A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases
Phase: PHASE3
Conditions: Cognitive Impairment, Metastatic Malignant Neoplasm in the Brain, Solid Neoplasm
Sponsor: NRG Oncology

NRG-CC001 
1  
- Version Date: September 26, 2017 
NRG ONCOLOGY 
 
NRG-CC001 
(ClinicalTrials.gov NCT #: 02360215) 
 
A RANDOMIZED PHASE III TRIAL OF MEMANTINE AND WHOLE-BRAIN 
RADIOTHERAPY WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE IN 
PATIENTS WITH BRAIN METASTASES 
 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (24AUG2017) 
Principal Investigator 
Paul Brown, MD 
Mayo Clinic 
200 First St. SW 
Rochester, MN 55905 
507-284-2949/Fax: 507-284-0079 
brown.paul@mayo.edu 
Co-Principal Investigator 
Vinai Gondi, MD 
Northwestern Medicine Cancer Center 
Warrenville 
4405 Weaver Parkway 
Warrenville, IL 60555 
630-352-5350/Fax: 630-352-5349 
vgondi@chicagocancer.org 
Modality Co-Chair/Neurocognitive 
Jeffrey S. Wefel, PhD, ABPP 
MD Anderson Cancer Center  
Department of Neuro-Oncology, Unit 431 
P.O. Box 301402  
Houston, TX 77230 
713-563-0514/Fax: 713-794-4999 
jwefel@mdanderson.org 
Modality Co-Chair/Neuro-Oncology  
Mark R. Gilbert, MD 
National Cancer Institute 
National Institutes of Health 
Bloch Bldg. 82, Rm. 235 
9030 Old Georgetown Road 
Bethesda, MD 20892 
301-402-6383/Fax: 301-480-2246  
mark.gilbert@nih.gov 
Modality Co-Chair/Medical Physics 
Wolfgang A. Tomé, PhD, FAAPM 
Department of Radiation Oncology 
Montefiore Medical Center 
Albert Einstein College of Medicine 
1300 Morris Park Avenue 
Block Building Room 106 
Bronx, NY 10461 
718-430-3100/Fax: 718-405-8561 
wtome@montefiore.org 
Modality Co-Chair/Quality Of Life 
Terri S. Armstrong, PhD, ANP-BC, FAANP 
NOB, CCR, NCI, NIH 
Building 82.  Room 201 
Bethesda, MD 20892 
240-760-6003 
Terri.Armstrong@nih.gov 
Study Team continued on next page 
 
 

NRG-CC001 
2  
- Version Date: September 26, 2017 
NRG-CC001  
 
A RANDOMIZED PHASE III TRIAL OF MEMANTINE AND WHOLE-BRAIN 
RADIOTHERAPY WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE IN 
PATIENTS WITH BRAIN METASTASES 
 
Study Team continued (6/2/16) 
Modality Co-Chair/Utilities and Comparative 
Effectiveness 
Andre A. Konski, MD, MBA, MA FACR 
Department of Radiation Oncology  
University of Pennsylvania  
Perelman School of Medicine 
The Chester County Hospital  
701 E. Marshall Street 
West Chester, PA 19380 
610-431-5530 
andre.konski@uphs.upenn.edu 
Modality Co-Chair/Imaging  
Joseph A. Bovi, MD 
Medical College of Wisconsin 
Department of Radiation Oncology 
Froedtert Memorial Lutheran Hospital 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53222 
414-805-4477/Fax: 414-805-4369 
jbovi@mcw.edu 
Modality Co-Chair/Imaging 
Cliff Robinson, MD 
Washington University in St. Louis 
Department of Radiation Oncology 
4921 Parkview Place, Box 8224 
St. Louis, MO 63110 
314-362-8567/Fax: 314-362-8521 
crobinson@radonc.wustl.edu 
Modality Co-Chair/TRP 
Deepak Khuntia, MD 
Varian Medical Systems and the Targeted 
Radiation Institute of VMOC 
3100 Hansen Way, E-175 
Palo Alto, CA 94304 
650-776-0069 
Deepak@khuntia.com 
Modality Co-Chair/TRP 
David R. Grosshans, MD, PhD 
UT MDACC 
1840 Old Spanish Trail #1150 
Houston, TX 77054 
713-745-8795/Fax: 713-563-1521 
dgrossha@mdanderson.org 
Modality Co-Chair/Radiology 
Tammie L.S. Benzinger, MD, PhD 
Mallinckrodt Institute of Radiology 
Washington University School of Medicine in 
St. Louis – Campus Box 8131 
510 South Kingshighway Boulevard 
St. Louis, MO 63110 
Clinical Phone: 314- 362-5949 
Research Phone: 314- 362-1558 
benzingert@wustl.edu 
Statistician 
Stephanie Pugh, PhD  
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0850/Fax: 215-928-0153 
pughs@nrgoncology.org 
 
Study Team continued on next page 

NRG-CC001 
3  
- Version Date: September 26, 2017 
NRG-CC001 
 
A RANDOMIZED PHASE III TRIAL OF MEMANTINE AND WHOLE-BRAIN 
RADIOTHERAPY WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE IN 
PATIENTS WITH BRAIN METASTASES 
 
NRG Oncology Contact Information (24AUG2017) 
Data Management 
For questions concerning eligibility or data 
submission 
Clinical Data Coordinator  
Roseann Bonanni, CTR, CCRP 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3223/Fax: 215-930-8840 
bonannir@nrgoncology.org 
RTQA 
For questions concerning RT data submission 
(include if applicable) 
Dosimetrist 
Denise Manfredi, BS, RT(T) 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3219 
dmanfredi@acr.org 
RT Credentialing 
(include if applicable) 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
RT data submission to TRIAD 
(include if applicable) 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & amendments 
Protocol Administrator 
Kathryn Okrent, MA 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0856/Fax: 215-928-0153 
okrentk@nrgoncology.org 
 

NRG-CC001 
4  
- Version Date: September 26, 2017 
NRG-CC001 
 
A RANDOMIZED PHASE III TRIAL OF MEMANTINE AND WHOLE-BRAIN 
RADIOTHERAPY WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE IN 
PATIENTS WITH BRAIN METASTASES 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Memantine 
Commercial 
N/A 
Exempt 
N/A 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 3 
September 26, 2017 
November 6, 2017 
Amendment 2 
August 24, 2017 
November 6, 2017 
Amendment 1 
August 17, 2016 
October 3, 2016 
Activation 
June 10, 2015 
July 13, 2015 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

NRG-CC001 
5  
- Version Date: September 26, 2017 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................5 
SCHEMA .........................................................................................................................................7 
OBJECTIVES ..................................................................................................................................8 
1.1       Primary Objective ....................................................................................................8 
1.2       Secondary Objectives...............................................................................................8 
1.3       Exploratory Objectives  ...........................................................................................8 
2          BACKGROUND .................................................................................................................8 
2.1       Rationale for Proposed Study ..................................................................................8 
2.2   
Significance of the Study .......................................................................................12 
2.3 
Neurocognitive Function Assessment ....................................................................12 
2.4 
Patient-Reported Outcomes (PROs) and Health-Related Quality of Life  ............12 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA  .......................13 
3.1 
Patient Selection Guidelines  .................................................................................13 
3.2 
Eligibility Criteria  .................................................................................................14 
3.3 
Ineligibility Criteria  ..............................................................................................15 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........16 
5.         TREATMENT PLAN/Regimen description ......................................................................17 
5.1 
Drug Therapy .........................................................................................................17 
5.2 
Radiation Therapy ..................................................................................................18 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................25 
5.4 
Duration of Therapy ...............................................................................................25 
6.         TREATMENT MODIFICATIONS/MANAGEMENT .....................................................25 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................26 
7.1       Protocol Agent .......................................................................................................26 
7.2 
Adverse Events ......................................................................................................26 
7.3 
CTEP-AERS Adverse Event Reporting Requirements .........................................28 
8. 
REGISTRATION and STUDY ENTRY PROCEDURES   ..............................................30 
8.1       Site Registration Requirements ..............................................................................31 
8.3       Pre-registration Requirements ...............................................................................33 
8.3.1  Neurocognitive Function Testing Certification .....................................................33 
8.4       RT-Specific Pre-Registration Requirements ..........................................................34 
8.5       Patient Enrollment .................................................................................................37 
9.0 
DRUG INFORMATION ...................................................................................................38 
9.1 
Investigational Study Agent ...................................................................................38 
9.2 
Commercial Agent: Memantine .............................................................................38 

NRG-CC001 
6  
- Version Date: September 26, 2017 
10. 
PATHOLOGY/BIOSPECIMEN .......................................................................................39 
10.1 
Biomarkers .............................................................................................................39 
10.2 
Biospecimen Submission Table .............................................................................40 
10.2.1  Optional Specimen Submissions............................................................................40 
11. 
SPECIAL STUDIES (NON TISSUE) ...............................................................................41 
11.1 
Imaging Biomarkers ...............................................................................................41 
11.2 
Neurocognitive Evaluation ....................................................................................45 
11.3 
Patient Reported Outcomes ...................................................................................45 
12. 
MODALITY REVIEWS ...................................................................................................46 
13. 
DATA AND RECORDS ...................................................................................................46 
13.1    Data Management/Collection .................................................................................46 
13.2    Summary of Data Submission ................................................................................47 
13.3    Global Reporting/Monitoring .................................................................................47 
14. 
STATISTICAL CONSIDERATIONS...............................................................................47 
14.1 
Study Design ..........................................................................................................47 
14.2 
Study Endpoints .....................................................................................................48 
14.2.1  Primary Endpoint ...................................................................................................48 
14.2.2  Secondary Endpoints .............................................................................................48 
14.3 
Primary Objectives Study Design ..........................................................................48 
14.4 
Study Monitoring of Primary Objectives ...............................................................50 
14.5 
Accrual Considerations ..........................................................................................50 
14.6 
Secondary or Exploratory Elements  .....................................................................51 
14.7 
Exploratory Hypotheses and Endpoints .................................................................54 
14.8 
Gender/Ethnicity/Race Distribution .......................................................................55 
REFERENCES ..............................................................................................................................56 
APPENDIX I .................................................................................................................................63 
APPENDIX II ................................................................................ Error! Bookmark not defined. 
 
APPENDIX III ............................................................................... Error! Bookmark not defined. 
 
 
 

NRG-CC001 
7  
- Version Date: September 26, 2017 
NRG-CC001 
A Randomized Phase III Trial Of Memantine and Whole-Brain Radiotherapy With or 
Without Hippocampal Avoidance in Patients With Brain Metastases 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STEP 1: REGISTRATION 
STEP 2: RANDOMIZATION 
Baseline neurocognitive assessment: HVLT-R, TMT, COWA (required) 
NOTE: Neurocognitive assessments can be uploaded at the time of Step 1 registration. 
 
STRATIFICATION 
RPA Class: (see Appendix III) 
1. Class I  
2. Class II  
Prior therapy: 
1. None 
2. Radiosurgery or surgical resection* 
 
 
Arm 1 
WBRT 30 Gy/10 fractions  
+  
Memantine**    
 
Arm 2 
WBRT with Hippocampal Avoidance 
using IMRT 30 Gy/10 fractions 
+ 
Memantine** 
 
*Radiosurgery or surgical resection within 8 weeks of Step 1 registration; otherwise stratify to None. 
 
**Memantine to be administered during and after WBRT or WBRT with hippocampal avoidance for a 
total of 24 weeks. 

NRG-CC001 
8  
- Version Date: September 26, 2017 
OBJECTIVES 
1.1       Primary Objective 
Determine whether the addition of HA-WBRT increases time to neurocognitive failure at 
months 2, 4, 6 and 12 as measured by neurocognitive decline on a battery of tests: the 
Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and 
Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making 
Test (TMT) Parts A and B. 
1.2       Secondary Objectives 
1.2.1 Determine whether the addition of HA-WBRT preserves neurocognitive function at 
months 2, 4, 6 and 12 as separately measured by each test, the HVLT-R for Total Recall, 
Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B. 
1.2.2 Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. 
D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)  
1.2.3 Assessment of quality adjusted survival and health outcomesusing the EQ-5D-5L. 
1.2.4 Compare cumulative incidence of progression and overall survival after WBRT versus 
HA-WBRT. 
1.2.5 Compare adverse events between the treatment arms according to the CTCAE v4.0 
criteria. 
1.3       Exploratory Objectives (6/2/16) 
1.3.1 Collect serum, whole blood, and imaging studies for future translational research 
analyses.   
1.3.2 Evaluate MR imaging biomarkers of white matter injury and hippocampal volumetry at 
baseline and 6 months as potential predictors of neurocognitive decline and differential 
benefit from HA-WBRT as compared to WBRT. 
1.3.3 Association of symptom burden and anxiety/depression with neurocognitive function 
1.3.4 Evaluate the potential correlation between the prognostic scoring systems RTOG RPA 
and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive 
function at baseline and overtime. 
 
2          BACKGROUND 
2.1       Rationale for Proposed Study 
Neurocognitive Effects of Cranial Radiotherapy 
Approximately 200,000 patients a year are treated with brain radiation for primary or 
metastatic brain tumors in the United States.(Robbins 2011) As recent advances in multi-
modality therapy have led to improvement in survival for many cancer patients, more 
attention has been directed toward long-term treatment-related morbidity. Specifically, 
the effect of radiotherapy on the long-term cognitive performance of these patients is a 
major concern, as the morbidity can be devastating with a significant impact on both 
patient and caregiver quality of life (QOL).(Chien 2003; Laack 2004) 
 
Brain metastases are the most common form of intracranial tumor in adults, with an 
annual incidence approximately 10 times greater than primary brain tumors.(Siegel 2012; 
De Vita 2001) Brain metastases are a significant cause of morbidity and mortality, 
occurring in approximately 20 to 40 percent of adult cancer patients (Nussbaum 1996) 
with an incidence as high as 200,000 cases per year in the U.S. alone.(Eichler 2007)  It is 
expected the incidence of brain metastases will continue to increase due to improvement 

NRG-CC001 
9  
- Version Date: September 26, 2017 
in survival from systemic therapies. 
 
Historically, patients with brain metastases had very limited survival of a few months.  
However, subgroups of patients exist in which prolonged survival is possible. A recursive 
partitioning analysis (RPA)  of prognostic factors from  Radiation Therapy Oncology 
Group (RTOG) brain metastases trials of 1200 patients from three consecutive RTOG 
trials found Karnofsky performance score (KPS) to be the strongest predictor of 
survival.(Gaspar 1997)    RTOG 0614 treated 554 patients with whole brain radiotherapy 
(WBRT) but excluded patients with a KPS < 70 (i.e. RTOG RPA Class III).(Brown 
2012)  The median survival on this trial was over 7 months; by excluding poor 
performance status patients the study population was enriched with patients with an 
expected survival that was long enough to suffer the negative effects of WBRT. 
 
Whole brain radiotherapy is the most common treatment for brain metastasis. 
Unfortunately, the majority of patients with brain metastases experience cognitive 
deterioration after WBRT.  For example, a large trial prospectively evaluated patients 
with a battery of cognitive tests; by 6 months after WBRT 59% of patients had a greater 
than 2 SD decline in their performance in one or more tests.(Meyers 2004)  RTOG 0614 
prospectively tested brain metastases patients with a similar battery and found 80% of 
patients had evidence of cognitive deterioration 6 months after WBRT.(Brown 2012)  
With the high rate of cognitive decline over time and its impact on patient and caregiver 
QOL, it is imperative that interventions be developed to maintain cognitive function in 
this population over time. 
 
Memantine and Prevention of Neurocognitive Toxicity   
Glutamate is the principle excitatory amino acid neurotransmitter in cortical and 
hippocampal neurons.(Orrego 1993) One of the receptors activated by glutamate is the N-
methyl-D-aspartate (NMDA) receptor, which is involved in learning and 
memory.(Danysz 1998) Ischemia can induce excessive NMDA stimulation and lead to 
excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA 
receptors may protect against further damage in patients with vascular 
dementia.(Lancelot 1998)  One such agent is memantine, an NMDA receptor antagonist.  
Memantine is a non-competitive, low-affinity, open-channel blocker that has been shown 
to be neuroprotective in pre-clinical models.(Chen 1997; Chen 1992; Pellegrini 1993)   
Additionally, in two placebo-controlled phase III trials, memantine proved to be a well-
tolerated, effective treatment for vascular dementia, especially for patients with small-
vessel disease.(Orgogozo 2002; Wilcock 2002)  
 
The RTOG therefore launched a placebo-controlled, double-blind, randomized trial to 
evaluate the potential protective effect of memantine on neurocognitive function in 
patients receiving WBRT (RTOG 0614).(Brown 2012)  Patients received WBRT and 
were randomized to receive placebo or memantine, 20 mg per day, within 3 days of 
initiating radiotherapy, for 24 weeks.   Between March 2008 and July 2010, 554 patients 
were accrued of whom 508 were eligible.  Patient and treatment characteristics were well 
balanced between arms.  Grade 3 or 4 toxicities and study compliance were similar 
between arms.  No differences in overall or progression-free survival were seen between 

NRG-CC001 
10  
- Version Date: September 26, 2017 
the arms.  The memantine arm had significantly longer time to cognitive decline (HR 
0.78; 95% CI, 0.62 to 0.99; p=0.02) and the probability of cognitive function preservation 
at 24 weeks was 30.6% in the memantine and 19.7% in the placebo arm.  There was less 
decline on the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) in 
the memantine arm (median decline of 0) compared to the placebo arm (median decline 
of 0.90) at 24 weeks (p=0.059) that was not statistically significant, as 149 analyzable 
patients at 24 weeks resulted in only 35% statistical power for the primary endpoint.  
There was less decline on the HVLT-R Delayed Recognition in the memantine arm at 24 
weeks (p=0.0149) and the Mini Mental State Exam (MMSE) (p=0.0093).  Fewer patients 
receiving memantine experienced decline on Controlled Oral Word Association (COWA) 
at 8 weeks (2% vs. 13% deterioration; p=0.0015). Linear regression models for the 
complete case data revealed significant differences favoring the memantine arm for 
COWA at 8 (p=0.008) and 16 weeks (p=0.0041) and for Trail Making Test (TMT) Part A 
and MMSE (p=0.0137 and 0.0038, respectively) at 24 weeks. Using the imputed data, the 
investigators found a significant difference for COWA scores at 8 weeks (p=0.0103) 
favoring the memantine arm. 
 
In summary, the addition of memantine during and after WBRT resulted in better 
cognitive function over time—specifically delaying time to cognitive decline and 
reducing the rate of decline in memory, executive function, and processing speed.  
Although memantine showed evidence of better cognitive preservation after WBRT in 
patients with brain metastases, nearly 70% of patients still experienced cognitive 
deterioration by 6 months.  With this high rate of cognitive deterioration it is imperative 
that additional interventions be developed to improve on the results achieved by 
memantine.   
 
Rationale for WBRT with Hippocampal Avoidance 
Evidence suggests that the pathogenesis of radiation-induced neurocognitive deficit may 
involve radiation-induced injury to proliferating neuronal progenitor cells in the 
subgranular zone of the hippocampus.(Mizumatsu 2003)   It has been found that 
relatively small doses of radiation cause apoptosis in the subgranular zone of young rats 
and mice. .(Mizumatsu 2003; Gondi 2010)  Clinical studies suggest that radiation-
induced damage to the hippocampus plays a considerable role in the cognitive decline of 
patients. In particular, deficits in learning and memory observed in patients who have 
received cranial irradiation are thought to be related to hippocampal injury.(Abayomi 
1996; Roman 1995) Thus there is interest in using advance radiation techniques such as 
intensity modulated radiotherapy (IMRT) to conformally avoid the hippocampal region 
during WBRT (HA-WBRT) to reduce the dose to the hippocampus, thereby putatively 
limiting the radiation-induced cognitive decline.   
 
Feasibility of WBRT with Hippocampal Avoidance 
Novel techniques have been developed to achieve HA-WBRT using linear accelerator 
(LINAC)-based IMRT delivery systems widely available at multiple academic and 
community radiation oncology practices.(Gondi 2010)   RTOG 0933, a recently 
completed phase II trial of HA-WBRT for brain metastases, disseminated this knowledge 
and provided experience with these techniques. (Gondi 2013; Gondi 2014) In addition to 

NRG-CC001 
11  
- Version Date: September 26, 2017 
accruing 113 patients in 19 months at an accrual rate of 6 patients per month, this trial 
also built a technological infrastructure at RTOG to credential 113 physicians and 84 
RTOG sites spanning community and academic institutions in the techniques of 
hippocampal contouring and HA-WBRT treatment planning.   
 
WBRT with Hippocampal Avoidance and Prevention of Neurocognitive Toxicity   
The primary endpoint of RTOG 0933 was mean relative decline in HVLT-R delayed 
recall score from baseline to 4 months, defined as follows ∆〖HVLT〗_ i=(〖HVLT〗_B-
〖HVLT〗_F)/〖HVLT〗_B , where B=baseline and F=follow-up and a positive change 
indicates a decline in function. Based upon historical control data of 30% mean relative 
decline in HVLT-R delayed recall at 4 months compared to baseline in patients treated 
with WBRT without hippocampal avoidance, RTOG 0933 hypothesized that 
hippocampal avoidance during WBRT would lead to a 50% relative improvement over 
historical control, with a mean relative decline of 15% or less.  
 
Analysis of RTOG 0933 demonstrates that the primary endpoint was highly significant, 
with a mean relative decline in HVLT-R delayed recall score from baseline to 4 months 
of 7.0% (95% confidence interval (CI): -4.7% to 18.7%), which was significant in 
comparison to the historical control (p=0.0003).  The memory preservation benefit of 
hippocampal avoidance was maintained at 6 month follow-up, with a mean relative 
decline in HVLT-R delayed recall score from baseline to 6 months of 2.0% (95% CI: -
9.2% to 13.1%).  Similar preservation was also observed in the remaining HVLT-R 
domains.   For instance, probability of HVLT Total Recall deterioration (defined as >5 
point drop in Total Recall score from baseline to 4 months) after HA-WBRT was 19%.  
In comparison to the MD Anderson phase III trial of SRS with or without WBRT (Chang 
2009), this result compared favorably to the 49% rate following SRS+WBRT. In addition 
to HVLT, RTOG 0933 included other assessments of verbal learning memory as well as 
visuo-perceptual and spatial learning and memory, both of which demonstrated no 
significant change from baseline following HA-WBRT.  HA-WBRT was also associated 
with preservation of patient-reported quality of life, assessed using the Functional 
Assessment of Cancer Therapy and its validated brain subscale and the Barthel Activities 
of Daily Living.(Caine 2014) 
 
Safety of WBRT with Hippocampal Avoidance 
Following HA-WBRT on RTOG 0933, two grade 3 toxicities of fatigue and headache 
were observed; there were no grade 4 or higher toxicities.  Of the 67 patients who 
developed progression, 3 patients (4.5%) experienced relapse in the hippocampal 
avoidance region with no difference in overall survival of these 3 patients compared to 
the 64 patients who did not relapse in the hippocampal avoidance region (i.e. 4 month 
median survival for each cohort of patients developing intracranial progression). (Gondi 
2010)  In addition, for the entire cohort there was no detriment in PFS (5.9 mos.) or OS 
(6.8 mos.) compared to historical controls.(Meyers 2004; Chang 2009)  These data 
underscore the absence of survival impact of the rare relapse in the hippocampal 
avoidance region following HA-WBRT, the effectiveness of salvage radiosurgery, and 
the overall safety of HA-WBRT for patients with brain metastases. 
We seek to build upon the results of RTOG 0614 and the highly promising findings, 

NRG-CC001 
12  
- Version Date: September 26, 2017 
safety profile and robust accrual of RTOG 0933 to develop a trial that more definitively 
addresses the hypothesis that hippocampal avoidance may decrease radiotherapy-induced 
memory decline.   Thus, we propose a phase III study of WBRT and memantine versus 
HA-WBRT and memantine for patients with brain metastases, stratified by RPA class 
and prior treatment.  The primary endpoint will be time to neurocognitive failure with 
secondary endpoints such as quality of life, translational biomarkers, cumulative 
incidence of intracranial relapse and overall survival. 
   
2.2   
Significance of the Study 
As previously mentioned, 200,000 patients per year are treated with brain radiation for 
primary or metastatic brain tumors in the United States alone.(Robbins 2011) This is a 
very large patient population at risk of developing cognitive deterioration after 
radiotherapy, with a significant impact on patients, their caregivers, and society as a 
whole.  Although our prior trial, RTOG 0614, showed better cognitive function over time 
with the addition of memantine, nearly 70% of patients still experienced cognitive 
deterioration by 6 months.  Clearly, with this high rate of cognitive deterioration better 
treatments to prevent cognitive deterioration after radiotherapy are required.  Therefore, 
in an effort to build on our earlier successes from RTOG 0614 and with the highly 
promising findings of RTOG 0933 we propose a randomized phase III trial of WBRT and 
memantine versus HA-WBRT and memantine for patients with brain metastases. 
 
2.3 
Neurocognitive Function Assessment 
Neurocognitive outcomes have been recognized as being crucial in the brain metastasis 
population (Lin 2013). The Neurocognitive Clinical Trial Battery is a brief, sensitive, 
repeatable, highly standardized, objective battery of neurocognitive tests that have been 
demonstrated to be practical in terms of burden on the patient and site, with good 
compliance in multicenter clinical trials (Meyers 2004; Armstrong 2013; Brown 2013; 
Gilbert 2014).  The following battery of tests was utilized in RTOG 0614, which serves as 
the basis for the current trial.  Neurocognitive function will be assessed using the 
Hopkins Verbal Learning Test – Revised (HVLT-R, Benedict 1998), Trail Making Test 
(TMT, Tombaugh 2004), and the Controlled Oral Word Association (COWA, Ruff 
1996).  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 8.3.1).   
 
2.4 
Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) 
Radiation therapy can affect brain functioning, resulting in alterations in neurologic and 
neurocognitive function. In addition, the treatment also can result in systemic effects that 
can result in symptoms such as fatigue that can impact function and cause alterations in 
health-related quality of life (HRQOL). Therefore, tumor response and impact on 
neurocognitive function may not fully describe the impact of this treatment on the patient. 
Patient-reported outcome measures (PROs) provide a mechanism to assess this benefit. 
(Gondi 2013) Evaluating the impact of this approach on both the acute effects of 
radiation therapy and the potential benefit of mitigation of neurocognitive decline is an 
important secondary endpoint of this study. We hypothesize that mean symptom severity 

NRG-CC001 
13  
- Version Date: September 26, 2017 
and mean symptom interference as well as mean neurologic and cognitive factor score 
and change score from baseline will be higher in the WBRT arm. We also predict that the 
total symptom severity on the M.D. Anderson Symptom Inventory Brain Tumor 
(MDASI-BT); the symptom interference subscale; and the specific items of fatigue, 
neurologic factor items and cognitive factor items score loss will be prognostic. 
 
HRQOL will be measured using the EQ-5D-5L, a well established, validated measure 
that has been used in brain metastases populations.(Langley 2013; Takura 2010) 
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) Both the 
EQ-5D-5L and MDASI-BT are brief and therefore are not a significant burden for 
patients to complete.  Data will be analyzed longitudinally and compared between 
treatment arms. 
 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
(24AUG2017) 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact IROC Philadelphia RT (see protocol cover page).  
 
3.1 
Patient Selection Guidelines (6/2/16) 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. Patients must be willing to complete 
neurocognitive assessments at pre-specified time points outlined in the protocol. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception during the therapy (i.e. WBRT 
and memantine) part of the trial. 
3.1.3 Submission of serum and whole blood is strongly encouraged for all patients. 
Investigators should check with their site Pathology department regarding release of 
biospecimens before approaching patients about participation in the trial. Samples will be 
submitted for banking for the translational research portion of this protocol and future 
studies. (See details in Sections 9 and 10.) 
 

NRG-CC001 
14  
- Version Date: September 26, 2017 
3.2 
Eligibility Criteria (24AUG2017) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
Prior to Step 1 Registration: 
3.2.1 Brain metastases outside a 5-mm margin around either hippocampus must be visible on 
contrast-enhanced MRI performed ≤21 days prior to Step 1 registration. An allowed 
exception, regarding ability to image brain metastases, would be that patients who had 
undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not 
have to have visible disease but do need a pre-surgery MRI or CT scan demonstrating 
brain metastases. However, the brain metastases could not have been within 5 mm of 
either hippocampus.  (Only report on Step 1 if it meets the stratification variable; see the 
schema page.) 
3.2.2 Patients must have a post gadolinium contrast-enhanced three-dimensional spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field 
echo (TFE) MRI scan and an axial T2/FLAIR sequence. To yield acceptable image 
quality, the 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. This MRI must be obtained ≤21 days prior to step 1 registration. See NRG-CC001 
protocol page of the NRG website for imaging-specific frequently asked questions. 
 
Sites should contact the Imaging Co-Chairs for further information or assistance if 
needed.  
 
3.2.3  Patients must provide study-specific informed consent prior to registration. 
 
Prior to Step 2 Registration: 
3.2.4 The following baseline neurocognitive assessments must be completed prior to Step 2 
registration: HVLT-R, TMT, and COWA. The neurocognitive assessment will be 
uploaded into a folder in the NRG RAVE System for evaluation by Dr. Wefel.  Once the 
upload is complete, within 1 business day a notification will be sent to the RA to proceed 
to Step 2.  
NOTE: Completed baseline neurocognitive assessments can be uploaded at the time of 
Step 1 registration. 
3.2.5 Pathologically (histologically or cytologically) proven diagnosis of solid tumor 
malignancy within 5 years prior to Step 2 registration. If the original histologic proof of 
malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is 
required (e.g., from a systemic metastasis or brain metastasis). 
3.2.6 History and physical examination within 28 days prior to Step 2 registration 
3.2.7 Age ≥ 18; 
3.2.8 Karnofsky Performance Status of ≥70 within 28 days prior to Step 2 registration; 
3.2.9 Adequate renal function ≤28 days prior to Step 2 registration defined as follows: 
 Serum creatinine ≤ 3 mg/dL (265 μmol/L) and creatinine clearance ≥30 ml/min 
 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). 

NRG-CC001 
15  
- Version Date: September 26, 2017 
3.2.10 Patients may have had prior therapy for brain metastasis, including radiosurgery and 
surgical resection. Patients must have completed prior therapy by at least 14 days prior to 
Step 2 for surgical resection and 7 days for radiosurgery. 
3.2.11 Negative serum pregnancy test (in women of childbearing potential) ≤14 days prior to 
Step 2. Women of childbearing potential and men who are sexually active must practice 
adequate contraception while on study. 
3.2.12 Patients who are primary English or French speakers are eligible.    
 
3.3 
Ineligibility Criteria (24AUG2017) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Prior external beam radiation therapy to the brain or whole brain radiation therapy. 
 Prior single-fraction or fractionated radiosurgery is permitted.   
3.3.2 Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior 
chemotherapy. 
3.3.3 Radiographic evidence of hydrocephalus or other architectural distortion of the 
ventricular system, including placement of external ventricular drain or 
ventriculoperitoneal shunt. 
3.3.4 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 
registration  
 Chronic obstructive pulmonary disease exacerbation or other acute respiratory 
illness precluding study therapy at the time of registration  
 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 registration. Note also that HIV testing is not required for 
eligibility for this protocol. 
3.3.5 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 involved in this study has unknown 
effects on the unborn fetus. 
3.3.6 Prior allergic reaction to memantine 
3.3.7 Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine) 
3.3.8 Intractable seizures while on adequate anticonvulsant therapy—more than 1 seizure per 
month for the past 2 months 
3.3.9 Patients with definitive leptomeningeal metastases 
3.3.10 Patients with brain metastases from primary germ cell tumors, small cell carcinoma, 
unknown primary, or lymphoma. 
3.3.11 Contraindication to MR imaging such as implanted metal devices or foreign bodies 
3.3.12 Contraindication to gadolinium contrast administration during MR imaging, such as 

NRG-CC001 
16  
- Version Date: September 26, 2017 
allergy or insufficient renal function 
3.3.13 Current use of (other NMDA antagonists) amantadine, ketamine, or dextromethorphan 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
(24AUG2017) 
 
PRE-TREATMENT ASSESSMENTS 
Prior to Step 1 Registration (calendar days; may be required for eligibility) 
 
Brain MRI w/ contrast* 
21 
Informed consent 
Prior to registration 
Prior to Step 2 Registration(calendar days) 
 
(Required) Baseline neurocognitive: 
HVLT-R, TMT, COWA (upload required to 
proceed to Step 2) 
7 
Histological/cytological evaluation 
Within 5 yrs. prior to registration 
Neurologic exam 
28 
History/physical exam 
28 
Karnofsky performance status 
28 
Serum creatinine, creatinine clearance, 
BUN 
28 
Serum pregnancy test 
(if applicable) 
14 
English or French is primary language 
(English or French  must be the patient’s primary 
language) 
 
 
Pre-treatment 
QOL: MDASI-BT, EQ-5D-5L 
(If patient consents) Specimen collection 
*Thin slice MRI required as outlined in Section 5.2.3. 
 
 
 

NRG-CC001 
17  
- Version Date: September 26, 2017 
 
ASSESSMENTS DURING TREATMENT 
Assessments 
(All from the start of treatment) 
 
 
 
 
From start of WBRT/HA-WBRT:  
at months 2, 4, and 6 
 
 
 
 
 
 
Physical exam 
Neurologic exam 
Karnofsky performance status 
Serum creatinine, creatinine clearance, 
BUN 
Brain MRI w/ contrast* 
(Required) Neurocognitive: HVLT-R, 
COWA, TMT  (upload in RAVE required) 
QOL: MDASI-BT, EQ-5D-5L 
(If consent given) Specimen collection 
* Thin slice MRI is required for 6 month and highly recommended for 2 and 4 month follow-up as 
outlined in Section 5.2.3.  
All assessments are from the start of treatment 
 
ASSESSMENTS IN FOLLOW UP 
Assessments 
From start of WBRT/HA-WBRT: 
at month 12 
Physical exam 
Neurologic exam 
Karnofsky performance status 
Serum creatinine, creatinine clearance, BUN 
Brain MRI/CT w/ contrast 
(Required) Neurocognitive: HVLT-R, COWA, 
TMT (upload in RAVE required) 
2, 4, 6, and 12 months from the start 
of treatment 
QOL: MDASI-BT, EQ-5D-5L 
(If consent given) Specimen collection 
 
 
 
5.         TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
Drug Therapy  
 
Memantine should start the same day as WBRT/HA-WBRT and must start no later 
than before the fourth WBRT/HA-WBRT treatment. 
 
If a patient is enrolled on the study and they are unable to acquire memantine they 
should remain on the study and otherwise proceed forward per study. 
 
5.1.1 Both extended release memantine (Namenda XR) and twice daily memantine dosing will 
be allowed.  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 (10mg divided twice daily). Dose is escalated by 

NRG-CC001 
18  
- Version Date: September 26, 2017 
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 
 
 
Patients continue on memantine for 24 weeks. 
 
Extended Release Memantine 
The target dose for extended release memantine is 28 mg. Dose is escalated by 7 mg 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.  Memantine is well absorbed after oral 
administration and absorption is not affected by food and therefore can be taken with or 
without food. Missed doses should be documented but patients should not try to make up 
missed doses. 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 (available on the forms page of the NRG-CC001 protocol page) 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.    
 
5.2 
Radiation Therapy (6/2/16) 
 
Protocol treatment must begin within 21 calendar days after randomization. 
 

NRG-CC001 
19  
- Version Date: September 26, 2017 
NOTE 1: Patients can only be enrolled by treating physicians and institutions that have 
passed pre-enrollment benchmark cases for hippocampal contouring and HA-WBRT 
treatment planning.  Treating physicians and institutions that were credentialed for NRG-
CC003 (phase IIR/III study of prophylactic cranial irradiation with or without 
hippocampal avoidance for small cell lung cancer) or RTOG 0933 (phase II study of 
hippocampal avoidance during WBRT for brain metastases) will be permitted to enroll 
patients on NRG-CC001, since benchmark cases are similar between these trials.  
However, the first case they enroll on NRG-CC001 will require pre-treatment review of 
hippocampal contouring and HA-WBRT treatment before proceeding with protocol 
treatment.  See Section 8.4 for further details. 
 
NOTE 2: The first patient enrolled from each credentialed treating physician and 
institution in Arm 2 (WBRT with hippocampal avoidance) will require a Pre-Treatment 
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. See Section 8.4 for specifics on 
submission requirements. 
 
NOTE 3:  Treating physicians and institutions that passed one (1) pre-treatment review of 
a patient enrolled on the hippocampal avoidance arm of NRG-CC003 (phase IIR/III study 
of prophylactic cranial irradiation with or without hippocampal avoidance for small cell 
lung cancer) will be permitted to enroll patients on NRG-CC001 without Pre-Treatment 
Review. 
 
5.2.1 Treatment Technology 
This protocol requires photon treatment.  3DCRT is allowed in Arm 1. Field-in-field 
approaches to 3DCRT to optimize homogeneity are permitted for Arm 1.  Inverse 
planned IMRT is not allowed for Arm 1. IMRT is required for Arm 2.  Fixed-gantry 
IMRT, helical tomotherapy or VMAT can be used for Arm 2.  All participating sites must 
be credentialed for IMRT. 
 
Megavoltage beam of 6MV or greater must be used for Arms 1 or 2, 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.   
 
5.2.2 Immobilization and Simulation 
Immobilization 
Patients will be immobilized in the supine position using an immobilization device such 
as an Aquaplast mask over the head.  Patients will be treated in the immobilization 
device. 
 
Simulation Imaging  
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. For patients 

NRG-CC001 
20  
- Version Date: September 26, 2017 
enrolled on Arm 2 (HA-WBRT experimental arm), 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. 
 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
For Arms 1 and 2: Post gadolinium contrast-enhanced three-dimensional spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo 
field echo (TFE) axial MRI scan and axial T2 FLAIR sequence acquisitions. 
NOTE: ALTHOUGH NOT REQUIRED A PRECONTRAST AXIAL THREE-
DIMENSIONAL IMAGING SEQUENCE IS ALSO STRONGLY ENCOURAGED.   
 
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.  
 
See NRG-CC001 protocol page of the NRG website for imaging-specific frequently asked 
questions. 
 
These imaging sequences should be obtained with the patient in the supine position.  The 
MRI sequences are required at baseline as an eligibility criterion for enrollment in the 
study and also required at 6-month follow-up. Immobilization devices used for CT 
simulation and daily radiation treatments need not be used when obtaining these imaging 
sequences, but an attempt should be made to image the patient in as close to the same 
plane as the CT simulation as possible to facilitate fusion of the MRI and CT images. 
 
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 Imaging Co-Chairs for further information or assistance if 
needed. 
 
Note: The MRI study is mandatory irrespective of randomization to the experimental or 
control arm of this study. 
 
For Arm 2, the MRI for radiotherapy planning and treatment-planning CT should be 
fused semi-automatically for hippocampal contouring. 
 
5.2.4 Definition of Target Volumes and Margins 
For Arm 1, the target volume shall include the entire cranial contents, with flashing 
beyond skin and a minimum margin of 0.75 cm on the skull base as visualized on the 
digitally reconstructed radiograph (DRR) from the CT simulation scan.  This flashing 

NRG-CC001 
21  
- Version Date: September 26, 2017 
accounts for beam penumbra and day-to-day set-up variation.     
 
For Arm 2, 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 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 
(see Section 5.2.5).  No set-up 
margin is added. 
 
5.2.5 Definition of Critical Structures and Margins 
For Arm 1, care should be taken to minimize the dose to the lens.  These can be 
contoured on the simulation CT and visualized on the DRR.   
 
For Arm 2, 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. 
OpticNerve_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 

NRG-CC001 
22  
- Version Date: September 26, 2017 
dataset only. 
OpticNerve_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. 
 
5.2.6 Dose Prescription 
For Arms 1 and 2, 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. 
 
For Arm 1, dose is specified as the target dose, which shall be the dose on the central x-
ray at mid-separation for two opposed coaxial equally weighted beams.  “Compensating 
beams” that block hot spots (these hot spots are typically present along midline due to 
less tissue present in these regions compared to mid-brain) are allowed to achieve better 
dose homogeneity.  All portals shall be treated during each treatment session. 
 
For Arm 2, 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 (See Section 5.2.7). 
 
5.2.7 Compliance Criteria 
Arm 1: There are no compliance criteria specific to radiation therapy planning or 
delivery. 
 
Arm 2: 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 
 

NRG-CC001 
23  
- Version Date: September 26, 2017 
Name of 
Structure 
Dosimetric Parameter 
Per Protocol 
Variation 
Acceptable 
Notes 
PTV_3000 
 
D2%(Gy) 
≤ 37.5 
37.5 to 40  
Dose to hottest 2% 
of PTV_3000 
D98%(Gy) 
≥ 25 
22.5 to 25 
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) 
≤ 9 
9 to 10  
Dose to 100% of 
Hippocampus 
Dmax(Gy) 
≤ 16 
16 to 17  
Dose to hottest 
0.03 cc volume 
of Hippocampus 
OpticNerve_L 
Dmax(Gy) 
≤ 30 
30 to 37.5 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_L 
OpticNerve_R 
Dmax(Gy) 
≤ 30 
30 to 37.5 Gy 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_R 
OpticChiasm 
Dmax(Gy) 
≤ 30 
30 to 37.5 
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 
 
5.2.8 Treatment Planning Procedures and Priorities 
Arm 1:  Three-dimensional approaches to radiotherapy planning will be used for patients 
enrolled in the WBRT reference arm. There are no treatment-planning priorities. 
 
Arm 2:  Intensity-modulated radiotherapy will be used for patients enrolled in the WBRT 
with hippocampal avoidance arm.  In optimizing planning, the following treatment-

NRG-CC001 
24  
- Version Date: September 26, 2017 
planning priorities should be followed: 
 
 
1. OpticChiasm  
 
2. OpticNerve_L or OpticNerve_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. 
 
5.2.9 Dose Calculations 
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. 
 
Arm 2: 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.  
 
5.2.10 Patient-specific QA 
Arm 1: Patient-specific QA not required but should follow guidelines of enrolling 
institution. 
 
Arm 2: 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. 
 
5.2.11  Daily Treatment Localization/IGRT 
Verification orthogonal films or images are required.  For all forms of IMRT dose 
delivery, 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. 
 
5.2.12 Case Review  
Arm 1: No case review will be performed. 
 
Arm 2:  Case reviews will be ongoing and performed remotely for all patients enrolled in 

NRG-CC001 
25  
- Version Date: September 26, 2017 
Arm 2.  Case reviews will be conducted by a team of Co-Chairs, including the Principal 
Investigators Drs. Brown and Gondi, and the Imaging Co-Chairs Drs. Bovi and 
Robinson. 
Pre-treatment reviews are required. See section 5.2 for details 
 
  See Section 8.4 for specifics on submission requirements. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
 
5.3.2 Prohibited Therapies 
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 discouraged and other medications should be 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), 
 
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 
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. 
 
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  

NRG-CC001 
26  
- Version Date: September 26, 2017 
*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 protocol 
treatment. 
* For males: CrCl = [140-age (years)] ꞏ Weight (kg)/[72 ꞏ serum creatinine (mg/dL)] 
For females: CrCl = 0.85 ꞏ [140-age (years)] ꞏ Weight (kg)/[72 ꞏ serum creatinine (mg/dL)] 
 
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 protocol 
treatment 
* For males: CrCl = [140-age (years)] ꞏ Weight (kg)/[72 ꞏ serum creatinine (mg/dL)] 
For females: CrCl = 0.85 ꞏ [140-age (years)] ꞏ Weight (kg)/[72 ꞏ serum creatinine (mg/dL)] 
 
7.  ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   Protocol Agent 
 
Commercial Agent 
The commercial agent in NRG-CC001 is Memantine. 
7.2 
Adverse Events 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4 for adverse event (AE) reporting. The CTCAE version 4 is identified 
and located on the CTEP web site at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below 
will be reported via the CTEP Adverse Event Reporting System (CTEP-AERS) 
application accessed via the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865).  
7.2.1 Adverse Events (AEs)  

NRG-CC001 
27  
- Version Date: September 26, 2017 
Definition of an 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). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm] 
 7.2.2 Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in Section 7.3 will be reported via CTEP-AERS. 
SAEs that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table in Section 7.3.  Contact the CTEP-AERS Help Desk if assistance is 
required. 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that 
results in any of the following outcomes: 
 Death; 
 A life-threatening adverse drug experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect; 
 Important medical events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered an SAE, when, based upon medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition.  
7.2.3 Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system within 30 days of AML/MDS diagnosis. 
 
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 following treatment with an agent 
under an NCI IND/IDE 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 
 

NRG-CC001 
28  
- Version Date: September 26, 2017 
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 
reporting via CDUS unless otherwise specified. 
 
7.3 
CTEP-AERS Adverse Event Reporting Requirements (24AUG2017) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting 
System, accessed via the CTEP web site, 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865. 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and 
satisfies NRG requirements for expedited 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. . Once internet connectivity is 
restored, an AE report must be submitted electronically into CTEP-AERS. 
 
 CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour 
notification is electronically submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS 24-hour notification must be followed by a 
CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 
hour CTEP-AERS notification are defined in the expedited reporting table 
below. 
 Supporting source documentation is requested by CTEP as the IND sponsor 
for this study and NRG as needed to complete adverse event review.  When 
submitting supporting source documentation, include the protocol number, 
patient ID number, and CTEP-AERS ticket number on each page, and contact 
the NRG Operations Center (215-574-3191) for sourse document submission 
assistance. 
 A serious adverse event that meets expedited reporting criteria outlined in the 
following table but is assessed by the CTEP-AERS System as “expedited 
reporting NOT required” must still be reported to fulfill NRG Oncology safety 
reporting obligations.  Sites must bypass the “NOT Required” assessment; the 
CTEP-AERS System allows submission of all reports regardless of the results 
of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described 
in the table below. Important: All AEs reported via CTEP-AERS also must be reported 

NRG-CC001 
29  
- Version Date: September 26, 2017 
on the AE section of the appropriate case report form (see Section 13.2). 
 
SAE Reporting Requirements During Course 1, Memantine + RT (weeks 1-3) 
Expeditiously report all AEs that meet the requirements per the reporting table below 
during concurrent memantine and RT and for 30 days after end of RT. 
 
SAE Reporting Requirements During Course 2, Memantine alone (weeks 4-24) 
After the 30 day window from end of RT, only expeditiously report AEs reasonably 
related to protocol treatment that meet the requirements per the reporting table below; all 
other AEs (non-serious or unrelated) should be reported via routine AE reporting process.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a Commercial Agent within 30 Days of the Last 
Administration of the Agent in this Study 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 

NRG-CC001 
30  
- Version Date: September 26, 2017 
1Serious adverse events that occur more than 30 days after the last administration of commercially available 
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: 
 All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing a Commercially Available Agent: None 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES  (26SEPT2017) 
Access requirements for OPEN, Medidata Rave, and TRIAD: Site staff will need to be 
registered with CTEP and have a valid and active CTEP Identity and Access Management 
(IAM) account.  
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration 
type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 

NRG-CC001 
31  
- Version Date: September 26, 2017 
Documentation Required 
IVR 
NPIVR 
AP 
A 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
 Added to a site roster 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 Act as the site-protocol PI on the IRB approval 
 
Additional information can be found on the CTEP website.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
8.1       Site Registration Requirements (26Sept2017) 
8.1.1 This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
IRB Approval  
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.   Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
 An active Federal Wide Assurance (FWA) number 
 An active roster affiliation with the Lead Network or a participating organization 
 A valid IRB approval 
 Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 Active registration status 
 The IRB number of the site IRB of record listed on their Form FDA 1572 
 An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit IRB approval documentation to the CTSU Regulatory 
Office. For sites using the CIRB, IRB approval information is received from the CIRB 
and applied to the RSS in an automated process. Signatory Institutions must submit a 
Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to 
indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 

NRG-CC001 
32  
- Version Date: September 26, 2017 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU members’ 
website by entering credentials at https://www.ctsu.org.  
 
8.1.2 Requirements for NRG-CC001 Site Registration (26Sept2017) 
 IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
 IROC Credentialing Status Inquiry (CSI) Form 
NOTE:   For studies with a radiation and/or imaging (RTI) component, the 
enrolling site must be aligned to a RTI provider.  To manage provider associations 
access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component.   
 Credentialing documentation received from IROC Houston for this trial- See 
Section 8.4 Table for details. 
 IRB/REB approved consent (Non-North American and Canadian sites only: 
English and native language versions*) *Note: International and Canadian 
Institutions must provide certification/verification of IRB/REB consent translation 
to NRG Oncology (described below). 
 Other RT-Specific Requirements: See Section 8.4. 
 Neurocognitive Function Testing Certification: See Section 8.3.1. 
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission 
 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 

NRG-CC001 
33  
- Version Date: September 26, 2017 
 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration on the members’ section of the CTSU website.   
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 Click on the Regulatory tab  
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
French Speaking Canadian and International Institutions: 
 
Translation of documents is critical. The institution is responsible for all translation costs. 
All regulatory documents, including the IRB/REB approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to 
the prohibitive costs involved NRG will accept, at a minimum, a verified translation. A 
verified translation consists of the actual REB approved consent document in English and 
in the native language, along with a cover letter on organizational/letterhead stationery 
that includes the professional title, credentials, and signature of the translator as well as 
signed documentation of the review and verification of the translation by a neutral third 
party. The professional title and credentials of the neutral third party translator must be 
specified as well. Sites are NOT permitted to translate the Neurocognitive Tests. For sites 
testing native French speakers, the French versions of the tests must be obtained from the 
NRG Oncology website just as the English versions are obtained from the NRG 
Oncology website. 
8.2.3 Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
Prior to clinical trial commencement, Canadian institutions must also complete and 
submit via the Regulatory Submission portal on the CTSU website:   
 Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site 
Information Form,  
 Qualified Investigator Undertaking Form, and  
 Research Ethics Board Attestation Form.  
 
8.3       Pre-registration Requirements 
8.3.1 Neurocognitive Function Testing Certification  
Only a certified test administrator is permitted to administer the neurocognitive tests to 
study participants.  Test administrators must meet certification requirements for 
administering neurocognitive assessments (see Appendix II and the Neurocognitive 
Training Procedure Letter on the NRG Oncology website). Upon review and successful 
completion of the Neurocognitive Certification process, Jeffrey S. Wefel, PhD, 
Neurocognitive Co-Chair, will notify both the certified examiner and NRG Oncology that 
the examiner has successfully completed this requirement. The certified test administrator 
must be proficient in the language (English or French) in which the test is administered to 
the patient. Refer to the protocol-specific material on the NRG Oncology website for 

NRG-CC001 
34  
- Version Date: September 26, 2017 
certification requirements. 
 
8.4       RT-Specific Pre-Registration Requirements (26Sept2017) 
All sites must be IMRT Credentialed. For detailed information on the specific technology 
credentialing requirements 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, the IROC-Houston QA Center will notify your institution 
and NRG Headquarters when all credentialing requirements have been met and the 
institution is RT credentialed to enter patients onto this study.  This document must be 
uploaded by the site to the CTSU Regulatory Submission Portal for RSS to be updated.   
 
Benchmark Testing 
In order for a site to receive official credentialing for HA-WBRT, the institution and the 
treating physician must have passed benchmark testing for hippocampal contouring and 
HA-WBRT treatment planning AND pass the pre-treatment review on one case enrolled 
on NRG-CC001. Please note the exceptions to this requirement below in Notes 2, 3, and 
4. Benchmark testing is limited to two (2) physicians per site. Benchmark testing for 
hippocampal contouring and HA-WBRT treatment planning is no longer available. 
 
A treating physician who has not participated in or passed benchmark testing can enroll 
and treat patients on study so long as the patient’s contouring and HA-PCI treatment plan 
is reviewed by another physician who has passed benchmark testing at the treating site. 
 
Treating physicians and institutions credentialed for RTOG 0933 (Phase II study of 
hippocampal avoidance during WBRT for brain metastases) or NRG-CC003 (Phase 
IIR/III of prophylactic cranial irradiation with or without hippocampal avoidance for 
small cell lung cancer) can enroll patients in this trial without having to repeat the 
Benchmark QA test. However, the first case they enroll on NRG-CC001 will require pre-
treatment review of hippocampal contouring and HA-WBRT treatment before proceeding 
with protocol treatment. 
 
While the trials limit credentialing to 2 physicians per site, the trials do NOT limit accrual 
to 2 physicians per site.  Instead, we ask sites to enable any physician to accrue a patient 
to this study and to develop the hippocampal contours and hippocampal avoidance IMRT 
plan (should the patient be randomized to the experimental arm). However, we mandate 
that if a patient is enrolled by a non-credentialed physician, they ask one of the 
credentialed physicians at their site to review the contours/plan to ensure that they meet 
protocol criteria. When enrolling the patient, the system asks two questions: 1) Who is 
the enrolling the physician? and 2) Who is the credentialed physician who will be 
approving the contours?  Again, these do not need to be the same physician. 
 
To be Grandfathered from 0933 or CC003, complete a Credentialing Status Inquiry (CSI) 
Form (see the procedures and instructions table below) must be submitted in order to 
receive a letter and have RSS updated.  

NRG-CC001 
35  
- Version Date: September 26, 2017 
 
If an institution has successfully passed the Benchmark test for HA-WBRT planning on a 
non-VMAT (Volumetric Modulated Arc Therapy) IMRT modality, but would like to 
treat patients using VMAT, then the site will need to repeat the Benchmark test for HA-
WBRT planning for the VMAT platform.  In this case, the site can use their previous 
Benchmark submission.  
 
 

NRG-CC001 
36  
- Version Date: September 26, 2017 
 
 
 
 
RT 
Credentialing 
Requirements 
NRG-CC001 
 
Treatment Modality 
Key Information 
 
 
3DCRT 
(Arm 1) 
 
IMRT 
Mandatory 
for all sites 
(Arm 2) 
Facility 
Questionnaire 
 
  
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. 
Credentialing 
Status Inquiry 
Form 
 
  
To determine whether your institution needs to complete any 
further credentialing requirements, please complete the 
“Credentialing Status Inquiry Form” found under credentialing 
on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org) 
Benchmark 
Cases 
 
  
Benchmark cases are to be downloaded and completed by each 
treating physician at each institution before submission to 
IROC-Philadelphia RT via TRIAD.  Sites are to generate an 
IMRT plan for WBRT with hippocampal avoidance as per 
protocol criteria.  See below for further details. 
EXCEPTION:  Treating physicians and sites credentialed for 
RTOG 0933 (phase II study of hippocampal avoidance during 
WBRT for brain metastases) or NRG-CC003 (phase IIR/III 
study of prophylactic cranial irradiation with or without 
hippocampal avoidance for small cell lung cancer) will not be 
required to pass Benchmark Testing for NRG-CC001. 
Phantom 
Irradiation 
 
  
An anthropomorphic phantom study provided by the IROC-
Houston QA Center must be successfully completed. 
Instructions for requesting and irradiating the phantom are 
found on the IROC -Houston web site 
(http://irochouston.mdanderson.org). 
Additional Information 
 
Credentialing Issued to: 
Institution 
 
 
 Credentialing requires passing of benchmark testing AND passing 
of pre-treatment review of one (1) case enrolled on NRG-CC001.   
 
Credentialing for HA-WBRT treatment planning is site-specific.  
Credentialing for hippocampal contouring will be specific to each 
treating physician.  
 
   
 
IROC-Houston QA Center will notify the institution and NRG 
Headquarters that all desired credentialing requirements have been 
met.  
Radiation 
Oncologist 
 
 
 

NRG-CC001 
37  
- Version Date: September 26, 2017 
8.4.1 Digital RT Data Submission to NRG Oncology Using TRIAD 
TRIAD is the image exchange application used by the NRG Oncology. TRIAD 
provides sites participating in NRG clinical trials a secure method to transmit 
DICOM RT and other objects.  TRIAD anonymizes and validates the images as 
they are transferred. 
 
TRIAD Access Requirements: 
  Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account, and be 
registered as an AP, NPIVR or IVR.  Please refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account and 
complete registration in RCR. 
 To submit images, the site physics user must be on the site’s affiliated rosters and 
be assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. 
NRG users should contact your site Lead RA to be added to your site roster.  
Users from other cooperative groups should follow their procedures for 
assignment of roster roles. 
 RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to 
be able to submit images. TRIAD installation documentation can be found at 
http://www.rtog.org/CoreLab/TRIAD.aspx.    
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
8.5       Patient Enrollment (26Sept2017) 
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.   
8.5.1 Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at  < 
https://ctepcore.nci.nih.gov/iam >) and a 'Registrar' role on either the LPO or 
participating organization roster.  Registrars must hold a minimum of an AP registration 
type.  All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes 
the patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org 

NRG-CC001 
38  
- Version Date: September 26, 2017 
or from the OPEN tab on the CTSU members’ web site https://www.ctsu.org.  To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval.   
 
Prior to accessing OPEN site staff should verify the following: 
 The following baseline neurocognitive assessments must be completed prior to 
Step 2 registration: HVLT-R, TMT, and COWA (see Section 3 for details). 
 All eligibility criteria have been met within the protocol stated timeframes. 
 All patients have signed an appropriate consent form and 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. 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  
 
9.0       DRUG INFORMATION  
9.1 
Investigational Study Agent 
 
Not applicable for this study. 
 
9.2 
Commercial Agent: Memantine 
 
 
Use of twice daily or extended release dosing is allowed. See Section 6. 
 
Adverse Events 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
9.2.1 Availability/Supply  
 
Please see Section 6 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 Memantine in this protocol meets the criteria described under Title 21 CFR 
312.2(b) for IND exemption. The IND exemption letter is available on the NRG 
Oncology website via the regulatory resources tab of the NRG-CC001 page. 
 

NRG-CC001 
39  
- Version Date: September 26, 2017 
10. PATHOLOGY/BIOSPECIMEN   
10.1 
Biomarkers (6/2/16) 
For patients undergoing brain irradiation, there are no biomarkers to predict which 
individuals will experience substantial cognitive impairment.  Data on this topic is 
speculative in nature, and primarily extrapolated from our rapidly growing knowledge of 
the mechanism of Alzheimer’s type dementia, which resembles radiation induced 
dementia (Raber 2010).  Contributing factors likely include inflammation and 
neuroimmune-mediated toxicity, alterations in growth factor signaling and 
parenchymal/neural stem cell as well as direct neuronal damage, endothelial cell damage 
and vascular dysfunction, oxidative damage and genetic susceptibility. In order to be 
prepared to correlate biomarkers to the development of neurocognitive decline after brain 
irradiation, serum will be collected during this trial at baseline (after registration, but 
prior to treatment), at 2, 4, 6 and 12 months from the start of radiation.  Whole blood also 
will be collected at baseline.  Possible analyses of these body fluid biospecimens are 
described below. The specimens and assays to be collected are consistent with that 
obtained by predecessor trials including RTOG 0614, NCCTG 103 (an RTOG endorsed 
study), and to a lesser extent, RTOG 0933. This will allow for longitudinal study 
comparisons and validation of candidate biomarkers. 
10.1.1  Genetic Markers 
The apolipoprotein E (ApoE) gene encodes for ApoE and is located on chromosome 19. 
ApoE is involved in the uptake, transport and distribution of lipid, is expressed at high 
levels in the brain, and is believed to play an important role in neuronal repair and 
synaptic function (Mahley 2009, Chen 2010).  ApoE is polymorphic and has three major 
alleles, ApoE2, ApoE3, ApoE4.  The E4 allele has been associated with cognitive 
dysfunction after damaging events such as cardiac bypass surgery (Tardiff 1997) and 
traumatic brain injury (Nicoll 1995, Jordan 1995).  Additionally, testing of middle-aged 
E4 carriers reveals cognitive difficulties (Greenwood 2009).  Finally, the E4 allele is an 
established risk factor for Alzheimer’s dementia (Caselli 2009). Data suggest that patients 
having the Apo E4 isoform realize Alzheimer’s dementia far earlier than those without 
it12. This allele is present in 16% of the general population and 50% of patients with late 
onset Alzheimer’s dementia (Teunissen 2002). Given potentially similar mechanisms of 
dementia between Alzheimer’s and radiation-induced dementia (e.g. vascular or 
metabolic), Apo E4 genotyping may prove to be a predictor of radiation induced neuronal 
damage. Apo E genotyping will be performed to assess whether a subgroup of patients 
exists that is genetically predisposed to developing neurocognitive decline (or 
neuroprotection).  As this field continues to evolve, it is expected that genome wide 
association studies will also be important in identifying other possible biomarkers and 
accordingly, adequate whole blood will be obtained to allow for these future explorations. 
 Inflammatory Markers 
Markers of inflammation are elevated with aging and their increase has been 
associated with neurocognitive decline (Krabbe 2004, Yaffe 2003). Epidemiological 
and retrospective data reveals an improvement in neurocognitive function with the 
use of NSAID’s in patients with Alzheimer’s dementia, hence, supporting an 
inflammatory process involved in neurocognitive decline (Teunissen 2002). Chronic 
inflammation as a result of mass effect from tumor or treatment (radiation) related 
inflammation may be associated with neurocognitive deficits and can be measured in 

NRG-CC001 
40  
- Version Date: September 26, 2017 
plasma. Interleukin 1 (IL-1), Interleukin 6 (IL-6), and Tumor Necrosis Factor alpha 
are proinflammatory cytokines that are a measure of inflammation and have been 
shown to be elevated in patients with Alzheimer’s dementia (Blum-Degen 1995, 
Martinez 2000, Cacabelos 1994, Tarkowski 1999). In this study, inflammatory 
biomarkers, serum will be obtained at baseline (after registration, but prior to 
treatment) and at the various time points indicated above in order to assess whether 
inflammation changed as a result of type of therapy and what impact or correlation 
this has with cognitive outcomes. 
10.1.2 Oxidative Stress 
Evidence suggests surrogates for oxidative damage may be biomarkers for radiation-
induced neurotoxicity (Abayomi 1996; Roman 1995). Decreased cerebral perfusion 
results in decreased oxygen and glucose delivery that eventually leads to energy 
deprivation which is the cause of oxidative stress in the brain (Lancelot 1998). Oxidative 
stress from either tumor or radiation may be a predictor and measure of neurocognitive 
decline. Isoprostanes are one of the best-described indicators of oxidative stress and can 
be measured in vivo (Gondi 2010). Our approach to measuring oxidative stress will 
consist of quantifying protein carbonyl content spectrophotometrically, measuring lipid 
hydroperoxides, and finally, quantitating isoprostane levels in patient serum.   
10.1.3 Hormone and Growth Factors 
Aging and memory decline is associated with the disruption of hormone regulation, 
including glucocorticoids, gonadal steroids, and growth hormone (Gondi 2013). Cortisol, 
human chorionic gonadotropin (hCG), insulin-like growth factor-1 (IGF-1), and neuronal 
growth factor (NGF), have all recently been associated with cognitive decline in 
Alzheimer’s disease (Ding 2006, Tuszynski 2005). ELISA testing of serum specimens for 
each hormone and growth factor will be performed following completion of the trial.  
 
10.2 
Biospecimen Submission Table (24AUG2017) 
10.2.1 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. 
 
See detailed specimen collection/processing/shipping instructions on the protocol-
specific page on the NRG Oncology website. 
 
 
 
 
Optional Study: Correlation of biomarkers to the development of neurocognitive decline after 
brain irradiation 
The specimens are being collected in order to be prepared to correlate biomarkers to the development of 
neurocognitive decline after brain irradiation (see Section 10.1 for further details). 
 
 
Required Form: ST form (include study #, case #, patient initials, NRG/NCI institution ID# and 
name, treatment time point of specimens) 
 
Biospecimen Kits: Available from the NRG Oncology Biospecimen Bank-San Francisco 
 
Shipping days for frozen biospecimens: Monday-Wednesday (U.S. sites); Monday-Tuesday 

NRG-CC001 
41  
- Version Date: September 26, 2017 
(Canada and Non-North American). 
 
Shipping costs: One return label per case is provided for batch shipping of frozen biospecimens 
only. 
 
For questions, contact:  
NRG Oncology Biospecimen Bank-San Francisco 
415-476-7864/FAX 415-476-5271 
NRGBB@ucsf.edu 
 
Specimen Type 
Collection Time 
Points 
 
Collection Information and  
Requirements/Instructions for 
Site 
 
Shipping 
 
For detailed specimen collection 
and shipment instructions, see 
protocol-specific website 
Specimen 1: 
Serum-red top 
tube 
(Collection tube  
is not included in 
kit- is provided 
by site) 
Baseline: Prior to  
WBRT or HA-
WBRT 
 
2, 4, 6 and 12 
mos. following 
the start of WBRT 
or HA-WBRT 
 
Processed Serum aliquots – 
minimum of  0.5 mL per aliquot in 
five (5) 1 mL cryovials. Store at -
80°C (-70°C to -90°C) until ready 
to batch ship on Dry ice.  
 
 
Storage:  -80°C and ship frozen 
 
Serum sent frozen in batches on dry 
ice via overnight courier to NRG 
Biospecimen Bank - San Francisco 
Specimen 2: 
Whole Blood for 
DNA: 5-10 mL 
of anticoagulated 
whole blood in 
EDTA tube 
(purple/lavender 
top) and mix 
(Collection tube  
is not included in 
kit- is provided 
by site) 
 
 
Baseline: Prior to  
WBRT or HA-
WBRT 
 
 
Frozen whole blood samples 
containing 1.0 mL per aliquot in 
three (3) 2 mL cryovials 
 
Store at -80°C (-70°C to -90°C) 
until ready to batch ship on Dry 
ice.  
 
Whole blood sent frozen on dry ice 
with serum samples by overnight 
courier to NRG Biospecimen Bank - 
San Francisco 
 
 
 
 
11.       SPECIAL STUDIES (NON TISSUE) 
11.1 
Imaging Biomarkers (6/2/16) 
Although cognitive decline is a known potential complication following WBRT it is not 
well understood why some patients decline while others do not or why some patients 
decline more than others. Previous research has shown a relationship between treatment 
specific variables and the degree of brain injury following radiation therapy. Higher total 
radiation dose, higher dose per fraction, and increased brain volume irradiated have all 
been associated with greater radiation-induced brain injury (Roman, 1995). However, 
holding dose constant, the role of patient specific variables in influencing outcome 
following radiation has not been well investigated. A few studies have shown a 
relationship between age at time of treatment and neurological injury following radiation. 
Older age at time of treatment has been associated with poorer neurological outcome and 
a greater degree of treatment related white matter damage (Conill 2007; Swennen 2004; 

NRG-CC001 
42  
- Version Date: September 26, 2017 
Wassenberg 2001). The presence of cardiovascular risk factors, such as hypertension and 
history of smoking, has also been associated with increased white matter damage 
following WBRT in some (Swennen 2004) but not all studies (Conill 2007). There is data 
suggesting that the greater amount of white matter lesion burden prior to WBRT is 
associated with increased white matter damage following treatment (Conill 2007; 
Wassenberg 2001). However, these studies were limited by relatively small sample sizes, 
utilization of qualitative rather than quantitative methods for measuring white matter 
injury, and lack of control for the effects of the disease (e.g., white matter changes from 
lesion induced edema) and other treatments (e.g., radiosurgery) on white matter findings. 
Sabsevitz, Bovi, et al (2013) published the first study to use quantitative volumetric 
methods in a relatively large group of brain metastases patients to examine the effects of 
pre-treatment white matter status on treatment induced white matter injury. Pre-treatment 
white matter health was shown to be a stronger predictor of post treatment white matter 
damage than age when radiated, dosing parameters, and cardiovascular risk factors.  
 
A body of data also exist exploring additional variables predictive of neurocognitive 
decline in the spectrum from healthy aging to mild cognitive impairment (MCI) and 
subsequent Alzheimer’s disease (AD).  In addition to genetic (ApoE4) and baseline 
clinical variables (female sex, family history, and education, etc.), hippocampal 
volumetry with MRI has emerged as another possible imaging biomarker predictive of 
cognitive decline.  (Teipel 2013) A high-resolution structural MRI only requires 5-10 
minutes of time, and standardized manual and automated hippocampus volumetry 
analysis methods are well described. (Jack 2008) Manual volumetry has been shown to 
have 80-90% diagnostic accuracy in distinguishing AD vs. controls (Jack 1997) and 
modern automated volumetry has a high correlation with the more labor intensive manual 
techniques (R2 > 0.8) while retaining similarly strong group discrimination. (Csernansky 
2005, Colliot 2008) A number of studies also have demonstrated that baseline 
hippocampal volume, either alone or in concert with other clinical and biologic variables, 
is a significant predictor for subsequent cognitive decline. In one large study of 1,156 
cognitively normal patients who participated in the Mayo Clinic Study of Aging 
MRI/MRS study from 2005-2010, at a median follow-up of 2.8 years, 214 patients had 
progressed to MCI or dementia (6.1%/yr, 95% CI 5.3-7.0%). (Kantarci 2013) Likewise, 
baseline hippocampal volume also may predict for rate of neurocognitive decline.  In a 
study of 211 participants of the Rush Memory and Aging Project, faster cognitive decline 
was associated with smaller hippocampal volumes at baseline. (Fleischman 2013) 
 
Highly promising preliminary data from RTOG 0933 has demonstrated that WBRT with 
hippocampal avoidance (HA-WBRT) significantly reduces the risk of neurocognitive 
decline compared with historical controls, as measured by the primary endpoint, mean 
relative loss in HVLT-R delayed recall at 4 months (7% vs 30%, p=0.0003).  (Gondi 
2013) These results provide additional compelling evidence to a growing body of clinical 
literature supporting the hippocampus and/or the white matter tracts leading into and out 
of the hippocampus as a centerpiece for modulation of neurotoxicity after cranial 
radiotherapy. (Gondi 2013, Peiffer 2013) Notably, of the 42 analyzable patients at 4 
months, 14 (33.3%) had significant deterioration on HVLT-R delayed recall (as assessed 
using the reliable change index) compared with pre-treatment testing.  (Gondi 2014) A 

NRG-CC001 
43  
- Version Date: September 26, 2017 
preliminary analysis of clinical variables revealed that only baseline neurologic function 
(defined as at least some symptoms versus no symptoms) was predictive of decline in 
HVLT-R immediate recall and delayed recall on multivariate analysis. Similarly, in a 
combined analysis of neurocognitive and quality of life data from two large prospective 
trials evaluating the impact of PCI on SCLC (RTOG 0212) and NSCLC (RTOG 0214), 
only baseline impairment in HVLT-R and age > 60 were predictive of subsequent decline 
in HVLT-R on multivariate analysis. (Gondi 2013) 
 
We hypothesize that (1) abnormal FLAIR volume and/or hippocampal volume at baseline 
will be predictive of subsequent neurocognitive decline after WBRT or HA-WBRT, (2) 
baseline imaging biomarkers will identify patients who derive the least benefit from HA-
WBRT, and (3) changes between baseline and 6 month imaging will correlate with 
neurocognitive decline. 
 
For data consistency, it is very important that a standardized protocol be obtained.  A 3 
Tesla MRI is preferred (minimum 1.5 Tesla MRI system is required).  If possible 
participants should be scanned on the same MRI scanner at each visit.  MRI protocols 
meeting the study requirements are available for download from ADNI 
(http://adni.loni.usc.edu/methods/documents/mri-protocols). Assistance with site-specific 
scanner configuration or imaging workflows may be obtained by contacting the Modality 
Co-Chair/Radiology, Tammie L.S. Benzinger, MD, PhD, benzingert@wustl.edu. 
 
MRI FLAIR DICOM images will be downloaded to a local workstation for processing. 
Abnormal FLAIR volumes will be created in a semi-automated fashion by empirically 
thresholding the FLAIR images to highlight regions of abnormality, followed by manual 
editing to exclude normal regions misclassified (e.g., gray matter, choroid plexus, etc.). 
Volumes will be edited by three trained individuals using a consensus approach who are 
blind to the neurocognitive outcome data.  FLAIR volumes will be measured throughout 
the brain, excluding cerebellum and midbrain structures. In order to address the potential 
confounding effects of the disease on white matter findings, semi-automated methods 
will be used to highlight metastases and any surrounding (i.e., contiguous voxels) 
abnormal FLAIR and the latter volumes will be subsequently masked out or removed 
from analyses.  
 
Hippocampal volumes (R, L, bilateral) will be extracted.  The physician contoured 
hippocampal volumes will be calculated from the RT STRUCT data set.  If only the 
composite bilateral HIPPOCAMPUS volume is available from the RT STRUCT data set, 
it will be separated manually into HIPPOCAMPUS_L and HIPPOCAMPUS_R for 
purposes of analysis.  Automatically derived hippocampal volumes also will be 
calculated with FreeSurfer software (Martinos Center for Biomedical Imaging) using the 
original 3D MRI DICOM files per a validated process established through the 
Alzheimer’s Disease Neuroimaging Initiative (ADNI).  Hippocampal volumes (including 
ratios of HIPPOCAMPUS to CTV and PTV) will then be correlated with declines in 
neurocognitive outcomes.  Hippocampal volumes as derived from physician contours and 
auto-contours will be analyzed to determine which, if any, have the highest predictive 
value. 

NRG-CC001 
44  
- Version Date: September 26, 2017 
 
11.1.1 Study eligibility requires a gadolinium contrast-enhanced three-dimensional spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field 
echo (TFE) MRI scan along with axial T2/FLAIR sequence acquisitions. A pre-contrast 
SPGR, MP-RAGE, or TFE scan is also highly recommended.  Imaging is to be obtained 
within 21 days of Step 1 registration. The purpose of this baseline imaging study is to 
rule out intracranial metastases prior to enrollment and for hippocampal contouring 
should the patient be randomized to the hippocampal avoidance experimental arm of this 
study.  This imaging study will be submitted for centralized quality assurance review of 
hippocampal contouring and hippocampal avoidance treatment planning.  
 
For this exploratory analysis of imaging biomarkers, the MRI scan also will be used to 
provide assessment of white matter changes and hippocampal volumetry. It is required 
that MRI imaging be submitted at baseline and 6 months post treatment to compare the 
imaging biomarkers in patients treated on the standard and experimental arms.  As 
exploratory objectives of this study, T2/FLAIR and SPGR, MP-RAGE or TFE sequences 
will be submitted for central analysis. Abnormal FLAIR volumes will be created in a 
semi-automated fashion by trained individuals using a consensus approach and blinded to 
the cognitive outcome data.  Automated hippocampal volumetry will be performed on the 
pre-contrast SPGR, MP-RAGE or TFE sequences using FreeSurfer (Boston, MA).  
FreeSurfer has been widely used in multiple large multi-institutional trials and, for 
hippocampal volumetry in particular, has been shown to be highly accurate compared 
with expert manual tracing (Morey 2009). 
 
 Post gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), 
magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo 
(TFE) MRI scan and axial T2 FLAIR sequence acquisitions. NOTE: 
ALTHOUGH NOT REQUIRED A PRECONTRAST AXIAL THREE-
DIMENSIONAL IMAGING SEQUENCE IS ALSO STRONGLY 
ENCOURAGED 
 
 To yield acceptable image quality, the pre (if performed) and post gadolinium 
contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE MRI scan should 
use the smallest possible axial slice thickness not exceeding 1.5 mm.  
 
 See NRG-CC001 protocol page of the NRG website for imaging- specific 
frequently asked questions. 
 
 If your institution doesn’t 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 may contact the Imaging Co-Chairs for further information or assistance if needed.            
MRI scans are non-invasive and provide no additional risk to the patient. 
 

NRG-CC001 
45  
- Version Date: September 26, 2017 
Submission of imaging will be required on all patients.  See Section 8.4 for specifics on   
submission requirements and procedures. All imaging will be anonymized by TRIAD to 
ensure patient confidentiality.    
 
11.2 
Neurocognitive Evaluation 
The Neurocognitive Clinical Trial Battery is a brief, sensitive, repeatable, highly 
standardized, objective battery of neurocognitive tests has been demonstrated to be 
practical in terms of burden on the patient and site, with good compliance in multicenter 
clinical trials (Meyers 2004; Armstrong 2013; Brown 2013; Gilbert 2014).  The tests have 
published normative data that take into account age and, where appropriate, education 
and gender. As in RTOG 0614, six alternate forms of the HVLT-R and two alternate 
forms of the COWA will be employed to minimize practice effects. 
 
11.3 
Patient Reported Outcomes (all patients are required to participate) 
Symptom Burden (NOTE: Translations not available for this protocol; enrollment 
restricted to English and French-speaking participants.) 
 
 
Symptom burden will be assessed using the MDASI-BT-modified (Armstrong 2006). 
The MDASI-BT has demonstrated reliability and validity in the primary brain tumor 
patient population, including predictive validity for tumor recurrence (Armstrong, 
Mendoza et al. 2006, Armstrong, Vera-Bolanos et al. 2011). The MDASI-BT was 
developed and validated for use in the brain tumor patient population and typically 
requires less than 4 minutes to complete.  It consists of 23 symptoms rated on an 11-point 
scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being “not 
present” and 10 being “as bad as you can imagine.” Each symptom is rated at its worst in 
the last 24 hours. Symptoms included on the instrument are those commonly associated 
with cancer therapies and those associated with neurologic and cognitive symptoms 
associated with the tumor itself.  The MDASI-BT also includes ratings of how symptoms 
have interfered with different aspects of the patient’s life in the last 24 hours. These 
interference items include: general activity, mood, work (includes both work outside the 
home and housework), relations with other people, walking, and enjoyment of life. The 
interference items also are measured on 0-10 scales. 
 
Health Related Quality of Life 
Health related quality of life will be assessed using the EQ-5D-5L. 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 & Janssen, 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 

NRG-CC001 
46  
- Version Date: September 26, 2017 
box below. The digits for 5 dimensions can be combined in a 5-digit number describing 
the respondent’s health state. 
 
12.       MODALITY REVIEWS 
12.1     Radiation Therapy Quality Assurance Reviews (6/2/16) 
For Arm 2 Only: The Radiation Oncology Co-Chairs, Paul Brown MD, Vinai Gondi 
MD, Joseph Bovi MD, Cliff Robinson MD, Deepak Khuntia MD, David Grosshans MD, 
PhD, or Andre Konski MD will perform an RT Quality Assurance Review after IROC-
Philadelphia RT has received complete data. These reviews will be completed remotely 
and will be ongoing. 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 for all cases enrolled, whichever occurs first.  The scoring mechanism is: Per 
Protocol, Acceptable Variation, and Unacceptable Deviation.   
 
12.2     Drug Quality Assurance Reviews 
The Co-Principal Investigator, Paul Brown, MD, will perform a Quality Assurance 
Review of all patients on this trial.  The goal of the review is to evaluate memantine 
protocol compliance. The review process is contingent on timely submission of treatment 
information data as specified in Section 13.2. The scoring mechanism is: Per 
Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable.   
 
Dr. Brown will perform a Quality Assurance Review after NRG Headquarters has 
received complete data for the first 20 cases enrolled. Dr. Brown will perform the next 
review after NRG Headquarters has received complete data for the next 20 cases 
enrolled. The final cases will be reviewed within 3 months after this study has reached 
the target accrual or as soon as NRG Headquarters has received complete data for all 
cases enrolled, whichever occurs first. 
 
13.       DATA AND RECORDS 
13.1     Data Management/Collection (26Sept2017) 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave,  the 
site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave role (Rave CRA, Read-
Only, CRA (Lab Admin, SLA or Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin 
role, the user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.   
 
Each person responsible for data entry must be on the NRG roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 

NRG-CC001 
47  
- Version Date: September 26, 2017 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Once an account is activated, eLearning modules will 
be available for Rave RDC instructions.  Please note, site users will not be able to access 
the study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
13.2    Summary of Data Submission 
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 Sections 7.1 and 7.2 for information about expedited and 
routine reporting.   
 
Summary of Data Submission: Refer to the NRG Oncology website. 
 
See Section 8.4 for TRIAD account access and installation instructions. 
 
All neurocognitive materials for every patient at every time point must be uploaded to 
Medidata Rave® within 7 days after test administration. 
 
See Section 8.4 for TRIAD account access and installation instructions. 
13.3    Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design (24AUG2017) 
14.1.1 Stratification 
Patients will be stratified according to RPA class (I vs. II) and prior therapy (none vs. 
radiosurgery or surgical resection). 
14.1.2 Randomization 
Patients will be randomized 1:1 to receive WBRT 30 Gy/10 fractions plus memantine or 
WBRT with Hippocampal Avoidance using IMRT 30 Gy/10 fractions plus memantine 

NRG-CC001 
48  
- Version Date: September 26, 2017 
using a permuted block procedure (Zelen 1974). 
14.1.3 Total Accrual 
The total accrual for this study will be 510 patients as described in detail in Section 
14.3.3. 
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint 
Time to neurocognitive failure, as measured by neurocognitive decline on HVLT-R, 
COWA, and TMT Parts A and B 
14.2.2 Secondary Endpoints 
 Preservation of neurocognitive function, as measured by neurocognitive decline on 
HVLT-R, COWA, and TMT Parts A and B, and Clinical Trial Battery Composite 
(CTB COMP) score 
 Symptom burden, as measured by the MDASI-BT 
 Health outcomes, as measured by the EQ-5D-5L 
 Intracranial progression 
14.2.3 Exploratory Endpoints  
 Effect of white matter injury and hippocampal volume on neurocognitive function 
 Effect of RTOG RPA and the diagnosis-specific graded prognostic assessment (DS-
GPA) on neurocognitive function 
 Correlation of symptom burden and anxiety/depression with neurocognitive function 
 Relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive 
function.  
 
14.3 
Primary Objectives Study Design (24AUG2017) 
14.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis of this phase III study is that the addition of HA-WBRT as 
compared to WBRT will increase time to neurocognitive failure, as measured by 
cognitive decline on a battery of tests (HVLT-R, COWA, and TMT), from 53.8% in the 
WBRT arm to 42.8% in the HA-WBRT arm at 6 months. 
14.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed 
 
Neurocognitive failure is the first failure, defined as a neurocognitive decline using the 
reliable change index (RCI) on at least one of the following assessments: HVLT-R, TMT, 
or COWA (Jacobson 1991; Chelune 1993).  The HVLT-R has 3 parts that will be 
analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition.  
The TMT has 2 parts that will be analyzed separately: Part A and Part B.  This endpoint 
will be evaluated at the time points when neurocognitive testing is administered.  In 
RTOG 0614, this endpoint showed a statistically significant difference in favor of the arm 
receiving WBRT and memantine compared to the arm receiving WBRT and placebo 
(Brown 2012).  Of note, composite neurocognitive endpoints such as this have been used 
in many other studies such as the landmark trial by Meyers et al. evaluating cognitive 
function before and after WBRT for patients with brain metastases (Meyers JCO 2004). 
Because of these results and the fact that this composite endpoint encompasses multiple 
cognitive domains, it is being used as the primary endpoint in this study. 
 
The cumulative incidence approach will be used to estimate the median time to 

NRG-CC001 
49  
- Version Date: September 26, 2017 
neurocognitive failure to account for the competing risk of death.  Gray’s test will be 
used to test for statistically significant difference in the distribution of neurocognitive 
failure times (Gray 1988).  The cause-specific Cox proportional hazards regression model 
will be used to evaluate the effect of stratification variables (RPA class and prior therapy)  
and other baseline characteristics, such as KPS, DS-GPA grade, FLAIR volume change, 
and hippocampal volume,  on time to neurocognitive decline (Cox 1972). 
 
Analysis for Reporting the Initial Treatment Results 
This major analysis will occur after at least 233 NCF failure events have been observed. 
It will include: 
 tabulation of all cases entered and those excluded from the analyses with the reasons 
for exclusion given 
 distributions of important prognostic baseline variables  
 the frequencies and severity of adverse events by treatment arm  
 compliance rate of treatment delivery 
 observed results with respect to the primary and secondary endpoints 
 
The analysis will be conducted on an intent-to-treat basis using all randomized at-risk 
patients.  Patients will be grouped by assigned treatment in the analysis. The primary 
hypothesis of treatment benefit will be tested using Gray’s test with a 2-sided 
significance level of 0.05. Additional analyses of treatment effect will be performed using 
the Cox proportional hazard model with the stratification factors included as fixed 
covariates, as well as any factors that show an imbalance between the arms (e.g. age, 
gender, race, etc.) or mentioned in the analysis plan. Where feasible, treatment 
comparisons with respect to the primary endpoint (NCF) will be compared within each 
ethnic and racial category. 
14.3.3 Sample Size and Power Calculations  
In this phase III study, the primary endpoint is time to neurocognitive function failure and 
the potential impact of HA-WBRT compared to WBRT.  Due to the competing risk of 
death, the method described by Pintilie (2002) will be used to estimate sample size using 
data from RTOG 0614. This study showed a significant 11% reduction in neurocognitive 
function failure compared to patients receiving placebo (p=0.01) using the cumulative 
incidence method and Gray’s test. The memantine arm showed a neurocognitive function 
failure of 53.8% at 6 months (corresponding to a monthly hazard of 0.198 utilizing 
Pintilie’s method) and a death rate (as a competing risk) of 30.7% (corresponding to a 
monthly hazard of 0.113).  It is assumed there is an 11% absolute reduction in 
neurocognitive function failure (monthly hazard rate of 0.129) and a similar death rate 
using HA-WBRT, resulting in a hazard ratio of 0.65.  Assuming two-sided α=0.05, 230 
events in both arms combined are required to achieve 90% statistical power utilizing 
Pintilie’s method. In order to estimate the sample size, the probability of neurocognitive 
function failure provided that some failures may not be observed due to death, needs to 
be calculated. The following formula will be used: 
 
𝑃௘௩ൌ
𝜆௘௩
𝜆௘௩൅𝜆௖௥
∗൭1 െ𝑒ିሺఒ೐ೡାఒ೎ೝሻ∗௙ି௘షሺഊ೐ೡశഊ೎ೝሻ∗ሺ೑శೌሻ
ሺ𝜆௘௩൅𝜆௖௥ሻ∗𝑎
൱ 

NRG-CC001 
50  
- Version Date: September 26, 2017 
 
where ev represents the event of interest, cr represents the competing risk, a is the length 
of the accrual period and f is the additional follow-up time after accrual ends.  Using this 
formula, the probability of neurocognitive function failure over a 63 month study (57 
months for accrual and 6 months of additional follow-up) for WBRT is 0.631 and for 
HA-WBRT is 0.570.  The overall probability of neurocognitive function failure for the 
duration of the study is 0.601.  The total sample size required is the number of events 
required divided by the probability of neurocognitive function failure, resulting in 382 
patients.  Due to possible ineligible and non-compliant patients, the sample size will be 
increased by 25%.  Thus, 510 patients will need to be accrued in order to ensure 382 
evaluable patients. 
 
14.4 
Study Monitoring of Primary Objectives (6/2/16) 
Interim Analysis for the Data Monitoring Committee  
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
 
Interim Analysis to Monitor the Study Progress   
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published. In general, the interim reports will 
contain the following information: 
 patient accrual rate with a projected completion date (while the study is still accruing) 
 total patients accrued  
 distributions of important pre-treatment and prognostic baseline variables  
 the frequencies and severity of adverse events by treatment arm 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoints, time to neurocognitive failure, or any secondary 
endpoints, with the exception of reporting of adverse events. 
 
14.5 
Accrual Considerations (24AUG2017) 
14.5.1 Accrual Rate 
For the preceding trial, RTOG 0614, the expected accrual rate was 12 patients per month 
over 4 years.  In actuality, the trial accrued at a rate of 20 patients per month and 
completed accrual in just over 2 years, 2 years sooner than anticipated.  RTOG 0933 
accrued 113 patients at an accrual rate of 6 patients per month.  Target accrual was 
reached 19 months from trial activation, significantly sooner than the initially projected 
total accrual period of 26 months.  Therefore, for the current proposed trial, we would 
expect a uniform accrual rate of 9 patients per month.  Accrual will be monitored with 
respect to DCP accrual guidelines. 
14.5.2 Accrual Goal 
The accrual goal is 510 patients. 
14.5.3 Study Duration 
 
Based on patient accrual in previous RTOG brain metastases studies, there will be 
negligible accrual during the initial 6 months while institutions are obtaining IRB 

NRG-CC001 
51  
- Version Date: September 26, 2017 
approval.  From activation, the study would complete accrual in 63 months with 57 
months of active accrual.  
14.5.4 Estimated Duration for Completion of Primary Endpoint 
The design accounted for 6 months of additional follow-up after meeting the target 
accrual which would result in completion of the primary endpoint approximately 69 
months from group activation or 63 months from study activation. 
 
14.6 
Secondary or Exploratory Elements (including correlative science aims) 
(24AUG2017) 
14.6.1 Secondary Hypotheses and Endpoints 
 Evaluate neurocognitive function, as measured by the HVLT-R, COWA, TMT and 
CTB COMP (the arithmetic mean of the HVLT-R, TMT, and COWA outcomes).  
Specifically, it is hypothesized neurocognitive function will be preserved in the HA-
WBRT compared to the WBRT arm. 
 Evaluate symptom burden as measured by the M.D. Anderson Symptom Inventory-
Brain Module (MDASI-BT). Specifically, it is hypothesized that the following 
subscales on the MDASI-BT will result in higher symptom burden for patients 
receiving WBRT as compared to HA-WBRT: symptom severity, symptom 
interference, neurologic factor, and neurocognitive factor score.  It is also 
hypothesized that baseline symptom severity and symptom interference along with 
the specific items of fatigue, neurologic factor items, and neurocognitive factor items 
will be prognostic of neurocognitive decline. 
 Assess quality adjusted survival using the EQ-5D-5L. 
 Evaluate overall survival 
 Evaluate intracranial disease progression 
 Evaluate adverse events as measured by CTCAE v4.0 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Neurocognitive Function 
Neurocognitive function will be measured by the HVLT-R, COWA, and TMT.  The 
HVLT-R has 3 parts that will be analyzed separately: Total Recall, Delayed Recall, and 
Delayed Recognition. The TMT also has 2 parts that will be analyzed separately: TMT 
Part A and TMT Part B.  The COWA has a single outcome measure that will be 
analyzed.  Standardized scores that adjust for age, education, and gender when necessary 
will be analyzed.  For discrete time point analyses, the change from baseline to each 
follow-up time point (2, 4, 6, and 12 months from the start of treatment) will be 
calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-
Whitney test, depending on the normality of the data.  Neurocognitive decline using the 
reliable change index (RCI) for the HVLT-R, COWA, and TMT also will be compared 
between treatment arms at each follow-up time point using Fisher’s exact test (Jacobson 
1991; Chelune 1993). 
 
A mixed effects model will be used to assess changes of standardized neurocognitive 
scores across time using all available data while adjusting for stratification variables and 
other baseline characteristics.  Mixed models are a general class of models for analyzing 
repeated measures data, which allow modeling of the covariance among the repeated 
measures as well as random effects such as patient-specific intercepts and slopes and can 

NRG-CC001 
52  
- Version Date: September 26, 2017 
incorporate fixed and time-varying covariates.  Fixed effects will consist of stratification 
factors (RPA class and prior therapy) and potentially other baseline covariates, such as 
KPS, DS-GPA grade, FLAIR volume change, and hippocampal volume.  Since missing 
data is expected, patients with missing data will be compared to patients with complete 
data at each follow-up time with respect to baseline characteristics.  If any of these 
characteristics are found to be significantly different, then they will be incorporated into 
the mixed effects model.  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). 
 
Symptom Burden 
Four subscales (symptom severity, symptom interference, neurologic factor, and 
cognitive factor score) as well as certain individual items (fatigue, neurologic factor 
items, and cognitive factor items) of the MDASI-BT will be analyzed.  For discrete time 
point analyses, the change from baseline to each follow-up time point (2, 4, 6, and 12 
months from the start of treatment) will be calculated and compared between treatment 
arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the 
data.   
 
Mixed effects models will be used to assess changes of the four subscale scores 
(symptom severity, symptom interference, neurologic factor, and cognitive factor score) 
across time using all available data while adjusting for stratification variables and other 
baseline characteristics.  Since missing data is expected, it will be handled in a similar 
way as described for Neurocognitive Function above.  
 
To assess the prognostic ability of baseline symptom severity, symptom interference, 
fatigue, neurologic factor items, and neurocognitive factor items on time to 
neurocognitive decline, the cause-specific Cox proportional hazards regression model 
will be used (Cox 1972).   
 
Assessment of Quality Adjusted Survival 
 
The VAS and index scores from the EQ-5D-5L will be calculated at each time point 
(baseline, 2, 4, 6, and 12, months from the start of treatment) and compared between 
treatment arms using a t-test  with a 2-sided significance level of 0.05.  If there are 
significant differences, then a cost analysis will be conducted.   
 
Quality-adjusted survival (QAS) is defined by the weighted sum of different time 

NRG-CC001 
53  
- Version Date: September 26, 2017 
episodes added up to a total quality-adjusted survival time.  A Markov model will be used 
to model cost for this analysis.  The Medicare reimbursement in dollars/QAS will be 
calculated as a function of the monetary cost per relative value of each health state and its 
duration.  The EQ-5D-5L index score at 6 and 12 months will be used for the cost-utility 
analysis. The z-test will be used to test the hypothesis that the cost-utility in the two 
treatment arms is the same with significance level of 0.05. The cost-utility using the 
Medicare reimbursement in dollars/QAS between the two treatment arms after adjusting 
for the baseline and stratification variables. 
 
Overall Survival 
Overall survival rates will be estimated using the Kaplan-Meier method (Kaplan 1958), 
and differences between treatment arms will be tested using the log rank test (Mantel 
1966). Overall survival will be measured from the date of randomization to the date of 
death, or, otherwise, the last follow-up date on which the patient was reported alive.  Of 
interest are survival rates at 6 and 12 months.  These rates will be compared between 
arms using a Chi-square test.  No treatment arm differences in overall survival are 
expected. 
 
The Cox proportional hazard model (Cox 1972) will be performed with the stratification 
variables and other baseline characteristics as fixed variables to assess the treatment 
effect while adjusting for patient-specific risk factors. 
 
Intracranial Progression 
The occurrence of intracranial progression will be defined as progression in the brain or 
death.  Intracranial progression will be assessed at the time of the primary endpoint 
analysis, which is expected to occur once all patients have 6 months of follow-up.  MRI 
scans at baseline and 6 months will be reviewed to determine intracranial progression 
centrally.  The 6 month comparison in intracranial progression rates between the 
treatment arms will be compared using a test of proportions.  It is expected that the rates 
will be similar in both treatment arms.   
 
Additionally, time to intracranial progression will be estimated using the Kaplan-Meier 
method (Kaplan 1958), and differences between treatment arms will be tested using the 
log rank test (Mantel 1966).  Time to intracranial progression will be measured from the 
date of randomization to the date of intracranial progression, death, or, otherwise, the last 
follow-up date on which the patient was reported alive. 
 
Progression in the parahippocampal regions also will be evaluated and reviewed centrally 
at 6 months.  Few events are expected based on the results of RTOG 0933 where only 
4.5% of patients experienced progression in this region (Gondi 2013; Gondi 2014).  A 
test of proportions will be used to compare the rates in each treatment arm at 6 months. 
 
Adverse Events 
Adverse events (AE) will be evaluated using the CTCAE v4.0.  Counts of all AEs by 
grade will be provided by treatment arm.  Counts and frequencies will be provided for the 
worst grade AE experienced by the patient by treatment arm.  The rate of all AEs related 

NRG-CC001 
54  
- Version Date: September 26, 2017 
to treatment and the rate of grade 3+ AEs regardless of relationship to treatment will be 
compared between treatment arms using a Chi-square test at a significance level of 0.05. 
14.6.3 Power Calculations 
 
Symptom Burden 
The meaningful effect size for quality of life 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). Consensus from the literature seems to indicate that 0.5 SD is a 
conservative estimate of an effect size that is likely to be clinically meaningful. In the 
absence of other information, the 0.5 SD is a reasonable and scientifically supportable 
estimate of a meaningful effect. 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 meaningful (Sloan 2005). This discussion is very applicable to the MDASI-BT.   
 
 
A two-sample t-test will be used with a 2-sided type I error of 0.05, there will be >90% 
statistical power to detect a medium effect size of 0.5 for a comparison of the change 
from baseline to 6 months from the start of treatment between the HA-WBRT and WBRT 
arms.  To account for the multiplicity of the factor and individual item scores which are 
assumed to be correlated, Hochberg’s method will be used (Hochberg 1988). 
 
14.7 
Exploratory Hypotheses and Endpoints 
Correlation of Symptom Burden and Anxiety/Depression with Neurocognitive Function 
An exploratory analysis, beginning with correlation coefficients, will be used to assess 
the association of symptom burden and anxiety/depression with neurocognitive function 
at each time point.  The symptom burden items of interest are the “distressed (upset)”, 
“sad”, and “mood” items.  From the EQ-5D-5L, the depression/anxiety item will be of 
interest.  
 
 
 
Radiographic Evaluation 
The effect of white matter injury and hippocampal volume (see Section 11.1 for more 
detail) on time to neurocognitive failure and baseline neurocognitive function will be 
examined.  Both of these will be evaluated through MRI scans using physician-contoured 
and auto-contoured scores. Concordance rates will be assessed using Kappa statistics.  
The auto-contoured scores will be used for the remaining analyses due to the number of 
physicians reviewing the scans. White matter injury is measured by FLAIR volume 
change and is a continuous variable.  Hippocampal volume is measured as a continuous 
variable also and both will be covariates considered in the Cox proportional hazards 
model to assess the impact on time to neurocognitive failure as described in Section 
14.3.2 and the longitudinal modeling of neurocognitive function described in Section 
14.6.2.  Pearson correlation coefficients will be used to assess the effect of hippocampal 
volume and FLAIR volume change on baseline neurocognitive function, as measured by 
the HVLT-R, COWA, and TMT. 
 
Effect of RTOG RPA and DS-GPA with Neurocognitive Function 
Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be 
correlated with both the RTOG RPA and the DS-GPA classification systems.  In this 

NRG-CC001 
55  
- Version Date: September 26, 2017 
study, patients of RPA class I and II will be enrolled.  Baseline neurocognitive function 
for each test will be compared between both RPA classes using either a t-test or 
Wilcoxon-Mann-Whitney test, depending on the normality of the data.   
 
The DS-GPA classification system puts patients in a class from 0, worst prognosis, to 4.0, 
best prognosis as described in Appendix I; however, our eligibility criteria with respect to 
KPS makes a grade of 0 unattainable, resulting in only 4 classes (Sperduto 2011).  
Because only certain disease sites (non-small cell and small-cell lung cancer, melanoma, 
breast cancer, renal cell carcinoma, and GI cancers) can be classified into a DS-GPA 
grade, it is possible some patients may be excluded from this analysis.  In RTOG 0933, 
lung, breast, and colon patients made up 75% of the patient population.  A Spearman 
correlation coefficient will be used to assess the correlation between each baseline 
neurocognitive function test and DS-GPA class.  Additionally, to describe the 
relationship of DS-GPA with changes in cognitive function over time, it will be included 
as a possible covariate in the modeling of cognitive function as described in Section 
14.6.2. 
 
14.8 
Gender/Ethnicity/Race Distribution (24AUG2017) 
No differences across patient subsets are anticipated. 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
17 
9 
26 
Not Hispanic or Latino 
269 
215 
484 
Ethnic Category: Total of all subjects 
286 
224 
510 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
4 
5 
Asian 
4 
6 
10 
Black or African American 
26 
29 
55 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
254 
184 
438 
Racial Category: Total of all subjects 
286 
224 
510 
 
 
 

NRG-CC001 
56  
- Version Date: September 26, 2017 
REFERENCES 
 
Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta oncologica 
(Stockholm, Sweden). 1996;35(6):659-663. 
Armstrong TS, Mendoza T, Gning I, et al. Validation of the M.D. Anderson Symptom Inventory 
Brain Tumor Module (MDASI-BT). J Neurooncol. Oct 2006;80(1):27-35. 
Armstrong TS, Vera-Bolanos E, Gning I, et al. The impact of symptom interference using the 
MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) on prediction of 
recurrence in primary brain tumor patients. Cancer. Jul 15 2011;117(14):3222-3228. 
Armstrong TS, Wefel JS, Wang M, Gilbert MR, Won M, Bottomley A, Mendoza TR, Coens C, 
Werner-Wasik M, Brachman DG, Choucair AK, Mehta M. Net clinical benefit analysis of 
radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant 
temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. 
J Clin Oncol. 2013 Nov 10;31(32):4076-84. doi: 10.1200/JCO.2013.49.6067. Epub 2013 Oct 7. 
 
Benedict, R.H.B., et al., Hopkins verbal learning test - Revised: Normative data and analysis of 
inter-form and test-retest reliability. Clinical Neuropsychologist, 1998. 12(1): p. 43-55 
 
Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and 
interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's 
disease patients. Neurosci Lett 1995;202:17-20. 
 
Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, Choucair A, Fox S, Suh JH, 
Roberge D, Kavadi V, Bentzen SM, Mehta MP, Watkins-Bruner D; Radiation Therapy 
Oncology Group (RTOG).  Memantine for the prevention of cognitive dysfunction in patients 
receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro 
Oncol. 2013 Oct;15(10):1429-37. doi: 10.1093/neuonc/not114. Epub 2013 Aug 16. 
 
Brown PD, Shook S, Laack N, et al. Memantine for the prevention of cognitive dysfunction in 
patients receiving whole-brain radiotherapy (WBRT): first report of RTOG 0614, a placebo-
controlled, double-blind, randomized trial. International Journal of Radiation Oncology, 
Biology, Physics. 2012;84(3S):S1. 
Cacabelos R, Alvarez XA, Franco-Maside A, Fernandez-Novoa L, Caamano J. Serum tumor 
necrosis factor (TNF) in Alzheimer's disease and multi-infarct dementia. Methods Find Exp Clin 
Pharmacol 1994;16:29-35. 
 
Caine C, Mehta MP, Deshmukh S, Tome WA, Gondi V. CogState computerized memory tests in 
patients with brain metastases: secondary endpoint results of RTOG 0933. Paper presented at: 
ESTRO 33  2014; Vienna. 
Caselli RJ, Dueck AC, Osborne D, et al. Longitudinal modeling of age-related memory decline 
and the APOE epsilon4 effect. New England Journal of Medicine 2009;361:255-63. 
 
Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated 

NRG-CC001 
57  
- Version Date: September 26, 2017 
with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. 
Lancet Oncology. Nov 2009;10(11):1037-1044. 
Chelune GJ, Naugle RI, Luders H, Sedlak J, Awad IA. Individual change after epilepsy surgery: 
practice effects and base-rate information. Neuropsychology. 1993;7( ):41-52. 
Chen HS, Lipton SA. Mechanism of memantine block of NMDA-activated channels in rat retinal 
ganglion cells: uncompetitive antagonism. Journal of Physiology. 1997;499(Pt 1):27-46. 
Chen HS, Pellegrini JW, Aggarwal SK, et al. Open-channel block of N-methyl-D-aspartate 
(NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated 
neurotoxicity. Journal of Neuroscience. 1992;12(11):4427-4436. 
Chien LY, Lo LH, Chen CJ, Chen YC, Chiang CC, Yu Chao YM. Quality of life among primary 
caregivers of Taiwanese children with brain tumor. Cancer Nursing. Aug 2003;26(4):305-311. 
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and 
synaptic plasticity by selectively impairing ApoE receptor recycling. Proceedings of the National 
Academy of Sciences of the United States of America 2010;107:12011-6. 
 
Cohen J. Statistical power analysis for the behavioral sciences. Lawrence Erlbaum Associates, 
Hillsdale, New Jersey, 1988. 
 
Colliot, O., G. Chetelat, et al. (2008). Discrimination between Alzheimer disease, mild cognitive 
impairment, and normal aging by using automated segmentation of the hippocampus. Radiology 
248(1): 194-201. 
 
Conill, C., Berenguer, J., Vargas, M., Lopez-Soriano, A., Valduvieco, I., Marruecos, J., & 
Vilella, R. (2007). Incidence of radiation-induced leukoencephalopathy after whole brain 
radiotherapy in patients with brain metastases. Clinical Translational Oncology, 9, 590-595. 
 
Cox DR. Regression models and life tables. J Royal Stat Soc (series B). 1972;34:187-229. 
Csernansky, J. G., L. Wang, et al. (2005). Preclinical detection of Alzheimer's disease: 
hippocampal shape and volume predict dementia onset in the elderly. Neuroimage 25(3): 783-
792. 
 
Danysz W, Parsons CG, Karcz-Kubicha M, et al. GlycineB antagonists as potential therapeutic 
agents. Previous hopes and present reality. Amino Acids. 1998;14(1-3):235-239. 
De Vita VJ, Hellman S, Rosenberg S. Cancer; Principles and Practice of Oncology. 6th ed. ed. 
Philadelphia: Lippincot-Raven; 2001. 
Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F. Insulin-like growth factor I 
interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate 
aspects of exercise-induced cognitive function. Neuroscience 2006;140:823-33. 
 
Eichler AF, Loeffler JS. Multidisciplinary management of brain metastases. Oncologist. Jul 
2007;12(7):884-898. 

NRG-CC001 
58  
- Version Date: September 26, 2017 
Fairclough D. Design and analysis of quality of life studies in clinical trials (2nd ed.). Boca 
Raton, FL: Chapman & Hall/CRC; 2010. 
Fairclough DL, Peterson HF, Cella D, Bonomi P. Comparison of several model-based methods 
for analysing incomplete quality of life data in cancer clinical trials. Stat Med. Mar 15-Apr 15 
1998;17(5-7):781-796. 
Fleischman, D. A., L. Yu, et al. (2013). Faster cognitive decline in the years prior to MR imaging 
is associated with smaller hippocampal volumes in cognitively healthy older persons. Front 
Aging Neurosci 5: 21. 
 
Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors 
in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. International 
Journal of Radiation Oncology, Biology, Physics. Mar 1 1997;37(4):745-751. 
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, 
Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, 
Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ, 
Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma.  N Engl J 
Med, 370(8):699-708, 2/2014. 
 
Glasziou PP, Simes RJ, Gelber RD. Quality adjusted survival analysis. Stat Med. 9:1259-1276, 
1990. 
Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampal-sparing whole-brain radiotherapy: a 
"how-to" technique using helical tomotherapy and linear accelerator-based intensity-modulated 
radiotherapy. International Journal of Radiation Oncology, Biology, Physics. Nov 15 
2010;78(4):1244-1252. 
Gondi V, Tome WA, Marsh J, et al. Estimated risk of perihippocampal disease progression after 
hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. 
Radiotherapy & Oncology. Jun 2010;95(3):327-331. 
Gondi, V., M.P Mehta, et al. (2013). Memory Preservation with Conformal Avoidance of the 
Hippocampus during Whole-Brain Radiotherapy (WBRT) for Patients with Brain Metastases: 
Primary Endpoint Results of RTOG 0933. ASTRO 55th Annual Meeting, Late Breaking Abstract 
1. 
 
Gondi, V., S.L. Pugh, et al. (2014).  Preservation of memory with conformal avoidance of the 
hippocampal neural stem cell compartment during whole-brain radiotherapy for brain metastases 
(RTOG  0933): A phase 2 multi-institutional trial.  J Clin Oncol.  2014, Oct 27.  [Epub ahead of 
print].  
 
Gondi, V., B. P. Hermann, et al. (2013). Hippocampal dosimetry predicts neurocognitive 
function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult 
brain tumors. Int J Radiat Oncol Biol Phys 85(2): 348-354. 
 
Gondi V, Paulus R, Bruner DW, et al, Decline in tested and self-reported cognitive functioning 
after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation 

NRG-CC001 
59  
- Version Date: September 26, 2017 
Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013 
Jul 15;86(4):656-64. doi: 10.1016/j.ijrobp.2013.02.033. Epub 2013 Apr 15. 
 
Gondi V, Tome WA, Mehta MP.  Why avoid the hippocampus? A comprehensive review.  
Radiother Oncol 2010, 97(3): 370-6. 
 
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk, 
Annals of Statistics. 1988;16:1141-1154.  
Greenwood PM, Lambert C, Sunderland T, Parasuraman R. Effects of apolipoprotein E genotype 
on spatial attention, working memory, and their interaction in healthy, middle-aged adults: 
results From the National Institute of Mental Health's BIOCARD study. Neuropsychology 
2005;19:199-211. 
 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-802. 
Jack, C. R., Jr., R. C. Petersen, et al. (1997). Medial temporal atrophy on MRI in normal aging 
and very mild Alzheimer's disease. Neurology 49(3): 786-794. 
 
Jack, C. R., Jr., M. A. Bernstein, et al. (2008). The Alzheimer's Disease Neuroimaging Initiative 
(ADNI): MRI methods. J Magn Reson Imaging 27(4): 685-691. 
 
Jordan BD, Kanik AB, Horwich MS, et al. Apolipoprotein E epsilon 4 and fatal cerebral amyloid 
angiopathy associated with dementia pugilistica. Annals of Neurology 1995;38:698-9. 
 
Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful 
change in psychotherapy research. J Consult Clin Psychol. Feb 1991;59(1):12-19. 
Kantarci K, Weigand SD, Przybelski SA, et al. MRI and MRS predictors of mild cognitive 
impairment in a population-based sample. Neurology. 2013;81(2):126-133. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc.1958;53:457-81.  
Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol 
2004;39:687-99. 
 
Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults. Seminars in Oncology. 
2004;31(5):702-713. 
Lancelot E, Beal MF. Glutamate toxicity in chronic neurodegenerative disease. Progress in 
Brain Research. 1998;116:331-347. 
Langley RE, Stephens RJ, Nankivell M, et al. Interim data from the Medical Research Council 
QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients 
with brain metastases from non-small cell lung cancer? Clin Oncol (R Coll Radiol). Mar 
2013;25(3):e23-30. 

NRG-CC001 
60  
- Version Date: September 26, 2017 
Lin NU, Wefel JS, Lee EQ, Schiff D, van den Bent MJ, Soffietti R, Suh JH, Vogelbaum MA, 
Mehta MP, Dancey J, Linskey ME, Camidge DR, Aoyama H, Brown PD, Chang SM, Kalkanis 
SN, Barani IJ, Baumert BG, Gaspar LE, Hodi FS, Macdonald DR, Wen PY; Response 
Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain 
metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A 
report from the RANO group. Lancet Oncol. 2013 Sep;14(10):e407-16. doi: 10.1016/S1470-
2045(13)70308-5. Review. 
 
Little RA. Modeling the Drop-out Mechanism in Repeated-Measures Studies. J Am Stat Assoc. 
1995;90(431):1112-1121.  
Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from 
atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res 2009;50 Suppl:S183-8. 
 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its 
consideration. Cancer Chemotherapy Reports. 1966;5:163-70.  
Martinez M, Fernandez-Vivancos E, Frank A, De la Fuente M, Hernanz A. Increased 
cerebrospinal fluid fas (Apo-1) levels in Alzheimer's disease. Relationship with IL-6 
concentrations. Brain Research 2000;869:216-9. 
 
Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with 
brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a 
randomized phase III trial. Journal of Clinical Oncology. 2004;22(1):157-165. 
Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of 
adult neurogenesis to low doses of X-irradiation. Cancer Res. Jul 15 2003;63(14):4021-4027. 
Nicoll JA, Roberts GW, Graham DI. Apolipoprotein E epsilon 4 allele is associated with 
deposition of amyloid beta-protein following head injury. Nat Med 1995;1:135-7. 
 
Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, 
surgery, and survival. Cancer. Oct 15 1996;78(8):1781-1788. 
Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine 
in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial 
(MMM 300). Stroke. 2002;33(7):1834-1839. 
Orrego F, Villanueva S. The chemical nature of the main central excitatory transmitter: a critical 
appraisal based upon release studies and synaptic vesicle localization. Neuroscience. Oct 
1993;56(3):539-555. 
Peiffer, A. M., C. M. Leyrer, et al. (2013). "Neuroanatomical target theory as a predictive model 
for radiation-induced cognitive decline." Neurology 80(8): 747-753. 
 
Pellegrini JW, Lipton SA. Delayed administration of memantine prevents N-methyl-D-aspartate 
receptor-mediated neurotoxicity. Annals of Neurology. 1993;33(4):403-407. 
Pintilie M. Dealing with competing risks: testing covariates and calculating sample size. 

NRG-CC001 
61  
- Version Date: September 26, 2017 
Statistics in Medicine. 2002;21(22):3317-3324.  
Raber J. Unintended effects of cranial irradiation on cognitive function. Toxicologic Pathology 
2010;38:198-202. 
 
Rizopoulos D. Joint models for longitudinal and time-to-event data with applications in R. Boca 
Raton, FL: Chapman & Hall/CRC; 2012. 
Robbins ME, Bourland JD, Cline JM, Wheeler KT, Deadwyler SA. A model for assessing 
cognitive impairment after fractionated whole-brain irradiation in nonhuman primates. Radiation 
Research. Apr 2011;175(4):519-525. 
Roman DD, Sperduto PW. Neuropsychological effects of cranial radiation: current knowledge 
and future directions. International Journal of Radiation Oncology, Biology, Physics. 
1995;31(4):983-998. 
Ruff RM, Light RH, Parker SB, et al, Benton Controlled Oral Word Association Test: Reliability 
and updated norms. Arch Clin Neuropsychol, 1996. 11:329-338 
 
Sabsevitz, D.S., Bovi, J.A., Leo, P.D., LaViolette, P.S., Rand, S.D., Mueller, W.M., Schultz, C. 
J. (2013). The role of pre-treatment white matter abnormalities in developing white matter 
changes following whole brain radiation: a volumetric study. Journal of Neurooncology DOI 
10.1007/s11060-013-1181-8. 
 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a Cancer Journal for Clinicians. 
2012;62(1):10-29. 
Sloan J, Cella D, Hays R. Clinical significance of patient-reported questionnaire data: another 
step toward consensus. J Clin Epidemiol 58:1217-9, 2005. 
Sperduto, PW, Kased N, Roberge D, Xu Zhiyuan, Shanley R, Luo Xianghua, Sneed PK, Chao 
ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, 
Fiveash JB, Chiang V, Knisely JPS, Sperduto CM, Lin N, Mehta M.  “Summary report on the 
graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival 
for patients with brain metastases.  JCO 2011;30(4): 419-425. 
Swennen, M. H. J., Bromberg, J. E. C., Witkamp, Th. D., Terhaard, C. H. J., Postma, T. J., & 
Taphoorn, M. J. B. (2004). Delayed radiation toxicity after focal or whole brain radiotherapy for 
low-grade glioma. Journal of Neuro-Oncology, 66, 333-339. 
 
Takura T, Hayashi M, Muragaki Y, Iseki H, Uetsuka Y. [Study on medical economic evaluation 
methods for metastatic brain tumors therapy]. No Shinkei Geka. Jul 2010;38(7):629-637. 
Tardiff BE, Newman MF, Saunders AM, et al. Preliminary report of a genetic basis for cognitive 
decline after cardiac operations. The Neurologic Outcome Research Group of the Duke Heart 
Center. Annals of Thoracic Surgery 1997;64:715-20. 
 
Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis 
factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin 
Immunol 1999;19:223-30. 

NRG-CC001 
62  
- Version Date: September 26, 2017 
 
Teipel, S. J., M. Grothe, et al. (2013). Relevance of magnetic resonance imaging for early 
detection and diagnosis of Alzheimer disease. Med Clin North Am 97(3): 399-424. 
 
Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to 
Alzheimer's dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002;23:485-508. 
 
Oemar, M., Janssen, B. (2013). EQ-5D-5L User Guide: Basic information on how to use the EQ-
5D-5L instrument. The EuroQol Group. 
 
Tombaugh TN, Trail Making Test A and B:Normative data stratified by age and education. Arch 
Clin Neuropsychol, 2004. 19:203-214. 
 
Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy 
for Alzheimer disease. Nat Med 2005;11:551-5. 
 
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York, NY: 
Springer-Verlag; 2000. 
Wassenberg MW, Bromberg JE, Witkamp TD, Terhaard CH, Taphoorn MJ (2001) White matter 
lesions and encephalopathy in patients treated for primary central nervous system lymphoma. 
Journal of neuro-oncology 52 (1):73-80 
 
Wilcock G, Mobius HJ, Stoffler A, group MMM. A double-blind, placebo-controlled multicentre 
study of memantine in mild to moderate vascular dementia (MMM500). International Clinical 
Psychopharmacology. 2002;17(6):297-305.  
Yaffe K, Lindquist K, Penninx BW, et al. Inflammatory markers and cognition in well-
functioning African-American and white elders. Neurology 2003;61:76-80. 
 
Zelen M. The randomization and stratification of patients to clinical tials. J Chron Dis. 27:365-
375, 1974. 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-CC001 
63  
- Version Date: September 26, 2017 
APPENDIX I 
 
DIAGNOSIS-SPECIFIC GRADED PROGNOSTIC ASSESSMENT (DS-GPA) 
 
 
Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-
specific tool to estimate survival for patients with brain metastases. Journal of clinical oncology: official journal of the American 
Society of Clinical Oncology. 2012;30(4):419-425. 
 
Graded Prognostic Assessment (GPA) worksheet to estimate survival from brain metastases (BM) by 
diagnosis. Subtype: Basal: triple negative; LumA: ER/PR positive, HER2 negative; LumB: triple positive; 
HER2: ER/PR negative, HER2 positive. ECM, extracranial metastases; ER, estrogen receptor; HER2, 
human epidermal growth factor receptor 2; KPS, Karnofsky performance score; LumA, luminal A; 
LumB, luminal B; PR, progesterone receptor.  
 

NRG-CC001 
1  
- Version Date: September 26, 2017 
 
APPENDIX II (24AUG2017) 
 
CERTIFICATION AND ADMINISTRATION PROCEDURES FOR THE 
NEUROCOGNITIVE TEST BATTERY 
 
STEP 1 – EXAMINER CERTIFICATION FOR NRG-CC001 
 
Institutions with patients participating in the quality of life/neurocognitive function components 
of this study must meet certification requirements for administering neurocognitive 
assessments.  The healthcare professional (e.g., nurse, psychologist) who is responsible for test 
administration in this study must be pre-certified by Dr. Wefel (See Section 8.3).  Examiners who 
have completed the full certification procedure to perform these tests for RTOG 0825, 0834, 1114, 
NRG-BN001 or NRG-CC003 during the past 6 months do not need to complete the full 
certification procedure again, but the certification worksheet for NRG-CC001 must be faxed to 
Dr. Wefel for documentation purposes with information regarding the examiners prior certification 
(protocol number, date of certification). If these criteria are met, each examiner and NRG will be 
notified of the examiner’s recertification status for NRG-CC001. Examiners who have not 
completed the full certification procedure for RTOG 0825, 0834, 1114, NRG-BN001 or NRG-
CC003 within the past 6 months must complete the full certification procedure to be recertified to 
ensure continued familiarity with study procedures. All certified test administrators are required 
to attest to their proficiency in the language (English or French) in which the test is administered 
to the patient. Only certified test administrators proficient in the primary language of the patient 
are permitted to test the patient. 
 
Prior to registering and/or testing a patient, potential examiners must:  
1) Read the protocol 
2) Read this Appendix (Certification and Administration Procedures for the Neurocognitive 
Test Battery) 
3) Go to the NRG Oncology web site and use your username and password to access the 
link entitled, “Neurocognitive Training Procedure Letter” on the CC001 forms section of 
the NRG Oncology website. This letter will provide you with the web address and study 
specific password for the training video.  
4) Obtain copies of the Neurocognitive Function Test packets (containing the HVLT-R, 
TMT and COWA), and the NRG-CC001 Blank Forms, pages 46-49 (containing the 
Neurocognitive Function Coversheet), and the Training Video Post Test from the NRG 
Oncology website 
5) Watch the training video  
6) Complete the Training Video Post Test 
7) Complete a “practice” assessment with the Neurocognitive Function Test packet 
8) Complete the Certification Worksheet (Appendix I)  
9) All materials (i.e., Training Video Post Test, completed practice assessment and 
Neurocognitive Function Coversheet, certification worksheet) must be scanned and 
emailed (NeuropsychologyResearch@mdanderson.org) or faxed (713-794-4999) to Dr. 
Wefel, who will review it and correct any procedural errors with the trainee.   
10) If the trainee demonstrates competency, he/she will be notified of the certification 
approval to administer the tests to study subjects as part of NRG-CC001.  A certification 

NRG-CC001 
2  
- Version Date: September 26, 2017 
 
approval notice will be sent to NRG for the registration process and to ensure that only 
NRG-CC001-approved examiners are testing subjects on protocol NRG-CC001.  
11) All neurocognitive materials for every patient at every time point must be uploaded to 
Medidata Rave® within 7 days after test administration. 
 
STEP 2 – NEUROCOGNITIVE TEST PACKETS 
 
Two of the tests to be administered have alternate forms or versions in order to reduce the effects 
of practice.  The tests have been grouped together in Packets that contain alternate versions of 
these neuropsychological tests.  Please administer the tests in the order prescribed in the test 
packets.  To ensure that the correct order is maintained per patient, please ensure that the NCF test 
packets are used in the order provided. If for any reason neurocognitive testing was not performed 
at an applicable patient visit, please use the next sequential packet at the next applicable visit (ie 
Patient Visit 1 = Packet 1, Patient Visit 2 = neurocognitive testing missed, Patient Visit 3 = Packet 
2).   
 
 
Pre-Treatment 
Assessment 
Month 2** 
Month 4** 
Month 6** 
Month 12** 
NCF Packet 
Label 
Packet 1 
Packet 2 
Packet 3 
Packet 4 
Packet 5 
 
 
 
 
 
 
**Neurocognitive testing should be performed as close to the day of the MRI as possible. 
 
STEP 3 — TEST INSTRUCTIONS AND ADMINISTRATION PROCEDURES 
 
Additional comments: 
1.   Testing must be completed in one session.  Test instructions must be followed verbatim with 
every patient at every study visit.  All tests should be completed in black pen. 
2. Tests should be administered in the following order to every patient and at every study visit:   
HVLT-R Part A (Trials 1-3); Trail Making Test Part A; Trail Making Test Part B; COWA; 
HVLT-R Part B (Delayed Recall); and the HVLT-R Part C (Delayed Recognition). 
3.  You may fill the delay interval between COWA and HVLT-R Part B (Delayed Recall) with 
QOL questionnaires. 
4. Follow the instructions on the Forms Packet Index before submission of forms to NRG. 
5. All neurocognitive materials for every patient at every time point must be uploaded to 
Medidata Rave® within 7 days after test administration. Please keep all original test forms.  In 
the event of questions, contact Dr. Wefel. Results remain on file at the institution as source 
documentation pending request for submission by NRG or a study chair. 
6. All test results are recorded on the Neurocognitive Function Coversheet, which is found in the 
Forms Packet. Study/case-specific labels must be applied to all forms.   
7. Patients should not be given copies of their tests to avoid learning the material between test 
administrations. 
8. Before dismissing the patient, thank the patient for his/her participation.   
9.  In the event that a patient cannot complete a given test, please write the reason(s) on the test 
form AND the Neurocognitive Function Coversheet. 
 

NRG-CC001 
3  
- Version Date: September 26, 2017 
 
1. HOPKINS VERBAL LEARNING TEST-REVISED (HVLT-R) 
This test has three parts and six alternate forms: 
Part A - Free Recall:  Complete the three learning trials first 
Part B - Delayed Recall:  Complete after a 20 minute delay that includes administration of Trail 
Making Tests and COWA as well as the symptom self-report measures if appropriate 
Part C - Delayed Recognition:  Complete immediately after Delayed Recall 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 

NRG-CC001 
4  
- Version Date: September 26, 2017 
 
 
 
 
2.  TRAIL MAKING TEST [Timed Test] 
Part A – Sample:  The Sample for Part A must be completed/attempted by each patient and 
every assessment.  Place the Sample A worksheet flat on the table, directly in front of the patient 
(the bottom of the worksheet should be approximately six inches from the edge of the table).  
Give the patient a black pen and say: 
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw 
a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until 
you reach the end (point to the circle marked END).  Draw the lines as fast as you can. 
Ready, begin.” 
 
If the patient completes Sample A correctly and in a manner demonstrating that s/he understands 
what to do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point 
out the error and explain it. 
The following explanations of mistakes serve as illustrations: 
• “This is where you start (point to number 1)”  
• “You skipped this circle (point to the circle omitted)” 
• “You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked 
END” 
 
If it is clear that the patient intended to touch a circle but missed it, do not count it as an 
omission.  Remind the patient, however, to be sure to touch the circles.  If the patient still cannot 
complete Sample A, take his/her hand and guide him/her through the trail using the opposite end 
of the pen, lightly touching the worksheet to avoid making marks on the copy. Then say:  
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 
2), 2 to 3 (point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked 
END (point). Do not skip around, but go from one number to the next in proper order. 
Remember to work as fast as you can. Ready, begin.” 
 
If the patient does not succeed, or it becomes evident that s/he cannot do the task, 
DISCONTINUE testing and indicate the corresponding reason on the Trail Making Test Data 
Sheet and the Neurocognitive Function Coversheet.  If the patient completes Sample A correctly 
and appears to understand what to do, proceed immediately to Part A. 
 
Part A – Test:  After the patient has completed Sample A, place the Part A test worksheet 
directly in front of the patient and say: 
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the 
same way. Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 
3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do 
not skip around, but go from one number to the next in proper order. Remember to work as 
fast as you can. Ready, begin.”  
• Start timing as soon as the instruction is given to “begin” 
• Watch closely in order to catch any errors as soon as they are made.  If the patient makes 
an error, call it to his/her attention immediately and have him/her proceed from the point 
the mistake occurred 

NRG-CC001 
5  
- Version Date: September 26, 2017 
 
• The patient must complete the test in 3 minutes or less 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END” 
• If the patient does not complete the test within 3 minutes terminate the testing.  The test 
can also be discontinued if the patient is extremely confused and is unable to perform the 
task.  Collect the worksheet and complete the Trail Making Data Sheet and the 
Neurocognitive Function Coversheet indicating the reason the test was terminated and the 
last correct number reached on the test.  
• If the patient successfully completes the test collect the worksheet and record the time to 
completion on the Trail Making Test Data Sheet and the Neurocognitive Function 
Coversheet in minutes and seconds.  Then say, “That’s fine.  Now we’ll try another one.” 
 
Part B – Sample:  The Sample for Part B must be completed/attempted by each patient and every 
assessment.  Place the Sample B worksheet flat on the table, directly in front of the patient (the 
bottom of the worksheet should be approximately six inches from the edge of the table) and say: 
Examiner:  “On this page (point) are some numbers and letters. Begin at number 1 (point to 
1) and draw a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 
3), 3 to C (point to C) and so on, in order, until you reach the end (point to the circle marked 
END). Remember, first you have a number (point to 1), then a letter (point to A), then a number 
(point to 2), then a letter (point to B), and so on. Draw the lines as fast as you can. Ready, 
begin.” 
 
If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands 
what to do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out 
the error and explain it. 
The following explanations of mistakes serve as illustrations: 
• “You started with the wrong circle. This is where you start (point to number 1)” 
• “You skipped this circle (point to the circle omitted)”  
• “You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to 
B), B to 3 (point to 3) and so on, until you reach the circle marked END (point)” 
 
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission.  
Remind the patient, however, to be sure to touch the circles. If the patient still cannot complete 
Sample B, take their hand and guide them through the trail using the opposite end of the pen, 
lightly touching the worksheet to avoid making marks on the copy. Then say:  
Examiner:  “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 
to A (point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in 
order, until you reach the circle marked END (point). Ready, begin.” 
 
If the patient does not succeed or it becomes evident that s/he cannot do the task, 
DISCONTINUE testing and indicate the corresponding reason on the Trail Making Test Data 
Sheet and the Neurocognitive Function Coversheet.  If the patient completes Sample A correctly 
and appears to understand what to do, proceed immediately to Part A. 
 
Part B – Test:   
After the patient has completed Sample B, place the Part B Worksheet directly in front of the 
patient and say: 

NRG-CC001 
6  
- Version Date: September 26, 2017 
 
Examiner: “ Good! Let’s try the next one. On this page are both numbers and letters. Do this 
the same way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 
(point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, 
until you reach the circle marked END (point). Remember, first you have a number (point to 
1), then a letter (point to A), then a number (point to 2), then a letter (point to B), and so on. 
Do not skip around, but go from one circle to the next in the proper order. Draw the lines as 
fast as you can. Ready, begin.”   
• Start timing as soon as the instruction is given to “begin” 
• Watch closely in order to catch any errors as soon as they are made.  If the patient makes 
an error, call it to his/her attention immediately and have him/her proceed from the point 
the mistake occurred - do NOT start from the beginning 
• The patient must complete the test in 5 minutes or less 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END” 
• Collect the worksheet and record the time to completion on the Trail Making Test Data 
Sheet in minutes and seconds 
• If the patient does not complete the test within 5 minutes terminate the testing.  The test 
can also be discontinued if the patient is extremely confused and is unable to perform the 
task.  Collect the worksheet and complete the Trail Making Test Data Sheet and the 
Neurocognitive Function Coversheet indicating the reason the test was terminated and the 
last correct number or letter reached on the test.  
• At the top of both Sample forms and both Test forms please write: patient initials, NRG 
case number, date of evaluation, institution name, name of certified tester, and the certified 
tester’s phone number. 
 
3.  CONTROLLED ORAL WORD ASSOCIATION (COWA) [Timed Test] 
This test has three parts (letters) and two alternate forms. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-CC001 
7  
- Version Date: September 26, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

NRG-CC001 
8  
- Version Date: September 26, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

NRG-CC001 
73  
- Version Date: September 26, 2017 
 
APPENDIX III 
 
Recursive Partitioning Analysis (RPA) System 
 
 
 
 
Class I  
 
 
 
1. KPS ≥ 70,  
2. Primary controlled,  
3. Age < 65,  
4. Metastasis in brain only 
 
 
Class II 
 
   
   KPS ≥ 70 and 1 of the following: 
• Primary uncontrolled 
• Primary controlled, age ≥ 65 
• Primary controlled, age < 65, 
metastases in brain & other 
sites