible Side Effects of Stereotactic Radiosurgery (SRS) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving SRS, more than 20 and up to 100 may have: 
• Pain or discomfort during the procedure if a  head frame is used 
• the development of the same cancer in other areas of the brain 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving SRS, from 4 to 20 may have: 
• Headache 
• Localized hair loss which may be permanent  
• Nausea 
• Vomiting 
• Allergic reaction to the local anesthesia (rash, itching, nausea, or difficulty breathing)  
• Bleeding and/or infection around the head frame (if a head frame is used) 
• Swelling of the brain in the treated area which may require treatment with steroids 
• Memory loss, which may be permanent 
• Severe damage to or death of normal brain tissue, which may require surgery to 
remove  
 
RARE, AND SERIOUS 
In 100 people receiving SRS, 3 or fewer may have: 
• Decreased brain function such as motor function (coordination/movement) 
• Hardening of the arteries in the brain which rarely may lead to strokes many years after 
stereotactic radiosurgery 
• A second new cancer caused by radiation, in the brain or nearby organs which rarely 
may occur many years after stereotactic radiosurgery 
• Eye damage with the possibility of permanent blindness 
 
 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 


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• Write down in your medication diary when you take the study drug at home.   
 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant while you are receiving study treatment or, 
if you are receiving memantine, within 90 days after your last dose. 
 
 
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer.  This includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.  
• the costs of the stereotactic radiosurgery 
• the costs of the whole-brain radiation therapy and memantine (if you are in Group 1)  
• your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
 
• Administration and completion of the neurocognitive function and Patient Reported 
Outcomes assessments. 
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment 
 
 
 


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What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The study 
doctors have a privacy permit to help protect your records if there is a court case.  However, some of your 
medical information may be given out if required by law.  If this should happen, the study doctors will do 
their best to make sure that any information that goes out to others will not identify who you are.  
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records.  Your health information in the research database also may be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 
• NRG Oncology  
• The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study.  
• The FDA and the groups it works with to review research.   
• The NCI and the groups it works with to review research, including the Cancer Trials 
Support Unit (CTSU). 
• The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research, including the Imaging and Radiation Oncology Core (IROC).  
 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 


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may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor (*insert name of study doctor[s]*) at 
(*insert telephone number, and email address if appropriate*). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
 
Optional studies that you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with cancer in the future.  The results will not be added to your medical records and you or your 
study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies.  There is no penalty for saying “no.” You and 
your insurance company will not be billed for these optional studies.  If you sign up for, but 
cannot complete any of these studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 


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Optional sample collections for known laboratory studies and/or storage for 
possible future studies 
 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known future studies 
 
If you choose to take part in this optional study, researchers will collect blood for research on 
proteins and genes that may increase risk of developing new cancers in the brain or increase the 
chance of cognitive effects. 
 
Unknown future studies 
 
If you choose to take part in this optional study, blood will be collected and stored.  Storing 
samples for future studies is called “biobanking.”  The biobank is being run by NRG Oncology 
and is supported by the NCI.  Also, any health-related information, such as your response to 
cancer treatment, results of study tests, and medicines you took, will be stored for future use.  
This is a publicly funded study. Samples from publicly funded studies are required to be shared 
as broadly as possible. However, we will protect your privacy. The goal of this is to make more 
research possible that may improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 
identifies who they are and what their planned research project is. Before getting the samples and 
data, the researchers must agree to keep the data private, only use it for their planned research 
project, and never use it to try to identify you. 
 
Right now, we don’t know what research may be done in the future using your blood samples.  
This means that: 
 
• You will not be asked if you agree to take part in the future research studies.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
samples.  
 


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Unknown future research studies may include sequencing of all or part of your DNA.  This is 
called genomic sequencing.  Sequencing allows researchers to identify your genetic code. 
Changes in your genetic code may be passed down through your family.  For example, these 
genetic changes may be passed down to your children in the same way that eye and hair color are 
passed down.  These are called germline changes.   
 
What is involved in this optional sample collection? (06-APR-2023) 
 
If you agree to take part, here is what will happen next: 
 
1. About 1 tablespoon of blood will be collected from a vein in your arm before you start 
radiation treatment and about 2 months after you start treatment.   
2. Your sample will be stored in the biobank.  There is no limit on the length of time we will 
keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
3. Researchers can only get samples from the biobank after their research has been 
approved by experts.  Researchers will not be given your name or contact information.   
4. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information.   
 
What are the risks in this optional sample collection? 
 
• The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
• In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance.  (~For non-US participants, adapt the following two 
sentences as needed. ~) There are laws against the misuse of genetic information, but 
they may not give full protection. For more information about the laws that protect you, 
ask your study doctor or visit:  https://www.genome.gov/10002328/  
 
How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 


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2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 
 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, (*insert 
name of study doctor for main trial*), at (*insert telephone number of study doctor for main 
trial*), who will let the biobank know.  Then, any sample that remains in the biobank will be 
destroyed or returned to your study doctor.  This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
 
If you have questions about the use of your samples for research, contact the study doctor, 
(*insert name of study doctor for main trial*), at (*insert telephone number of study doctor for 
main trial*). 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for known future studies: 
 
I agree that my samples and related health information may be used for the laboratory study 
described above. 
 
 
YES 
 
NO 
 
Samples for unknown future studies: 
 


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I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
“yes”. 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
  
 
 
 
 


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Appendix I: Patient Instructions for Accessing the Patient Cloud Using Your Personal 
Device (06-APR-2023) 
Downloading the Patient Cloud ePRO App 
If you are using your personal device, and you do not have the Patient Cloud mobile app, 
use the following instructions. When downloading the app, you must use the Apple ID 
or Google account associated with the device. If the ePRO 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 ePRO mobile app available.  Ensure that the correct version of 
the ePRO mobile app is downloaded. 
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 smart devices):  
 
1. An Apple ID is required for downloading the ePRO Patient Cloud mobile app. 
2. Tap the App Store icon. 
3.  Search for  “Patient Cloud” and follow the installation 
instructions to download the app with this icon:  
   
For Android: 
1. A Google account is required for downloading the ePRO mobile app 
2. Tap the Play Store icon. 
3.  Search for  “Patient Cloud” and follow the installation 
instructions to download the app with this icon:   
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 ePRO mobile app. 
 
Note: You must have an activation code to begin this process. If you do not have an 
activation code, please contact your provider.  


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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 ePRO mobile app. 
1. If registering from the ePRO mobile app, tap “Have an Activation Code?” on the 
bottom of the log in page. If registering on the web, open the URL 
shield.imedidata.com on a web browser. 
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 response to the security questions. 
9. Tap Create my account to complete your registration.  
If you registered on the ePRO mobile app, it automatically logs you out. If you registered 
on the web, you are presented with the option to download the ePRO mobile app. You 
can then proceed to log in with the credentials you created. 
Logging in to the ePRO mobile 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 ePRO mobile 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 ePRO mobile 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 on 
the top left 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. You may reset your PIN by tapping the options menu on the top left of 
most pages and selecting Set PIN. 
Resetting Your Password 
You can reset your password by using the options menu at the top left of most pages 
(displays as 3 stacked horizontal bars). 


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1. Tap the options menu icon. 
2. Tap Reset Password. 
3. Follow the instructions to reset your password. 
 
Completing and Submitting Forms 
Once logged into the ePRO mobile app, forms related to your study are displayed on the 
Tasks List page. Select a form, and complete and submit the form. New forms can appear 
on the Tasks List page at any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• 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. 
• 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 
may be 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.