Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): A Prospective Pilot Study
Phase: NA
Conditions: Brain Tumor, Brain Metastases, Brain Cancer
Sponsor: Indiana University

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IUSCC-0710 version January 10, 2024 
Study Title 
Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): 
A Prospective Pilot Study 
Protocol Number: 
IUSCC-0710 
Principal Investigator: 
Kevin Shiue, MD 
535 Barnhill Dr. RT 041 
Indianapolis, IN 46202 
(317) 944-2524
KShiue@iuhealth.org 
Radiation Oncology 
Co-Investigator(s): 
Paul Anthony, MD 
Nasser Hanna, MD 
Shearwood McClelland III, MD-Case Western Reserve University 
Study Statistician: 
Yong Zang, PhD 
Support Provided By: 
Radiation Oncology  
Protocol Version Date: 
January 10, 2024 
NCT04047602

 
 
 
 
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IUSCC-0710 version January 10, 2024 
TABLE OF CONTENTS 
 
 
1. 
OVERVIEW ............................................................................................................................ 5 
2. 
BACKGROUND & RATIONALE ......................................................................................... 6 
3. 
OBJECTIVE(S) ....................................................................................................................... 8 
3.1 
Primary Objective ............................................................................................... 8 
3.2 
Secondary Objectives ........................................................................................ 8 
4. 
OUTCOME MEASURES ....................................................................................................... 9 
4.1 Primary Outcome Measure ...................................................................................................... 9 
4.2 
Secondary Outcome Measure ............................................................................ 9 
5. 
ELIGIBILITY CRITERIA ...................................................................................................... 9 
5.1 
Inclusion Criteria ................................................................................................ 9 
5.2 
Exclusion Criteria ............................................................................................. 10 
6. 
STUDY DESIGN .................................................................................................................. 10 
7. 
PATIENT REGISTRATION ................................................................................................ 10 
8. 
STUDY PROCEDURES ....................................................................................................... 11 
8.1 Cohorts Description ............................................................................................. 11 
8.2 Baseline/Screening Procedures ........................................................................... 11 
8.3 Stereotactic Radiosurgery ................................................................................... 11 
8.4 Follow-Up ............................................................................................................ 12 
8.5 One Month Follow-Up .......................................................................................... 12 
8.6 Long Term Follow up ........................................................................................... 12 
9. 
STUDY CALENDAR ........................................................................................................... 13 
TREATMENT DOSE AND DELIVERY .................................................................................... 14 
10.1 General Concomitant Medication and Supportive Care Guidelines ................... 15 
10. RESPONSE ASSESSMENT IN NEURO-ONCOLOGY BRAIN METASTASES (RANO-
BM) ............................................................................................................................................... 15 
11.1 Definitions Associated with RANO-BM (Lin et al., 2015) ................................... 15 
11.2 Response assessment of target and non-target lesions .................................... 17 
11.3 Other considerations .......................................................................................... 20 
11. RADIATION NECROSIS ..................................................................................................... 21 
12.1 Radiographic Radiation Necrosis ....................................................................... 21 
12.2 Symptomatic Radiation Necrosis ....................................................................... 22 
12. CRITERIA FOR EVALUATION/REMOVAL FROM STUDY ......................................... 22 
13. STATISTICAL METHODS.................................................................................................. 22 
14.1 General Considerations ..................................................................................... 22 
14.2 Study Design ..................................................................................................... 22 
14.3 Analysis Datasets .............................................................................................. 23 
14.4 Sample Size ................................................................................................... 23 
14.5 Patient Characteristics and significant protocol violations ................................. 23 
14.6 Disposition ......................................................................................................... 23 
14.7 Analysis of Primary Objectives .......................................................................... 23 
14.8 Analysis of Secondary Objectives ...................................................................... 24 
14. MULTICENTER GUIDELINES .......................................................................................... 24 
15.1 Study Documents .............................................................................................. 24 
15.2 Study Initiation ................................................................................................... 24 

 
 
 
 
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15.3 Patient Enrollment ............................................................................................. 24 
15.4 Data Monitoring ................................................................................................. 25 
15.5 Record Retention ............................................................................................... 25 
15. DATA FORMS AND SUBMISSION SCHEDULE ............................................................. 25 
16. PATIENT CONSENT AND PEER JUDGMENT ................................................................ 26 
17. DATA AND SAFETY MONITORING PLAN .................................................................... 26 
18. REPORTING ADVERSE EVENTS ..................................................................................... 27 
19.1 Definitions of Adverse Events ........................................................................ 27 
19.2 Determining Attribution to the Investigational Agent(s) .................................. 28 
19.3 Adverse Event (AE) and Serious Adverse Event (SAE) Reporting ................ 28 
19.5 Coordinating Center Reporting Responsibilities ............................................. 30 
19.6 Reporting to Participating Sites ...................................................................... 30 
19. Representation of Women and Minorities ............................................................................. 30 
20. REFERENCES ...................................................................................................................... 31 
21. APPENDICES ....................................................................................................................... 35 
Appendix I .............................................................................................................. 36 
Appendix II ............................................................................................................. 37 
 

 
 
 
 
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I U S C C- 0 7 1 0 versi o n Ja n uar y 1 0, 2 0 2 4 
P R O T O C O L SI G N A T U R E P A G E  
 
R a di os ur ger y D ose Re d ucti o n f or Brai n M etastases o n Im m u n ot hera p y ( R A D R E MI):  
A Pr os pecti ve Pil ot St u d y  
 
V E R SI O N D A T E: 1 0 J a n u ary 2 0 2 4  
I c o nfir m I ha ve rea d t his pr ot oc ol, I u n dersta n d it, a n d I will w or k acc or di n g t o t his pr ot oc ol a n d 
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g ui deli nes f or g o o d cli nical practices, or t he a p plica ble la ws a n d re g ulati o ns of t he c o u ntr y of t he 
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i n di vi d ual. I will acce pt t he m o nit or’s o verseei n g of t he st u d y. I will pr o m ptl y s u b mit t he 
pr ot oc ol t o a p plica ble et hic al re vie w b oar d(s).  
 
 
 
 
 
 
 
 
 
 
 
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IUSCC-0710 version January 10, 2024 
1. OVERVIEW 
 
Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): A 
Prospective Pilot Study 
 
Principal Investigator: Kevin Shiue, MD  
Co-Investigators: Ryan Rhome, MD PhD; Nasser Hanna, MD; Paul Anthony, MD, Shearwood 
McClelland III, MD (Case Western Reserve University) 
 
Primary objective: To demonstrate 6 month symptomatic radiation necrosis (SRN) rates following 
ICI concurrent with dose-reduced SRS 
 
Secondary objectives: 6-month local control (LC), 6-month radiographic radiation necrosis rates, 
12-month SRN, 12-month LC, Differences in SRS and LC at 12-months for SRS modality, single 
versus multi-agent ICI, and melanoma versus non-melanoma brain metastases 
 
Eligibility 
- 
> 18 years old 
- 
Biopsy-proven primary malignancy 
- 
Metastatic brain disease as visualized on brain MRI 
- 
No previous whole brain radiation therapy (WBRT) 
- 
Expected survival of 6+ months using ds-GPA 
 
Sample size: 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
- 
Age > 18 
- 
Previous histologic confirmation of malignancy 
- 
MRI-based diagnosis of metastatic brain disease 
 
Exclusion criteria 
- 
Brain metastases unable to be treated with single-fraction SRS (> 4 cm maximum diameter) 
Routine follow-up with clinical examinations and serial contrast-enhanced brain MRIs at 1, 
3, 6, 9, and 12 months post-SRS 
Register eligible patients with recent brain MRI-based diagnosis of metastatic brain disease 
Start immunotherapy (selection and continuation per treating Medical Oncologist); if patient 
already on immunotherapy, proceed to SRS 
Start SRS per treating Radiation Oncologist using RADREMI dosing 
(0-2 cm=18 Gy; 2.1-3 cm=14 Gy; 3.1-4 cm=12 Gy) 

 
 
 
 
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2. BACKGROUND & RATIONALE 
 
Epidemiology 
 
Occurring ten times more frequently than primary brain tumors, brain metastases are by far the 
most common intracranial malignancy (Nabors et al., 2017).  Associated with a median overall 
survival of 4-5 months, brain metastases afflict more than 200,000 people annually in the United 
States, comprising up to 30% of adults with cancer (Pruitt et al., 2017; Gibney et al., 2012; Fife et 
al., 2004; Davies et al., 2011).  
 
Treatment of Brain Metastases 
 
In general, treatment of metastatic brain disease involves surgical resection, whole brain radiation 
therapy (WBRT), stereotactic radiosurgery (SRS), and/or systemic therapy.  While conventional 
systemic therapies alone are typically not sufficient to control intracranial disease due to the 
presence of the blood-brain barrier, newer studies suggest efficacy of immunotherapy – 
predominantly via immune checkpoint inhibitors (ICI). Recent Level I evidence in patients with 
metastatic melanoma indicates that the 6-month local control rate of brain metastases treated with 
multi-agent ICI alone (nivolumab + ipilimumab) is 57% (Tawbi et al., 2018), compared to the 24% 
rate of ipilimumab alone (Margolin et al., 2012), the 22% rate of pembrolizumab alone (Goldberg 
et al., 2016), or the 50% rate of ipilimumab + fotemustine (DiGiacomo et al., 2012).  While the 
local control rate of multi-agent ICI is encouraging, it is important to remember that the 57% rate 
remains vastly inferior to the six-month local control rates of 87-91% achieved following single-
fraction SRS administered via linear accelerator or Gamma Knife (Tawbi et al., 2018; Bernard et 
al., 2012; Minniti et al., 2017; Matsunaga et al., 2018).  Candidates for SRS are typically patients 
with 1-10 brain metastases, while patients exceeding 10 brain metastases often receive WBRT 
instead of SRS (Yamamoto et al., 2014).  
 
 
Morbidity of Standard-Dose Stereotactic Radiosurgery + Immunotherapy for Metastatic 
Brain Disease 
 
A potential late toxicity of high-dose SRS for brain metastases is symptomatic radiation necrosis, 
which is associated with focal inflammation and intracranial edema at the irradiated site, often 
requiring steroid treatment (which is in itself counterproductive for optimizing efficacy of ICI; 
Kotecha et al., 2019) and/or craniotomy for resection of the necrosis in situations where the edema 
manifests as acute and potentially life-threatening neurologic deterioration. Albeit limited 
compared to the addition of SRS, the efficacy of multi-agent ICI alone in achieving local control 
of more than half of brain metastases (including a 26% complete response rate) at six months 
brings forth an important question: Are the doses of SRS currently being administered for brain 
metastases excessive given that a large proportion of the metastatic brain disease population is 
receiving systemic ICI treatment?   
 
Prior to the widespread use of immunotherapy, the radiographic radiation necrosis rate of SRS for 
metastatic brain disease was less than 5% (with the symptomatic radiation necrosis rate less than 
3%); however, a recent large study of 115 patients has indicated that in the current immunotherapy 
era, the true rate of symptomatic radiation necrosis with SRS + ICI is as high as 20% (Martin et 
al., 2018).  Unfortunately, studies examining SRS + ICI have rarely reported radiation necrosis 

 
 
 
 
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rates, and the vast majority of those doing so have failed to report symptomatic radiation necrosis 
rates (Cohen-Inbar et al., 2017; Williams et al., 2017; Anderson et al., 2017; Yusuf et al., 2017; 
Chen et al., 2018).  Only two studies have reported symptomatic radiation necrosis rates, revealing 
a range from 12-20% of treated patients (Skrepnik et al,. 2017; Martin et al., 2018). Unlike the 
majority of studies examining SRS + ICI, these two studies allow for determination of 
symptomatic radiation necrosis rates per patient rather than per treated lesion; for disease where it 
is common for patients to require treatment for multiple lesions, rates determined per patient will 
be substantially higher than those determined per treated lesion.  
 
This is not a trivial consideration, as up to 1 in 5 patients treated with SRS for metastatic brain 
disease may develop symptomatic radionecrosis. This toxicity has the potential to affect outcomes 
in this patient population, given the proven association between steroid use and poorer overall 
survival for patients on ICI (Kotecha et al., 2019), and the side effect profile of bevacizumab when 
used to address symptoms. The paucity of studies examining symptomatic radiation necrosis 
following SRS in brain metastasis patients who are receiving immunotherapy is further 
exacerbated by the lack of detail in the literature regarding radionecrosis rates relative to 
immunotherapy and SRS administration, and the dearth of prospectively collected data (Lehrer et 
al., 2019).  To date, only one study has reported the time from SRS to radiographic radiation 
necrosis rate (median: 14.7 months), with no studies reporting the time from SRS to symptomatic 
radiation necrosis (Skrepnik et al., 2017).  
 
 
Proposed Solution to Metastatic Brain Disease Treatment-Related Morbidity 
 
A potential solution to this problem involves dose-reduced SRS to a level which substantially 
reduces radionecrosis risk without sacrificing the approximately 80-85% six-month local control 
provided by the present dosing schema, which from RTOG 90-05 has remained 24 Gy for lesions 
0-2 cm, 18 Gy for lesions 2.1-3 cm, and 15 Gy for lesions 3-4 cm (Shaw et al., 2000). To maintain 
a dosing schema less toxic than the RTOG 90-05 regimen while remaining within SRS doses 
established by Level I evidence to provide local control (Brown et al., 2017), we propose the 
following dose-reduced SRS protocol for this Radiosurgery Dose Reduction for Brain Metastases 
on Immunotherapy (RADREMI) prospective pilot study: 18 Gy (0-2 cm lesions), 14 Gy (2.1-3 cm 
lesions), and 12 Gy (3-4 cm lesions) for brain metastases patients receiving at least one 
immunotherapy agent. These doses are consistent with Level I evidence comparing SRS with 
whole brain radiation therapy for metastatic brain disease, which revealed that SRS doses of 12-
20 Gy were sufficient to provide local control (Brown et al,. 2017). For perspective, it is important 
to remember that RTOG 90-05 was not a dose finding study, but rather a dose tolerance study; 
subsequent work has established improved local control compared to RTOG 90-05 while using 
lower doses than the RTOG 90-05 regimen (Shehata et al., 2004; Colaco et al., 2016). Given the 
efficacy of immunotherapy alone in treating melanoma brain metastases (Tawbi et al., 2018), it is 
reasonable to hypothesize that a lower SRS dose than the RTOG 90-05 schema will result in a  
combinatorial effect sufficient to provide local control without resulting in the 20% symptomatic 
necrosis rate seen with the present dosing schema (Martin et al., 2018).  
 
 
 
 
 

 
 
 
 
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Summary and Rationale 
 
In summary, this study seeks to assess the efficacy and safety of radiosurgery dose reduction for 
brain metastases patients receiving immunotherapy.  We hypothesize that: 1. Dose-reduced SRS 
will reduce the risk of radionecrosis compared to the 16% average rate per patient from the existing 
concurrent SRS + ICI literature (Skrepnik et al., 2017; Martin et al., 2018) with current SRS dose, 
and 2. Dose-reduced SRS demonstrates non-inferior efficacy (measured primarily through six-
month local tumor control) compared to the 80% local control rate associated with the RTOG 90-
05-established SRS dosing parameters. For the purposes of this study, radionecrosis will be defined 
as clinical symptomatology following SRS requiring steroid utilization and/or operative 
intervention in combination with imaging features strongly suggesting radionecrosis as 
demonstrated utilizing routine MRI, MR Perfusion, MR Spectroscopy, and/or PET imaging. 
Although the definition of concurrent SRS+ICI has varied greatly in the literature, ranging from 2 
weeks to 4 months with some studies defining administration within 4 months as concurrent 
(Anderson et al., 2017; Chen et al., 2018); for the purposes of this study, concurrent therapy will 
be defined as ICI administered within 30 days of SRS. We also hope to explore SRS radionecrosis 
rates in multi-agent versus single-agent immunotherapy, as well as in melanoma versus non-
melanoma brain metastases.  Local control will be defined as a less than 20% increase in tumor 
size following SRS, as previously described using Response Assessment in Neuro-Oncology 
(RANO) criteria (Lin et al., 2015).  
 
 
3. OBJECTIVE(S) 
 
3.1 Primary Objective 
 
To evaluate toxicity rates of brain metastasis after ICI concurrent with SRS at six months with 
regard to symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology 
requiring steroid administration (i.e. Decadron), bevacizumab (Avastin), and/or operative 
intervention concomitant with advanced and routine brain imaging findings consistent with 
radiation necrosis.   
 
3.2 Secondary Objectives 
 
• 6-month local control 
• 6-month radiographic radiation necrosis 
• 12-month symptomatic radiation necrosis 
• 12-month local control 
• 12-month radiographic radiation necrosis 
• 12-month local control rate by SRS modality 
• 12-month local control rate by single versus multi-agent ICI 
• 12-month local control rate by melanoma versus non-melanoma brain metastases 
• 12-month symptomatic radiation necrosis rate by SRS modality 
• 12-month symptomatic radiation necrosis rate by single versus multi-agent ICI 
• 12-month symptomatic radiation necrosis rate by melanoma versus non-melanoma brain 
metastases 
 

 
 
 
 
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4. OUTCOME MEASURES 
 
4.1 Primary Outcome Measure 
 
6 month symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology 
requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with 
advanced and routine brain imaging findings consistent with radiation necrosis.  Follow-up 
MRIs will be fused with the planning scan for this assessment.  
 
4.2 Secondary Outcome Measure 
 
1. 6 month local control, defined as a 6-month rate of any new, recurrent or progressing (as 
defined by RANO criteria) tumor within the planning target volume compared to pre-SRS 
on any post-treatment MRI by 6 months. Follow-up MRIs will be fused with the planning 
scan for this assessment.  
2. 6 month radiographic radiation necrosis, defined as brain imaging findings (MRI, MR 
Perfusion, MR Spectroscopy, and/or PET) consistent with radiation necrosis.   
3. 12 month local control 
4. 12 month symptomatic radiation necrosis 
5. 12 month radiographic radiation necrosis 
6. Evaluation of 12 month local control rate by SRS modality (Gamma Knife versus Linear 
Accelerator) 
7. Evaluation of 12 month local control rate by single agent versus multi-agent ICI 
8. Evaluation of 12 month local control rate by melanoma versus non-melanoma brain 
metastases 
9. Evaluation of 12 month symptomatic radiation necrosis rate by SRS modality (Gamma 
Knife versus Linear Accelerator) 
10. Evaluation of 12 month symptomatic radiation necrosis rate by single agent versus multi-
agent ICI 
11. Evaluation of 12 month symptomatic radiation necrosis rate by melanoma versus non-
melanoma brain metastases 
 
 
  
5. ELIGIBILITY CRITERIA 
 
5.1 Inclusion Criteria 
 
1. Brain MRI-confirmed 1-10 solid tumor brain metastases (Yamamoto et al., 2014) 
2. Biopsy-confirmed primary malignancy 
3. ds-GPA estimated median survival of at least 6 months, for histologies not included in the 
ds-GPA, publications or noted online at brainmetgpa.com, the PI will use either published 
or validated data or their best clinical judgment to determine the patient’s expected survival  
4. Stereotactic radiosurgery candidate per treating Radiation Oncologist 
5. ≥ 18 years old at the time of informed consent 
6. Ability to provide written informed consent and HIPAA authorization 
7. ALC > 800/ul (Ku et al., 2010) 
8. Patients currently on cytotoxic chemotherapy are eligible 
9. Patients receiving ICI up to 30 days prior to delivery of SRS are eligible  

 
 
 
 
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10. Patients having undergone operative resection for metastatic brain disease within 30 days 
of immune checkpoint inhibitor (ICI) administration are eligible. 
 
5.2 Exclusion Criteria 
 
1. Major medical illnesses or psychiatric impairments, which in the investigator’s opinion will 
prevent administration or completion of the protocol therapy and/or interfere with follow-
up 
2. Patients unable to receive MRI Brain 
3. Patients with more than 10 brain metastases on MRI Brain 
4. Any lesion > 4 cm maximum diameter 
5. Total volume of metastatic disease more than 30 cm3  
6. Previous whole brain radiation therapy 
7. For Cohort 1: Previous stereotactic radiosurgery where the 50% isodose line overlaps with 
current treatment field 
8. For Cohort 2: Patients whose treatment will have a dose overlap within the target from prior 
treatments of 20% or greater 
9. Already receiving chronic dexamethasone (chronic = > 2 weeks) prior to SRS 
10. Not a radiosurgical candidate per Radiation Oncology discretion  
11. Existing autoimmune disease 
12. Patients who have an unknown primary 
13. Histology not amenable for SRS (i.e. lymphoma). (Small Cell Lung Cancer IS amenable.) 
 
 
6. STUDY DESIGN 
 
This is a prospective multi-site, single arm, pilot study to determine the symptomatic radiation 
necrosis rate at 6 months utilizing dose-reduced stereotactic radiosurgery with immunotherapy 
for subjects with a diagnosis of 1-10 brain metastases from MRI and tissue diagnosis of primary 
malignancy. 
 
 
7. PATIENT REGISTRATION 
 
Potential patients will be identified and recruited per the recommendation of medical 
oncologists, tumor boards, Department of Radiation Oncology, outside physicians, or self-
referral. No advertisement will be used to recruit subjects. Patients who appear to be eligible 
for this trial will undergo the Informed Consent Process and be screened for eligibility utilizing 
the eligibility criteria. Eligible patients who complete the Informed Consent Process will be 
registered in the OnCore® database and assigned a patient ID number. Regulatory files will be 
maintained by the Radiation Oncology Research Office. Applicable regulatory documents must 
be completed and on file prior to registration of any patients.  
 
 
 
 
 

 
 
 
 
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8. STUDY PROCEDURES 
 
8.1 Cohorts Description 
This study will be divided into 2 main cohorts as described below. Both cohorts will have the 
same procedures completed and will follow the same timelines up to the 6-month follow-up. 
After 6 months, subjects will be followed on the most recent calendar for up to 5 years post last 
SRS.  
 
Cohort 1: All subjects initially screened and treated for this study. 
 
Cohort 2: If a subject is treated and during follow-up scans new lesion(s) are found, they may 
be treated for those new lesion(s). These must be patients who have not had a negative outcome 
or end-point event while enrolled on Cohort 1. These subjects will be consented on a cohort 
specific consent and follow all procedures listed below. 
 
Subjects may be treated multiple times, per procedures below.  
 
8.2 Baseline/Screening Procedures 
 
The following will be completed prior to radiosurgery: 
 
1. Written informed consent and HIPAA authorization  
2. Diagnostic MRI Brain 
3. Medical history and clinical examination performed by physician from neurology, 
neurosurgery, medical oncology, or radiation oncology. 
4. Absolute Lymphocyte Count (ALC) – total number of immune cells in mL of blood 
5. Baseline ds-GPA, and KPS; for histologies not included in the ds-GPA, publications or 
noted online at brainmetgpa.com, the PI will use either published or validated data or their 
best clinical judgment to determine the patient’s expected survival 
 
8.3 Stereotactic Radiosurgery 
 
Stereotactic radiosurgery will be delivered on all patients utilizing gamma knife or linear 
accelerator based techniques as per RADREMI dosing criteria (Section 10 Table 1) based on 
tumor diameter. All apparent, previously untreated brain metastases will be treated with 
radiosurgery at this time.  
 
If any of the following occurs during the MRI Brain planning scan, the subject will be 
withdrawn from study, not treated on protocol, and replaced: 
 
• The total number of brain metastases sums greater than 10. The subject will be 
withdrawn and not treated on protocol. 
 
• The total volume of brain metastases is greater than 30 cm3. The subject will be 
withdrawn and not treated on protocol. 
 
 

 
 
 
 
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8.4 Follow-Up 
 
Following delivery of stereotactic radiosurgery, all patients will be monitored clinically and 
with serial MRI Brain scans to determine local control and rate of radiation necrosis. Additional 
imaging and testing may be performed as deemed necessary by the treating physician.  
 
Initiation/continuation of immunotherapy, chemotherapy and/or other systemic agents will be 
per medical oncologist discretion.  
 
8.5 One Month Follow-Up  
 
A detailed medical history, toxicity assessment and physical examination including vital signs 
along with a brain MRI will be performed at 4 weeks after radiosurgery. 
 
8.6 Long Term Follow up 
 
Subjects will be followed approximately every 3 months (+/- 30 days) after SRS for 1 year. A 
detailed medical history (including necessity of any steroid administration), toxicity assessment 
and physical examination including vital signs will be performed at each visit. Each follow-up 
over this time period will also include a Brain MRI with the following sequences: without 
contrast, with contrast, FLAIR, Diffusion Tensor Imaging (DTI) and Perfusion Weighted 
Imaging (PWI). The MRI will be analyzed per RANO BM criteria (Section 11) for assessment 
of local control. The MRI will also be analyzed for radiation necrosis as discussed in Section 
12. Neurologic status will be assessed using the Neurologic Assessment in Neuro-Oncology 
(NANO) scale (Nayak et al., 2017).  
 
After the 1-year (12-month) follow-up period, subjects will be followed according to their 
treating physician per standard of care every 3-6 months. MRI Brain obtained during this time 
period may be used for assessment of primary and secondary endpoints; however, are not 
mandated to be obtained at particular time intervals. Patients who are unable to travel to Indiana 
University for follow-up appointments will have records sent to Indiana University at each 
follow-up. 
 
From year 2-5, the follow up period will be determined by their treating physician per standard 
of care, generally every 3-6 months.  MRIs will be obtained per treating physician discretion.  
 
 
 

 
 
 
 
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9. STUDY CALENDAR 
 
 
Baseline 
Screening* 
SRS 
(stereotactic 
radiosurgery)
* 
1 Month 
Follow Up1* 
3 Month 
Follow 
Up1* 
6 Month 
Follow Up1* 
9 Month 
Follow Up1* 
12 Month 
Follow 
Up2* 
 
Within 30 
days of SRS 
Gamma Knife 
or Linear 
Accelerator 
(LINAC) 
30 days post 
SRS 
90 days 
post SRS 
180 days 
post SRS 
270 days 
post SRS 
1 years post 
SRS 
Radiation Oncology 
consult and consent 
X 
 
 
Medical History 
(including steroid 
usage) 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
X 
X 
X 
X 
Vitals: weight/ht. BP7 
X 
X 
X 
X 
X 
X 
X 
ds-GPA5 
X 
 
 
Diagnostic MRI Brain6 
X 
 
 
KPS 
X 
 
 
 
 
 
 
MRI Brain Planning 
Scan4 
X 
 
 
ALC 
X 
 
 
Toxicity assessment 
X 
X 
X 
X 
X8 
MRI Brain with and 
without contrast3 
X 
X 
X 
X 
X 
 
Footnotes:  
1. Variations of +/- 30 days from the scheduled visit are permitted 
2. After 12-months post-SRS, subjects will be followed at physician’s discretion, approximately every 3-6 
months per standard of care. Any MRI Brain, physical exam or vitals obtained at these appointments will be 
gathered. However, if these procedures are not performed per standard of care, this will not be a deviation.  
3. MRI Brain performed at Indiana University will have sequences including contrast, no contrast, FLAIR, DTI 
and PWI. If patient receives MRI Brain outside of Indiana University, a minimum of contrast, no contrast 
and FLAIR will need to be obtained and all sequences mentioned above are encouraged.  
4. Variations of -30 days from the scheduled visit are permitted for linear accelerator based SRS, and may 
include the baseline screening MRI at the treating radiation oncologist’s discretion.  
5. Will be calculated using www.brainmetgpa.com tool  
6. Diagnostic brain MRI is considered standard of care and will be performed as part of standard of care if 
subjects have not already undergone the procedure prior to enrollment. 
7. Height is only required at the baseline screening visit.  
8. After 12 months, only clinically relevant AEs will be recorded. 
 
* 
Subjects may be treated multiple times. Subjects cannot be enrolled if the treatment will have a dose overlap 
within the target from prior treatments of 20% or greater. Once it is determined that they will receive 
treatment if they are in follow-up, they will be enrolled onto cohort 2 and re-start all procedures beginning 
with baseline screening.  

 
 
 
 
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TREATMENT DOSE AND DELIVERY 
         
The total radiosurgery dose will be specified according to tumor size as noted in Table 1.    All 
 patients will be treated to this dose in one session. 
 
 
Table 1: RADREMI Dose Criteria  
Maximum Tumor 
Diameter 
Prescribed Dose  
≤ 20 mm 
18 Gy 
21 – 30 mm 
14 Gy 
31 – 40 mm 
12 Gy 
 
FDA-approved stereotactic localization procedures for imaging and treatment delivery will be 
used. With radiosurgery treatments using the Leksell Gamma Knife Perfexion®, target 
localization will be performed using the head frame coordinate system. The Leksell 
GammaPlan® will be used to generate the treatment plan with respect to the coordinate system 
created by localization. Target volume and isocenter determination will be based on an MRI 
Brain scan with the patient’s head in a stereotactic frame. The imaging study used to deliver 
the radiosurgical treatment must be the same as used to determine the size of the metastatic 
lesion(s). Stereotactic MRI slice thickness may not exceed 3 mm. The target volume will 
include the enhancing portion of the metastatic lesion. Surrounding areas of edema will not 
be considered part of the target volume. 
 
Linear accelerator based stereotactic localization will be performed using the Encompass® 
SRS thermoplastic mask immobilization system. The patient will undergo a 1mm slice 
thickness helical CT scan that will be fused with the MRI brain T1-weighted post-contrast 
axial scan used for target delineation. The CT-MRI fusion maximum correlation error must 
be less than 1.5mm. The imaging study used to deliver the radiosurgical treatment must be the 
same as used to determine the size of the metastatic lesion(s). Stereotactic MRI slice thickness 
may not exceed 3 mm. The target volume will include the enhancing portion of the metastatic 
lesion. Surrounding areas of edema will not be considered part of the target volume. 
 
The dose will be prescribed to the isodose surface (50 – 90%), which encompasses the margin 
of the metastasis, as defined by the imaging studies. The 100% dose will be recorded for each 
patient. 
 
For patients with multiple brain metastases, stereotactic radiosurgery will be delivered to each 
lesion that has not previously undergone stereotactic radiosurgery. The prescribed dose will 
be according to the RADREMI dosing schema as described in Table 1 above. Due to the 
volumetric summation constraint for the remaining metastases, no single lesion greater than 
4cm will be allowed on study, and, therefore, the above dose prescriptions can be used. If any 
two lesions are within 0.8 to 2 cm of each other, the intervening midplane dose will not exceed 
13 Gy. This may require treating each respective target with a lesser dose than dictated by the 
above table. This is designated to minimize toxicity in patients.  
 
Isodose distributions must be calculated, and the prescription isodose line clearly designated, 
for each target lesion in all planes.  
 

 
 
 
 
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Table 2: Critical Structures [36] 
Structure 
Maximum critical 
volume above 
threshold  
Threshold 
dose (Gy) 
Max Point 
Dose (Gy) 
Optic pathway 
<0.2 cc 
8 
10 
Brainstem 
<0.5 cc 
10 
15 
Cochlea 
N/A 
N/A 
9 
Medulla 
<1.2 cc 
7 
 
 
The dose to the above structures must meet constraints as designated by TG-101; the small 
size of the cochlea allows for only a max point dose and not a maximum critical volume 
above threshold or a threshold dose (Benedict et al., 2010).  If the above constraints cannot 
be met utilizing the prescribed radiosurgery dose Table 1, then the highest dose to the target 
volume will be used such that constraints can be met. This will be considered a minor 
deviation. 
 
    10.1 General Concomitant Medication and Supportive Care Guidelines 
  
For patients presenting with signs and symptoms relatable to peri-tumoral edema, including  
but not limited to nausea and headaches, dexamethasone will be prescribed at a dose level  
per clinician judgement. 
 
 For patients presenting with seizure, anti-seizure medication will be prescribed at a dose 
 level per clinician judgement. No specific type of anti-seizure medication is recommended 
 or prohibited.  
 
 Each patient will be given a prescription for 1mg Ativan to be taken approximately 30  
 minutes prior to the procedure, or otherwise at the physician’s discretion. 
 
 
10. RESPONSE ASSESSMENT IN NEURO-ONCOLOGY BRAIN METASTASES (RANO-BM)  
 
     11.1 Definitions Associated with RANO-BM (Lin et al., 2015) 
 
1. Measurable disease is defined as a contrast-enhancing lesion that can be accurately 
measured in at least one dimension, with a minimum size of 3 mm, and is visible on 
three or more axial slices that are preferably 1 mm or less apart with 0 mm skip (and 
ideally ≤ 1.5 mm apart with 0 mm skip). 
a. Additionally, although the longest diameter in the plane of measurement is to be 
recorded, the diameter perpendicular to the longest diameter in the plane of 
measurement should be at least 3 mm for the lesion to be considered measurable. 
i. Note: Recording of the 2nd dimension is at the radiologist’s discretion, if 
measurable.  
b. If the MRI is performed with thicker slices, the size of the measurable lesion at 
baseline should be at least double the slice thickness. Interslice gaps, if present, 
should also be considered in the determination of the minimum size of 
measurable lesions at baseline. 
 

 
 
 
 
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2. Non-measurable disease includes all other lesions, including lesions with longest 
dimension less than 3 mm, lesions with borders that cannot be reproducibly measured, 
dural metastases, bony skull metastases, cystic-only lesions, and leptomeningeal 
disease. 
 
3. Methods of measurement 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Consistent use of 
imaging techniques across all imaging time points is important to ensure that the 
assessment of interval appearance, disappearance of lesions, or change in size is not 
affected by scan parameters such as slice thickness. Use of thin section imaging is 
particularly important for the assessment of lesions less than 3 mm in longest diameter 
or small changes in lesion size, or both. 
 
Gadolinium-enhanced MRI is the most sensitive and reproducible method available to 
measure CNS lesions selected for response assessment. MRI is strongly encouraged 
as the default standard imaging technique, although CT with and without contrast 
could be considered in specific circumstances (e.g., countries with limited medical 
resources or contraindication for MRI). 
 
4. Tumor response assessment 
 
Only patients with measurable CNS disease at baseline should be included in protocols 
where objective CNS tumor response is the primary endpoint. For studies in which 
objective response is not the primary endpoint, the protocol must specify prospectively 
whether entry is restricted to those with measurable disease or if patients with non-
measurable disease are also eligible. 
a. Assignment of CNS response is independent of systemic disease response. CNS 
lesions are to be assessed according to RANO-BM criteria, whereas non-CNS 
lesions would most typically be assessed according to RECIST 1.1 criteria. 
 
b. Generally, CNS lesions should initially be re-assessed by MRI at protocol-
specified intervals 6–12 weeks apart, although there might be specific 
circumstances in which longer (or shorter) intervals are desirable. For patients 
who remain stable for extended periods of time, a longer interval between scans 
might be appropriate. All baseline assessments should be done as close as 
possible to the treatment start and no more than 4 weeks before the beginning of 
treatment. 
 
c. For previously treated lesions, we recommend documentation of how each lesion 
was previously treated (e.g., stereotactic radiosurgery, whole brain radiotherapy, 
surgical resection). 
 
d. When more than one measurable lesion in the CNS is present at baseline, all 
lesions up to a maximum of five CNS lesions should be identified as target 
lesions and will be recorded and measured at baseline. All measurements should 
be recorded in metric notation. Target lesions should be selected on the basis of 

 
 
 
 
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their size (longest diameter) and as those that can be measured reproducibly. For 
patients with recurrent disease who have multiple lesions, of which only one or 
two are increasing in size, the enlarging lesions should be prioritized as target 
lesions for the response assessment. 
 
e. Lesions with prior local treatment (i.e., stereotactic radiosurgery or surgical 
resection) can be considered measurable if progression has occurred since the 
time of local treatment. However, careful consideration should be given to 
lesions previously treated with stereotactic radiosurgery, in view of the 
possibility of treatment effect, which is discussed below. Whether such lesions 
can be considered measurable should be specified prospectively in the clinical 
protocol. If lesions not previously treated with local therapies are present, these 
are preferred for selection as target lesions. 
 
f. A sum of the diameters for all target lesions will be calculated and reported as 
the baseline sum of longest diameters. All other CNS lesions should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be classified as present, absent, or 
unequivocal progression, and followed up. 
 
      11.2 Response assessment of target and non-target lesions  
 
Please see Table 3 and Table 4 for a partial summary of this section. 
 
1. While on study, all CNS target lesions should have their actual measurement recorded, 
even if very small (e.g., 2 mm). If the lesion disappears, the value should be recorded 
as 0 mm. However, if the lesion is sufficiently small (but still present) to be assigned 
an exact measurement, a default value of 5 mm should be recorded on the case report 
form. 
 
2. Lesions might coalesce during treatment. As lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximum longest diameter of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion. 
 
3. New lesions can appear during treatment. The finding of a new CNS lesion should be 
unequivocal and not due to technical or slice variation. A new lesion is one that was 
not present on prior scans. 
 
i. If the MRI is obtained with slice thickness of 1.5 mm or less, the new lesion 
should also be visible in axial, coronal, and sagittal reconstructions of 1.5 mm 
or thinner projections. 
 
ii. If a new lesion is equivocal, for example because of its small size (i.e., ≤ 3 mm), 
continued therapy can be considered, and a follow-up assessment will clarify if 
it really is new disease. If repeated scans confirm a new lesion, progression 
should be declared using the date of the initial scan showing the new lesion. 

 
 
 
 
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iii. In the case of immunotherapy, however, new lesions alone cannot constitute 
progressive disease (see below). 
 
 
4. The RANO-BM group acknowledges the case of patients who have been treated with 
stereotactic radiosurgery or immunotherapy-based approaches, for whom there has 
been radiographical evidence of enlargement of target and non-target lesions, which do 
not necessarily represent tumor progression. If radiographical evidence of progression 
exists, but clinical evidence indicates that the radiological changes are due to treatment 
effect (and not to progression of cancer), additional evidence is needed to distinguish 
between true progression and treatment effect, in which case standard MRI alone is 
insufficient. The methods used to distinguish between true progression and treatment 
effect should be specified prospectively in the clinical protocol. Patients can be 
continued on protocol therapy pending further investigation with one or more of the 
following options. 
 
The scan can be repeated at the next protocol-scheduled assessment or sooner, and 
generally within about 6 weeks. An investigator can choose a shorter time interval if 
progressive symptoms or other clinical concerns arise. Continued tumor growth might 
be consistent with radiographical progression, in which case the patient should leave 
the study. Stabilization and shrinkage of a lesion can be consistent with treatment 
effect, in which case the patient can stay in the study. For patients with equivocal results 
even on the next restaging scan, the scan can be repeated again at a subsequent protocol-
scheduled assessment or sooner, although surgery or use of an advanced imaging 
modality (in the case of stereotactic radiosurgery), or both, are strongly encouraged. 
Surgical pathology can be obtained via biopsy or resection. 
 
i. For lesions treated by stereotactic radiosurgery, additional evidence of tumor 
progression or treatment effect (radionecrosis) can be acquired with an advanced 
imaging modality, such as perfusion MRI, magnetic resonance spectroscopy, or 
¹⁸FLT or ¹⁸FDG PET. Current recommendations suggest involving a 
multidisciplinary team to decide on the appropriate next step. Irrespective of the 
additional testing obtained, if subsequent testing shows that progression has 
occurred, the date of progression should be recorded as the date of the scan this 
issue was first raised. 
 
Patients can also have an equivocal finding on a scan (e.g., a small lesion that is 
not clearly new). Continued treatment is permissible until the next protocol-
scheduled assessment. If the subsequent assessment shows that progression has 
indeed occurred, the date of progression should be recorded as the date of the 
initial scan where progression was suspected. 
 
ii. In patients receiving immunotherapy-based treatment, an initial increase in the 
number and size of metastases can be followed by radiographical stabilization 
or regression. This pattern might be related to the mechanism of action of 
immunotherapy, including immune infiltrates, and the time to mount an effective 
immune response. Thus, progressive disease should not be solely defined by the 

 
 
 
 
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appearance of new lesions but rather as a minimum 20% increase in the sum 
longest diameter of CNS target and new lesions, as unequivocal progression of 
existing enhancing non-target CNS lesions, as unequivocal progression of 
existing non-enhancing (T2/FLAIR) CNS lesions, or as clinical decline related 
to the tumor. If immune response-related radiographical changes are suspected, 
we advise to not change treatment until a short interval scan is obtained. If the 
subsequent assessment confirms that progression has indeed occurred, the date 
of progression should be recorded as the date of the initial scan where 
progression was suspected. 
 
Note that the advanced imaging modalities discussed for treatment effect above 
have not been extensively studied with regards to immunotherapy-based 
approaches and therefore cannot be recommended to distinguish between tumor 
progression and immune-related changes at present. 
 
5. In the absence of clinical deterioration related to the tumor, an increase in corticosteroid 
dose alone should not be used as a sole determinant of progression. Patients with stable 
imaging results and whose corticosteroid dose has increased for reasons other than 
clinical deterioration related to the tumor do not qualify as having stable disease or 
progression. These patients should be observed closely, and if their corticosteroid dose 
can be reduced back to baseline, they will be considered as having stable disease, but 
if further clinical deterioration related to the tumor becomes apparent, they will be 
considered as having progression. 
 
The definition of clinical deterioration is left to the discretion of the treating physician, 
but it is recommended that patients who have a decrease in score on the Karnofsky 
performances scale from 100 or 90 to 70 points or less, a decrease of minimum 20 
points from 80 or less, or a decrease from any baseline to 50 points or less, for at least 
7 days, be considered as having neurological deterioration, unless this functional 
impairment is attributable to comorbid events, treatment-related toxicity, or changes in 
corticosteroid dose. 
 
Table 3. Response assessment of target and non-target lesions (Lin et al., 2015) 
Target lesions 
Complete response 
Disappearance of CNS target lesion(s) sustained for at least 4 weeks; with no new lesions, no use 
of corticosteroids and patient is stable or improved clinically. 
Partial response 
At least a 30% decrease in the sum longest diameter of CNS target lesion(s), taking as reference 
the baseline sum longest diameter sustained for at least 4 weeks; no new lesions; stable to decreased 
corticosteroid dose; stable or improved clinically. 
Progressive disease 
At least a 20% increase in the sum longest diameter of CNS target lesion(s), taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, at least one lesion must increase by an absolute value of 5 mm or 
more to be considered progression. 
Stable disease 

 
 
 
 
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Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum longest diameter while on study. 
Non-target lesions 
Non-target lesions should be assessed qualitatively at each of the time points specified in 
the protocol. 
Complete response 
Requires all of the following: disappearance of all enhancing CNS non-target lesions, no new CNS 
lesions. 
Non-complete response or non-progressive disease 
Persistence of one or more non-target CNS lesion or lesions. 
Progressive disease 
Any of the following: unequivocal progression of existing enhancing non-target CNS lesions, new 
lesion(s) (except while on immunotherapy-based treatment), or unequivocal progression of existing 
tumor-related non-enhancing (T2/FLAIR) CNS lesions. In the case of immunotherapy-based 
treatment, new lesions alone may not constitute progressive disease. 
 
     11.3 Other considerations 
 
1. Volumetric criteria are currently experimental and the existing data is not strong 
enough to support the universal requirement of volumetric response criteria in 
clinical trials. Nevertheless, the RANO-BM working group believes that 
assessment and reporting of volumetric data and response will further research in 
this future and encourage its inclusion as a secondary endpoint when feasible. For 
investigators choosing to report volumetric response data, please note the 
following recommendations. 
 
i. Partial volumetric response should be defined as 65% or greater decrease in 
the sum volume of CNS target lesions, in addition to the corticosteroid and 
clinical status criteria outlined previously. 
 
ii. Volumetric response should be reported as a waterfall plot to provide a global 
sense of potential efficacy. 
 
2. Response of non-CNS (extracranial) disease should be assessed separately from 
CNS (intracranial) disease.  
 
3. Please refer to Table 5 for RANO-BM recommendations for bi-compartmental 
assessment of response, i.e. when considering local control and distant brain failure 
separately. 
 
Table 4. Summary of the response criteria for CNS metastases proposed by RANO-BM 
 
Complete 
response 
Partial 
response 
Stable disease 
Progressive 
disease 
Target lesions 
None 
≥ 30% 
decrease in 
sum longest 
distance 
< 30% decrease relative 
to baseline but < 20% 
increase in sum longest 
distance relative to 
baseline 
≥ 20% increase in 
sum longest 
distance relative to 
nadir* 

 
 
 
 
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relative to 
baseline 
Non-target 
lesions 
None 
Stable or 
improved 
Stable or improved 
Unequivocal 
progressive 
disease 
New lesion(s)^ 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decreased 
Stable or decreased 
Not applicable# 
Clinical status 
Stable or 
improved 
Stable or 
improved 
Stable or improved 
Worse* 
Requirement for 
response 
All 
All 
All 
Any# 
*Progression occurs when this criterion is met. 
^A new lesion is one that is not present on prior scans and is visible in a minimum of two projections. If a 
new lesion is equivocal, for example because of its small size, continued therapy can be considered, and 
follow-up assessment will clarify if the new lesion is new disease. If repeat scans confirm there is 
definitely a new lesion, progression should be declared using the date of the initial scan showing the new 
lesion. For immunotherapy-based approaches, new lesions alone do not define progression. 
#Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration. 
 
 
 
Table 5. Sites of inclusion for assessment of bi-compartmental CNS outcomes.  
Local 
CNS 
lesions 
Distant 
CNS lesions 
Non-
CNS 
lesions* 
Bi-compartmental progression-free survival* 
x 
X 
X 
CNS progression-free survival 
x 
X 
Non-CNS progression-free survival* 
X 
CNSlocal progression-free survival 
x 
*Non-CNS disease is not assessed in the current protocol. 
 
 
11.  RADIATION NECROSIS 
 
12.1 Radiographic Radiation Necrosis 
 
Assessment for radiation necrosis will be done based on the contrast-enhanced, FLAIR, 
Diffusion tensor imaging (DTI) and Perfusion weighted imaging (PWI) MRI sequences.  
Radiation necrosis is typically a contrast enhancing lesion with surrounding edema noted on 
contrast-enhanced MRI and FLAIR respectively; however, this is difficult to distinguish from 
recurrent tumor. Therefore, DTI and PWI sequences will be analyzed as well. DTI uses 
fractional anisotropy that reflects the preferential direction of water diffusion along white 
matter tracks. Fractional anisotropy in radiation necrosis is lower than that for recurrent tumor 
due to lack of normal axonal fibers or cells within the necrotic area as compared to partially 
functioning axonal fibers and cells associated with recurrent tumor (Shah et al., 2012). PWI 

 
 
 
 
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assesses intra-lesional and peri-lesional cerebral blood volume. Recurrent tumor is more 
likely to be associated with higher cerebral blood volume than radiation necrosis as radiation 
necrosis is devoid of vasculature. The percentage of signal recovery ≥ 76.3% has a sensitivity 
of 96% and specificity of 100% for radiation necrosis as noted on PWI. (Barajas et al., 2009). 
 
12.2 Symptomatic Radiation Necrosis 
 
Assessment for symptomatic radiation necrosis will be performed based on patients meeting 
criteria for radiographic radiation necrosis who require steroid administration, bevacizumab, 
and/or operative resection to treat symptomatic cerebral edema.  These will be assessed at 
each post-SRS follow-up visit in conjunction with Brain MRIs.   
 
 
12. CRITERIA FOR EVALUATION/REMOVAL FROM STUDY 
 
Every subject should be encouraged to remain in the study. Possible reasons for early 
withdrawal may include, but are not limited to, the following: 
 
1. Withdrawal of consent – Subject decides to withdraw from the study. This decision must 
be an “independent decision” that is documented in the source documentation 
2.  Principal Investigator and/or treating physician discretion – The Principal Investigator 
and/or treating physician may choose to withdraw a subject from the study if there are 
safety or other concerns. 
3.  Subject non-compliance. 
4.  Subject lost to follow-up. 
5.  Subject enrolled in hospice care. 
6.  Subject death. 
 
 
13. STATISTICAL METHODS 
 
14.1 General Considerations 
 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics 
will be reported for both efficacy and safety outcomes. Continuous variables will be 
summarized by means, medians, minima, maxima and standard deviations. Categorical 
variables will be summarized by frequencies and percentages. Missing data will not be imputed. 
Additional exploratory analysis will be conducted when appropriate. Changes from the analysis 
plan will not require an amendment to the protocol unless it changes a significant feature in the 
protocol. If any changes occur, they will be documented in the clinical study report. The 
statistical analysis methods are outline below. 
 
14.2 Study Design  
 
This is a single-arm pilot study without blinding. 
 
 

 
 
 
 
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14.3 Analysis Datasets 
 
 
Enrolled Population 
 
The enrolled population comprises all subjects who meet the eligibility criteria and are     
 
registered onto the study.  
 
 
Safety Population 
 
The safety population comprises all subjects who have received at least one dose of           
 
radiation. This set will be used for safety analysis. 
 
 
Efficacy Population 
 
The efficacy population comprises all subjects who have completed stereotactic radiosurgery.  
This population will be used for efficacy analysis. 
 
14.4 Sample Size 
 
An optimum one-stage design is planned. We specify a historical 6 month symptomatic 
radiation necrosis rate of 16% and an expected 6 month symptomatic radiation necrosis rate of 
5%. Then, to achieve a power of 80% and control the type I error below 10%, a total of 40 
patients evaluable for symptomatic radiation necrosis will be enrolled in the study. If at most 4 
patients will experience symptomatic radiation necrosis in 6 months, the proposed dose 
reduction is claimed to be desirable. Otherwise, it is undesirable. We assume that at most 5% 
of the patients will not be evaluable for symptomatic radiation necrosis, which results in a total 
sample size of 42. In addition, we will add an interim analysis for the 6 month local control 
rate. When 20 patients have been enrolled in the study with their local control outcome being 
available, we will conduct a binomial exact test for the null hypothesis that the proposed method 
can maintain a 6 month local control rate of at least 75%. If p-value of this binomial test is less 
than 0.05, we will reject the null hypothesis and terminate this study earlier for futility. 
 
14.5 Patient Characteristics and significant protocol violations 
 
 
Baseline subject characteristics will be tabulated, such as demographics (age, race,  
 
gender), and disease characteristics (ds-GPA). 
 
14.6 Disposition 
 
 
The reasons for patient treatment and study discontinuation will be summarized. 
 
14.7 Analysis of Primary Objectives 
 
For the primary objective of 6 month symptomatic radiation necrosis for dose-reduced 
stereotactic radiosurgery concomitant with immunotherapy, the proportion of patients who have 
symptomatic radiation necrosis at 6 months will be calculated using Kaplan-Meier method 
along with a 95% confidence interval.  Testing the observed proportion smaller than a baseline 
6 month symptomatic radiation necrosis rate of 16% at a type I error rate of 5% using a one-
sided binomial exact test will be done. 
 
 

 
 
 
 
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14.8 Analysis of Secondary Objectives 
 
For the secondary objectives of 6-month local control, 6-month radiographic radiation necrosis, 
12-month symptomatic radiation necrosis, 12-month local control, 12-month radiographic 
radiation necrosis and 12-month local control rate by SRS modality, Kaplan-Meier methods 
will be used to provide point estimate with 95% confidence intervals. The method of Klein et 
al., (Klein et.al., 2007) will be conducted for the group comparison.  
 
14. MULTICENTER GUIDELINES 
 
15.1 Study Documents 
Each participating site must submit regulatory documents (informed consents, 1572s, Financial 
Disclosures, IRB approval documents, Continuing Reviews, Amendments, patient brochures or 
recruitment material etc.) to the Coordinating Center. The Coordinating Center will provide 
each site with a comprehensive list of the required documents prior to study start-up, throughout 
the duration of the study and upon study close-out. It is the responsibility of the participating 
site to maintain copies of all documentation sent to the Coordinating Center. 
 
 15.2 Study Initiation  
Before activating the clinical trial at each participating site, the IUSCCC CTO Multicenter 
Clinical Research Coordinator, or designee,  will ensure that: 
• Full Institutional Review Board (IRB) approval has been obtained.  
• Research staff at the participating site has been trained in data entry into OnCore®  
• A start-up meeting with each institution has taken place via telephone conference. The 
start-up meeting will cover protocol details (including eligibility criteria, treatment 
plan, etc.), responsibilities of the participating investigators, and reporting procedures.   
• A financial conflict of interest statement from each investigator has been obtained. 
 15.3 Patient Enrollment 
After eligibility is confirmed by the participating site staff, a completed eligibility checklist, 
supporting source documentation, and signed consent will be sent to IUSCCC for verification.  
The Multicenter Clinical Research Coordinator, or designee, will assign the patient a study 
number and return the enrollment information to the site.  The site staff will then register the 
patient in OnCore®. Additional details of this process can be found in the Study Procedure 
Manual.   

 
 
 
 
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 15.4 Data Monitoring 
All multicenter investigator initiated trials conducted at the IUSCCC are subject to data 
monitoring by the Multicenter Clinical Research Coordinator and the IUSCCC Compliance 
Office, or designee. External sites will be notified of upcoming monitoring visits and will be 
expected to provide the Multicenter Clinical Research Coordinator, IUSCCC Compliance 
Office, or designee, with de-identified source documents for remote monitoring of patients.  
Queries will be issued in OnCore® and a detailed monitoring report will be provided to the 
participating site.  The IUSCCC will also forward any monitoring and/or auditing reports to the 
DSMC.  
When a patient enrolled on this trial, or the trial itself, is selected for local monitoring or 
auditing, the participating site will forward the results to the Multicenter Clinical Research 
Coordinator, or designee. In addition, if a participating site patient is selected for local auditing 
by the IUSCCC DSMC, the site will be responsible for sending IUSCCC de-identified source 
documents.  
15.5 Record Retention 
Following closure of the study, each participating site will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at 
each site at such time that the records may be destroyed. 
 
 
15. DATA FORMS AND SUBMISSION SCHEDULE 
 
This study will utilize electronic Case Report Form completion in the OnCore® database. A 
calendar of events and required forms are available in OnCore®.  The OnCore® database is a 
comprehensive, web-based, Clinical Trial Management System (CTMS) which utilizes an 
Oracle database. OnCore® was developed by Forte Research Systems, Inc. and is used by the 
IUSCCC Clinical Trials Office (CTO) and supported by the Indiana Clinical and Translational 
Sciences Institute (CTSI).  OnCore® properly used is compliant with Title 21 CFR Part 11.  
 
OnCore® provides users secure access with unique IDs/passwords and restricts access by 
assigned roles, from any location, to record, manage, and report on data associated with the 
operation and conduct of clinical trials. 
 
All source documents are to remain in the patient’s clinic file.  All documents should be kept 
according to applicable federal guidelines.  Clinical trial data in OnCore® are periodically 
monitored by the IU Simon Comprehensive Cancer Center Data Safety Monitoring 
Committee.   
 
 
 

 
 
 
 
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16. PATIENT CONSENT AND PEER JUDGMENT 
 
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this 
study.   
 
Changes to the protocol, as well as a change of principal investigator, must also be approved 
by the Board.  Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Trials 
Office) and are subject to inspection at any time during the study.  Periodic status reports must 
be submitted to the Institutional Review Board at least yearly, as well as notification of 
completion of the study and a final report within 3 months of study completion or termination.   
 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
 
17. DATA AND SAFETY MONITORING PLAN 
 
Moderate Risk Trials  
Investigators will conduct continuous review of data and patient safety. Monthly review meetings 
for moderate risk trials are required and will include the principal investigator, clinical research 
specialist and/or research nurse (other members per principal investigator’s discretion). Monthly 
meeting summaries should include review of data, the number of patients, significant toxicities as 
described in the protocol, and responses observed.  Study teams should maintain meeting minutes 
and attendance for submission to the DSMC upon request.  
 
If there are no patients on treatment or in follow-up, email communication will be used in lieu of a 
teleconference, or in the circumstance where a scheduling conflict does not permit phone 
attendance.  
 
Data and Safety Monitoring Committee 
The IUSCCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review this 
study annually to review overall trial progress, toxicity, compliance, data integrity, and accrual per 
the Institutional DSMP. 
 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business.  Major issues may require further 
DSMC review or action. 
 
For any increase in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the principal investigator will notify the DSMC Chair 
immediately.  The notification will include the incidence of study adverse events, grades, and 
attributions, as well as investigator statements regarding comparison with risks per the IB/ package 
insert. 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance Officer 

 
 
 
 
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must be notified within 1 business day via email, and the IRB must be notified within 5 business 
days. Alternatively, the DSMC may initiate suspension or early closure of the study based on its 
review. 
 
 
 
Study Auditing and Monitoring 
All trials conducted at the IUSCCC are subject to auditing and/or monitoring per the Institutional 
DSMP. Reports will be reviewed by the full DSMC at the time of study review. 
 
Data Management/ Oncore Reporting Requirements 
The DSMC reviews data and study progress directly from Oncore; therefore, timely data entry and 
status updates are vital.  Study data must be entered within Oncore promptly, no later than one 
week from study visit occurrence.  Subject status in Oncore will be updated in real time, as this 
may affect overall trial enrollment status.  Global SAEs and deviations will be reviewed on a 
monthly basis by the DSMC Chair directly from Oncore. 
 
Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol 
Progress Committee (PPC) reviews study accrual twice per year, while the PPC coordinator reviews 
accrual quarterly. 
 
Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events 
(SAEs) will be captured in the Oncore system within 1 business day of notification. Initial SAE 
reporting 
will include as much detail as available, with follow-up to provide complete 
information. 
Attributions will be assessed to study drugs, procedures, study disease, and other alternate etiology. 
 
Protocol Deviation Reporting 
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the 
DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time of study 
review. For serious or repetitive protocol deviations, additional action may be required by the 
DSMC. 
 
 
18. REPORTING ADVERSE EVENTS 
 
19.1 Definitions of Adverse Events 
 
 
Adverse Event (AE) 
 
An adverse event is defined as untoward medical occurrence associated with the use of  a 
 
drug in humans, whether or not considered drug related. An adverse event can be ANY 
 
unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease 
 
temporarily 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’).  Adverse events will be graded according to       
the NCI Common Toxicity Criteria, Version 5.0. 
 

 
 
 
 
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Serious Adverse Event (SAE) 
 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
 
following: 
 
• 
Results in death or ANY death occurring within 30 days of last study intervention 
• 
Is life-threatening (defined as an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to study intervention  
 Hospitalization for elective treatment of a pre-existing condition unrelated 
to the study intervention 
 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
 
19.2 Determining Attribution to the Investigational Agent(s) 
 
Attribution: An assessment of the relationship between the AE and the medical intervention. 
CTCAE does not define an AE as necessarily “caused by a therapeutic intervention”. After 
naming and grading the event, the clinical investigator must assign an attribution to the AE 
using the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
19.3 Adverse Event (AE) and Serious Adverse Event (SAE) Reporting 
 
Adverse events (AEs) will be recorded from the time of study intervention and until 12 months  
after the end of SRS treatment, regardless of whether or not the event(s) are considered related 
to treatment. After 12 months, AEs related to SRS or any AEs that are grade 4 or higher will be 

 
 
 
 
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recorded.  All AEs considered related to trial medication will be followed until resolution, return 
to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
 
All SAE’s should be collected from study intervention until the 1-month follow up visit. SAEs 
related or possibly related to study treatment or a study procedure should be reported until the 
patient is off study. Any death occurring within 30 days after the study intervention must be 
reported as an SAE regardless of attribution. 
 
Reporting to the IRB: Adverse Events will be reported to the IRB within 5 days from 
becoming aware of the event  if they are: (1) unexpected, (2) related or possibly related to study 
participation, AND (3) suggests that the research places subject(s) or others at greater risk of 
harm than was previously known. 
 
 
Reporting to the Data Safety Monitoring Committee (DSMC): 
  
Regardless of study sponsorship, the DSMC chair and/or coordinator will review all expedited 
 SAE reports through OnCore®. Expedited reports are completed per IRB guidelines and may 
 include the IRB Prompt Reporting form, non-compliance form, AdEERS reports, MedWatch, 
 and additional SAE forms as required by the sponsor. Submission of this information to the 
 DSMC is additional to any other protocol-specified regulatory bodies (e.g., FDA,  
 pharmaceutical company) to be notified.   
 
When follow-up information is received, a follow-up expedited SAE reports monthly, and  
report findings to the DSMC quarterly.   
 
19.4 Reporting to the IU Simon Comprehensive Cancer Center 
 
Any serious adverse event or unanticipated problem occurring within 30 days of the 
treatment must be reported to the IU Simon Comprehensive Cancer Center within 1 business 
day of notification or discovery of the incident, using the MedWatch Form 3500A 
(Mandatory Reporting) or SAE Form.  SAEs that occur greater than 30 days from treatment 
must be reported to the IU Simon Comprehensive Cancer Center if the event is possibly, 
probably, or definitely related to the treatment.  This form must be accompanied by a cover 
letter which:  identifies the event, is signed by the local principal investigator or treating 
physician, includes the applicable study number and title, and contains the following: 
• Site assessment of the event attribution to investigational product or study procedure 
• Site assessment of event expectedness (expected vs. unexpected) 
• Assessment of whether or not the research places subjects at a greater risk of harm 
than was previously known or recognized 
• Assessment of the event’s effect on the risk to benefit ratio  
• Statement as to whether the informed consent statement should reflect changes in the 
potential risks involved 
• Statement as to whether the event has been reported previously, and if so, whether the 
frequency is considered unusually high 
 
 

 
 
 
 
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Send to:  
 
 
 
IUSCCC Clinical Trials Office 
ATTN: Multicenter coordinator/ IUSCC-0710 
  
 
 
 
 
Fax: (317) 274-8022 
E-mail: iusccsae@iupui.edu   
  
 
 
The Multicenter Clinical Research Coordinator, or designee, will distribute the reports to all 
participating sites, as per section 19.5 below. Copies of all serious adverse event reports or 
unanticipated problems reports will be kept on file in the IU Simon Comprehensive Cancer 
Center Clinical Trials Office. 
 
19.5 Coordinating Center Reporting Responsibilities 
 
In addition to the responsibilities above, the Coordinating Center will also be responsible for 
reporting events to the FDA as required. 
 
19.6 Reporting to Participating Sites 
 
The Multicenter Clinical Research Coordinator, or designee, will distribute reports which are 
serious, unexpected and suspected to be associated with the study intervention (possibly, 
probably or definitely related) to all participating sites in the form of an Expedited Safety 
Report (external safety/IND report) within 15 calendar days from determination that the 
suspected adverse reaction qualifies for reporting. Copies of these Expedited Safety Reports 
will be kept on file in the IU Simon Comprehensive Cancer Center Clinical Trials Office. 
 
 
19.  Representation of Women and Minorities 
Given the racial, ethnic, and gender diversity of the patient population at Indiana University, 
we expect the representation of women and minorities to be adequate, and consistent with their 
representations in the most recent United States census – this depiction of gender and racial 
representation is far more stringent than that demonstrated in vast majority of published 
immunotherapy and/or SRS series.  
 
 
 

 
 
 
 
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19. Yusuf MB, Amsbaugh MJ, Burton E, Chesney J, Woo S. Peri-SRS Administration of Immune 
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20. Chen L, Douglass J, Kleinberg L, et al. Concurrent immune checkpoint inhibitors and 
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25. Shehata MK, Young B, Reid B, et al. Stereotatic radiosurgery of 468 brain metastases < or =2 
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28. Woody NM, Greer MD, Reddy CA, et al. Validation of the Disease-Specific GPA for Patients 
With 1 to 3 Synchronous Brain Metastases in Newly Diagnosed NSCLC. Clin Lung Cancer. 
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29. Etchells E, Darzins P, Silberfeld M, et al. Assessment of patient capacity to consent to 
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30. Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced 
melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates 
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31. Nayak L, DeAngelis LM, Brandes AA, et al. The Neurologic Assessment in Neuro-Oncology 
(NANO) scale: a tool to assess neurologic function for integration into the Response 
Assessment in Neuro-Oncology (RANO) criteria. Neuro Oncol. 2017;19:625-635. 
32. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report 
of AAPM Task Group 101. Med. Phys. 2010;37:4078-4101.  
33. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal 
from the RANO group. Lancet Oncol. 2015;16:e270-e278. 
34. Shah R, Vattoth S, Jacob R, et al. Radiation necrosis in the brain: imaging features and 
differentiation from tumor recurrence. RadioGraphics. 2012;32:1343-1359.  
35. Barajas RF, Chang JS, Sneed PK, et al. Distinguishing recurrent intra-axial metastatic tumor 
from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-
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36. Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
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37. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and 
treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional 
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38. Sperduto PW, Yang TJ, Beal K, et al. Estimating survival in patients with lung cancer and 
brain metastases, an update of the graded prognostic assessment for lung cancer using 
molecular markers (Lung-molGPA). JAMA Oncol. 2017;3:827-831. 
39. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and 
comparison to three other indices for patients with brain metastases: an analysis of 1,960 
patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008;70:510-514. 
40. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic 
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41. Sperduto PW, Kased N, Roberge D, et al. Effect of tumor subtype on survival and the graded 
prognostic assessment for patients with breast cancer and brain metastases. Int J Radiat Oncol 
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42. 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 
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43. Villa S, Weber DC, Moretones C, et al. Validation of the new graded prognostic assessment 
scale for brain metastases: a multicenter prospective study. Radiat Oncol. 2011;6:23-31.  
44. Venur VA, Ahluwalia MS. Prognostic scores for brain metastasis patients: use in clinical 
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21. APPENDICES 
 
     22.1 APPENDIX I - TOXICITY CRITERIA 
NOTE:  the attached Appendix I contains reference to the DCT/NCI Common Toxicity   
Criteria, Version 5.0, used to grade toxicities in reporting an "ADR" (adverse drug reaction) 
as described in Section 19.0 of this protocol.  Other toxicity criteria (i.e., related to 
specialized treatments such as immunotherapy or BRMs) may be used as needed. 
 
  22.2 APPENDIX II- Performance Status 
 

 
 
 
 
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Appendix I 
 
NCI Common Toxicity Criteria 
 
Version 5.0 
Due to the size of the latest version of the Common Toxicity Criteria, copies of this appendix are 
not included with this protocol document. 
 
An electronic copy is available on the CTEP web site, http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
 

 
 
 
 
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Appendix II 
 
Performance Status Scales/Scores 
 
ECOG or Zubrod            Karnofsky                                           Lansky   
 
Score      Activity               Score                Activity                        Score               Activity 
0 
Fully active, able to 
carry on all pre-
disease performance 
without restriction. 
100 
 
 
90 
Normal, no complaints, no 
evidence of disease. 
 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
100 
 
 
90 
Fully active, normal. 
 
 
Minor restrictions in 
physically strenuous 
activity. 
1 
Restricted in 
physically strenuous 
activity but 
ambulatory and able 
to carry out work of 
a light or sedentary 
nature, e.g., light 
housework, office 
work. 
80 
 
 
 
 
70 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
Cares for self, unable to carry 
on normal activity or do active 
work. 
80 
 
 
 
 
70 
Active, but tires more 
quickly. 
 
 
 
Both greater restriction of 
and less time spent in 
play activity. 
2 
Ambulatory and 
capable of all 
selfcare but unable 
to carry out any 
work activities.  Up 
and about more than 
50% of waking 
hours. 
 
 
60 
 
 
 
50 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
 
 
Requires considerable 
assistance and frequent 
medical care. 
 
 
60 
 
 
 
50 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
 
 
Gets dressed, but lies 
around much of the day; 
no active play; able to 
participate in all quiet 
play and activities. 
3 
Capable of only 
limited selfcare, 
confined to bed or 
chair more than 50% 
of waking hours. 
40 
 
 
 
30 
Disabled, requires special care 
and assistance. 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
40 
 
 
 
30 
Mostly in bed; 
participates in quiet 
activities. 
 
In bed; needs assistance 
even for quiet play. 
4 
Completely 
disabled.  Cannot 
carry on any 
selfcare. Totally 
confined to bed or 
chair. 
20 
 
 
10 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
Moribund, fatal processes 
progressing rapidly. 
20 
 
 
10 
 
Often sleeping; play 
entirely limited to very 
passive activities. 
No play; does not get out 
of bed.