A Pilot Study Analyzing Preoperative Stereotactic Radiosurgery (SRS) With Gamma Knife (GK) for Brain Metastases
Phase: NA
Conditions: Brain Metastases
Sponsor: Medical College of Wisconsin

NCT04545814 
Official Title:  A Pilot Study Analyzing Preoperative Stereotactic Radiosurgery 
(SRS) With Gamma Knife (GK) for Brain Metastases 
Date:  August 30, 2023 
 

Study Short Title: GK-SRS-Brain Metastases 
 1 
 
Version No.: 5 
Version Date: 8/30/2023
A Pilot Study Analyzing Preoperative Stereotactic Radiosurgery (SRS) 
with Gamma Knifeט (GK) IconTM for Brain Metastases
Short Title:
Michael Straza, MD (Study PI)
Amber Retzlaff, MD (Co-PI)
Current Version Number and Date
V5.0 8/30/2023
Proprietary and Confidential
The information in this document is considered privileged and confidential and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.  
GK-SRS-Brain 
Metastases 
Study
Short Title
GK-S
Meta
S

 
 
Study Short Title: GK-SRS-Brain Metastases 
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Version No.: 5 
 
 
Version Date: 8/30/2023 
 
TITLE:       A Pilot Study Analyzing Preoperative Stereotactic Radiosurgery (SRS)  
with Gamma Knifeט (GK) IconTM for Brain Metastases 
MCW Protocol No.: Pending 
IRB Pro No.:  PRO00038835 
Clinical trials.gov No.: NCT04545814 
FDA IND No.: Pending 
Principal Investigator: 
Michael Straza, MD 
Assistant Professor 
Department of Radiation Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4477 
Email:  mstraza@mcw.edu 
 
Co-investigator:   
Amber Retzlaff, MD 
Resident 
Department of Radiation Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4477 
Email:  aretzlaff@mcw.edu 
 
 
Sub-investigator:  
Wade M. Mueller, MD 
Professor 
Department of Neurosurgery 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-5400 
Email:  WMueller@mcw.edu  
Sub-investigator:  
Christopher J. Schultz, MD, FACR, FASTRO 
Professor 
Department of Radiation Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4472 
Email:  CSchultz@mcw.edu  
 
 
Sub-investigator:  
Fernando Santos-Pinheiro, MD 
Assistant Professor 
Department of Neurology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-5204 
Email:   fsantos@mcw.edu  
 
Sub-investigator:  
Alissa Butts, PhD 
Assistant Professor 
Department of Neurology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-5204 
Email:   abutts@mcw.edu  
Biostatistician:  
Anjishnu Banerjee, PhD 
Assistant Professor 
Division of Biostatistics 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Email: abanerjee@mcw.edu  
 
Funder: 

 
 
Study Short Title: GK-SRS-Brain Metastases 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................... 5 
STUDY SCHEMA ...................................................................................................................... 7 
STUDY CALENDAR .................................................................................................................. 8 
LIST OF ABBREVIATIONS ......................................................................................................10 
1 BACKGROUND .....................................................................................................................12 
1.1 BRAIN METASTASES: EPIDEMIOLOGY AND PROGNOSTIC FACTORS .......................................12 
1.2 TREATMENT PARADIGM .....................................................................................................12 
1.3 HISTORICAL PERSPECTIVES ...............................................................................................12 
1.4 RECURRENCE PATTERNS ...................................................................................................13 
1.5 TOXICITY...........................................................................................................................13 
1.6 LEPTOMENINGEAL CARCINOMATOSIS ..................................................................................13 
1.7 STUDY RATIONALE ............................................................................................................14 
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS ................................................................14 
2.1 PRIMARY OBJECTIVES .......................................................................................................14 
2.2 SECONDARY OBJECTIVE(S) ................................................................................................15 
2.4 SECONDARY ENDPOINT(S) .................................................................................................15 
3 STUDY DESIGN ....................................................................................................................15 
3.1 GENERAL DESCRIPTION .....................................................................................................15 
3.2 DESIGN OF THE CURRENT STUDY .......................................................................................15 
3.3 ESTIMATED TIME FOR COMPLETION OF STUDY ENROLLMENT ................................................16 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND WITHDRAWAL............................16 
4.1 SUBJECT STATUS ..............................................................................................................16 
4.2 PRESCREENING AND SCREENING LOG ................................................................................16 
4.3 CONSENT ..........................................................................................................................16 
4.4 SCREENING PROCEDURES .................................................................................................17 
4.5 ELIGIBILITY CONFIRMATION ................................................................................................18 
4.6 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE ........................20 
4.7 LOST TO FOLLOW-UP .........................................................................................................20 
4.8 ACCRUAL SUSPENSION AND CLOSURE ................................................................................21 
4.9 END OF STUDY DEFINITION ................................................................................................21 
4.10 STUDY DISCONTINUATION AND CLOSURE ..........................................................................21 
5 TREATMENT PLAN ..............................................................................................................22 
5.1 INTERVENTION DESCRIPTION ..............................................................................................22 
5.1.1 Stereotactic Radiosurgery ......................................................................................................................... 22 
5.1.2 Surgical Resection ..................................................................................................................................... 23 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING REQUIREMENTS .24 
6.1 DEFINITIONS .....................................................................................................................24 
6.1.1 Adverse Event ............................................................................................................................................ 24 
6.1.2 Serious Adverse Event (SAE) ................................................................................................................... 24 
6.1.3 Attribution of an Adverse Event ............................................................................................................... 25 
6.1.4 Expectedness of an Adverse Event ........................................................................................................... 25 

 
 
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6.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE
 ...................................................................................................................................25 
6.2.1 Collection of Adverse Events .................................................................................................................... 25 
6.2.2 Reporting of Adverse Events and Serious Adverse Events ...................................................................... 26 
6.3 UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ....................26 
6.4 SUBJECT COMPLAINTS ......................................................................................................27 
7 STATISTICAL CONSIDERATIONS .......................................................................................27 
7.1 POWER CALCULATIONS .....................................................................................................27 
7.2 METHODOLOGY OF COMPARISONS BETWEEN GROUPS .........................................................27 
7.3 MISSING DATA AND INTERIM STOPPING ................................................................................27 
8 DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................28 
8.1  STUDY TEAM ....................................................................................................................28 
8.2  QUALITY ASSURANCE .......................................................................................................28 
8.3  CLINICAL TRIALS OFFICE ..................................................................................................28 
8.4  DSMC .............................................................................................................................28 
9 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ..............................29 
9.1 ETHICAL STANDARD ..........................................................................................................29 
9.2 REGULATORY COMPLIANCE................................................................................................29 
9.3 PRESTUDY DOCUMENTATION .............................................................................................29 
9.4 INSTITUTIONAL REVIEW BOARD ..........................................................................................29 
9.5 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ............................30 
9.6 PROTECTION OF HUMAN SUBJECTS ...................................................................................31 
9.6.1 Protection from Unnecessary Harm ......................................................................................................... 31 
9.6.2 Protection of Privacy ................................................................................................................................. 31 
9.7 CHANGES IN THE PROTOCOL .............................................................................................31 
9.8 INVESTIGATOR COMPLIANCE ..............................................................................................32 
10 DATA HANDLING AND RECORD KEEPING .....................................................................32 
10.1 OVERVIEW ......................................................................................................................32 
10.2 DATA MANAGEMENT RESPONSIBILITIES ............................................................................32 
10.2.1 Principal Investigator ............................................................................................................................. 32 
10.2.2 Research Coordinator ............................................................................................................................. 32 
10.2.3 Research Nurse/Medical Staff ................................................................................................................ 32 
10.2.4 Biostatistician .......................................................................................................................................... 32 
10.3 SOURCE DOCUMENTS ......................................................................................................33 
10.4 CASE REPORT FORMS .....................................................................................................33 
10.5 STUDY RECORD RETENTION ............................................................................................34 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................35 
APPENDIX 2. LOST TO FOLLOW-UP LETTER ......................................................................36 
APPENDIX 3. RESPONSE CRITERIA FOR CNS METASTASES PROPOSED BY RANO-BM
 .................................................................................................................................................37 
REFERENCES .........................................................................................................................38 

 
 
Study Short Title: GK-SRS-Brain Metastases 
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PROTOCOL SUMMARY 
Title 
A Pilot Study Analyzing Preoperative Stereotactic Radiosurgery (SRS)  
With Gamma Knifeט (GK) IconTM for Brain Metastases 
IND Sponsor 
Not applicable 
Principal 
Investigator  
Michael Straza, MD 
Study Population 
Patients with radiographically confirmed solid tumor brain metastases. 
Primary Objectives 
1. To assess feasibility of preoperative GK-SRS in patients with 
brain metastases treated with preoperative GK-SRS.   
2. To assess local control in patients with brain metastases treated 
with preoperative GK-SRS.   
Primary Endpoint 
1. Feasibility for this study will be defined as 50% of enrolled study 
subjects undergoing the surgical resection as per the protocol. 
2. Measure the rate of local control at the resection cavity and the 
development of new metastatic brain tumors elsewhere in the 
brain as identified on post-treatment MRI of the brain. 
Secondary 
Objectives 
1. To assess survival (CNS progression-free survival and overall 
survival) for patients undergoing preoperative SRS and surgical 
resection.  
2. To document rates of leptomeningeal carcinomatosis for patients 
undergoing preoperative SRS and surgical resection.  
3. To record incidence of radiation necrosis in patients undergoing 
preoperative SRS and surgical resection.  
4. To document quality of life measures using preoperative Gamma 
Knife® and to compare to historically cited rates using 
postoperative Gamma Knife®.  
Secondary Endpoint 
1. CNS progression-free survival and overall survival will be 
evaluated at six, 12, and 18 months after surgical resection. 
2. Rates of leptomeningeal carcinomatosis using preoperative SRS 
will be documented and compared to historically cited rates for 
postoperative SRS.  
3. Incidence of radiation necrosis will be measured by post-
treatment MRI. 
4. Quality of life measures will be collected and will be compared to 
historically cited rates. 
 
Study Design 
This is a single-arm, single-center, pilot study in which 10 completed 
patients with one to four brain metastases diagnosed on brain MRI 
within the past 30 days will be evaluated for study eligibility and enrolled 
as appropriate.  
Study Intervention 
Description 
Enrolled patients will receive SRS to all metastases followed by surgical 
resection of resectable metastases within one to 10 days following 

 
 
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SRS. Pathologic specimens will be analyzed, and the patient will enter 
a standard pattern of surveillance (brain MRI every three months for 
two years). 
Number of Subjects 
Up to fifteen subjects will be enrolled in this study to attain ten 
completed subjects. 
Estimated Time to 
Complete 
Enrollment: 
Approximately two years. 
 
 

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STUDY SCHEMA
Surgical resection Within 
1-10 days of SRS
Surveillance Imaging 
(Brain MRI q3 Months for 
2 years)
Pathological 
Analysis
Outcomes Assessed
x
6-Month Local Control
x
CNS Progression Free Survival
x
Overall Survival
x
Leptomeningeal Carcinomatosis
x
Radiation Necrosis
Screening
Diagnosis of Brain Metastasis on 
MRI Within the Past 30 Days
Planning MRI for SRS (Must 
Confirm Eligibility)
SRS Delivery
18-Month Follow-Up

 
 
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STUDY CALENDAR 
 
 
 
 
 
 
Procedure 
Screening1 
Radiosurgery Delivery 
Surgical 
Resection 
Post-
Surgical 
Resection 
Visit 
Follow-up2 
(until 18-months 
from post-
surgical resection 
visit) (18 months) 
Study Day/Visit Day 
Day – 30 to Enrollment 
Day 1 
Day 2 (+8 
days) 
1-month ±7 
days from 
radiosurgery 
Every 3 months 
±14 days   
Informed Consent 
X 
 
 
 
 
AE Reporting 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
SRS 
 
X 
 
 
 
Physical Exam3 
X 
 
 
X 
X 
Medical History 
X 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
X 
X 
Pregnancy Test 
(Serum or Urine)4 
X 
 
 
 
 
Neurocognitive 
Testing5 
X 
 
 
 
Every 6 months± 
14 days 
QOL Questionnaire6 
X 
 
 
X 
X 
MRI (Brain)7 
X 
 
 
X 
X 

 
 
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1. All screening procedures must occur within 30 days prior to enrollment. Treatment must start within 14 days of enrollment.  
2. If a subject has disease progression/relapse or subject withdrawal, then they will be followed as per follow-up requirements. 
3. Including height and weight on screening. Temperature, HR, RR, BP and O2 sats or as per institutional standards at all timepoints.   
4. For women of childbearing potential, a negative pregnancy test (serum or urine) must be obtained within 30 days prior to the first 
study intervention.   
5. Neurocognitive testing: Multilingual Aphasia Examination Controlled Oral Word Associated Test (COWAT), Trail Making Test, 
Parts A and B (TMT), and Hopkins Verbal Learning Test-Revised (HVLT-R). 
6. QOL Questionnaire: MDASI-BT, EQ-5D-5L. 
7. MRI (brain) w/ contrast. Radiographic assessments will be completed as per RANO criteria (see Appendix 3). 

 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MCWCC 
Medical College of Wisconsin Cancer Center 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 
PD 
disease progression 
PK 
pharmacokinetics 
PO 
per os (by mouth, orally) 
PR 
partial response 
QOL 
quality of life 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 

 
 
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SRC 
Scientific Review Committee 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO   
unanticipated problems involving risks to subjects or others 
 
 

 
 
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1 BACKGROUND 
1.1 Brain Metastases: Epidemiology and Prognostic Factors 
Brain metastases are the most common intracranial malignancy in adults and occur in up to 30 to 
40% of cancer patients.1-7 Common primary etiologies include breast cancer, lung cancer, renal 
cell carcinoma, and melanoma.2,5,7 Symptoms depend on specific intracranial location, tumor 
volume, mass effect, tumor histology, and tumor-related hemorrhage.2 In general, prognosis after 
diagnosis of brain metastasis is poor; however, longer survival is now being observed with 
improved systemic therapies as well as earlier detection at more limited stages of neurologic 
involvement.2,3,5,8,9 Favorable prognostic factors include young age (<60 years), good 
performance status, female gender, solitary metastasis, absence of neurologic symptoms, and 
well-controlled primary disease with absence of metastasis outside the central nervous 
system.2,3,10,11 
 
1.2 Treatment Paradigm 
 
Management is influenced by the number, location, and volume of brain metastases, as well as 
tumor histology, molecular markers, and recursive partitioning analysis (RPA) or graded 
prognostic assessment (GPA).1,5 Historically, approaches that have been investigated for 
treatment of one to four brain metastases include surgery alone, whole-brain radiation therapy 
(WBRT) alone, WBRT followed by surgery, surgery followed by WBRT, and surgery followed by 
SRS.1,5,11 Efficacy and timing of systemic treatment is an additional consideration for management 
of brain metastases depending on primary tumor histology.5 
 
1.3 Historical Perspectives 
 
Early studies by Patchell et al. demonstrated superior local control and overall survival with the 
addition of surgery to WBRT, as well as superior local control and lower rates of neurologic-related 
deaths with the addition of WBRT to surgery for treatment of solitary brain metastases.12,13 A 
Cochran review published in 2005, however, did not confirm an overall survival benefit with the 
addition of surgery to WBRT.2 As SRS was developed, studies  began evaluating WBRT with SRS 
boost.5 Collectively, these studies demonstrated a local control benefit using WBRT with SRS 
boost, as well as an overall survival benefit in patients with more favorable prognosis (favorable 
GPA, RPA Class 1, or solitary metastasis).5,6,11,14,15  
 
Due to concerns related to cognitive decline and quality of life measures with WBRT, studies on 
the use of SRS alone for a limited number of brain metastases ensued.5,6,11 These studies 
consistently reported superior local control and distant brain control with SRS plus WBRT 
compared to SRS alone, although conclusions related to overall survival were variable.5,6,11,16-20 
Aoyama et al. reported an overall survival benefit using SRS with WBRT only in those with higher 
GPA scores, while Chang et al. reported a superior overall survival with SRS alone.5,17,18 Kocher 
et al., Brown et al., and Churilla et al. reported no difference in overall survival with the addition 
of WBRT.19,21,22 A meta-analysis by Soon et al. concluded no difference in overall survival, while 
an individual patient-data meta-analysis by Sahgal et al. concluded that SRS alone provides a 
survival benefit for patients <50 years of age.16,20,23 In addition, a recently published retrospective 
review comparing survival outcomes with SRS alone versus WBRT alone reported improved 
survival with SRS alone in patients with limited brain metastases from lung or breast cancer.24 
 
 
 

 
 
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1.4 Recurrence Patterns 
 
Lesions >3 cc in size often require surgical intervention to relieve mass effect and neurologic 
symptoms.6,13 Risk of recurrence at the resection cavity has been reported to be approximately 
50%; consequently, postoperative radiation in the form of WBRT or SRS is frequently used to 
sterilize the surgical bed.6,12,19 Prospective data to support superiority of SRS versus WBRT in the 
postoperative setting is lacking, although there is some retrospective evidence to suggest that 
postoperative WBRT provides better intracranial local control than postoperative SRS for larger 
brain metastases but with no difference in OS.5,6 It should be noted that these comparisons are 
limited by the retrospective nature; in addition, optimal dose/fractionation schemes for 
postoperative SRS have not yet been determined with certainty.6,7 
 
1.5 Toxicity 
 
Multiple studies report worsened cognitive decline and quality of life with the addition of WBRT to 
either SRS or surgery for a limited number of brain metastases.3,5,6,18,21,25 Given evidence for 
WBRT-related toxicity along with the lack of clear survival benefit with the addition of WBRT (and 
potentially a survival benefit with SRS alone in certain populations), the current trend for 
management of limited brain metastases now favors surgery (+/- postoperative SRS) or SRS 
alone with reservation of WBRT as a salvage option.1,4-6,9,11 A number of studies are now 
evaluating the use of SRS in patients with multiple (more than four) brain metastases.3-5,8,11,26,27 
According to a recently published systematic review, SRS may be considered an option for 
patients with greater than four brain metastases provided the total tumor volume does not exceed 
13 cc and no single metastasis is larger than 3 cc in volume.1 While postoperative WBRT carries 
the cognitive and quality of life toxicities discussed above, SRS carries the risk of CNS necrosis 
(up to 23%).28,29 In an effort to reduce the risk of radiation necrosis with SRS applied to larger 
volumes while retaining efficacy, different dose and fractionation schedules are under 
investigation.6,7 
 
1.6 Leptomeningeal Carcinomatosis 
 
With increased utilization of postoperative SRS in place of WBRT and expanding data on 
outcomes, specific patterns of CNS failure are becoming clearer. A number of studies report 
excellent local control rates with postoperative SRS (up to 83 to 94% at 24 months) but with 
distant intracranial failure rates of 40 to 60% within 12 months.28,30 This is consistent with 
previously published data demonstrating inferior distant brain control with SRS compared to SRS 
with adjuvant WBRT.5,6,11,16-19  
 
Of increasing interest is the incidence of leptomeningeal carcinomatosis in patients with solid 
tumors and brain metastases. Rates of leptomeningeal disease with solid tumors are reported to 
be in the range of 5 to 15%.  Risk factors for leptomeningeal involvement include breast cancer 
histology (particularly triple-negative receptor status and infiltrating lobular carcinoma), as well as 
non-small cell lung cancer and melanoma histologies.31,32 Treatment options at the time of 
leptomeningeal failure typically include radiation, intrathecal chemotherapy, and/or systemic 
chemotherapy depending on histology.9,32 Prognosis with leptomeningeal metastasis is poor, with 
reported survival in the range of two to six months.9,16,31,32 
 
Neurosurgical risk factors for leptomeningeal carcinomatosis include piecemeal resection, 
opening of the ventricular system, and infratentorial lesions.31,33 In the setting of up-front surgery, 
the hypothesis is that any anatomic disruption that allows cerebrospinal fluid (CSF) contamination 
with tumor cells may predispose for leptomeningeal spread.9,29-31,34 Although postoperative SRS 

 
 
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provides excellent local control at the resection cavity, it does not address tumor cells that have 
seeded the CSF. Currently reported rates of leptomeningeal failure after surgery with 
postoperative SRS for brain metastases are in the range of 8 to 24%.33 
 
In 2016, Johnson et al. reported significantly greater incidence of leptomeningeal metastasis with 
surgery followed by SRS in comparison to SRS alone (16.9% vs. 5.2%, p<.01).9 Ma et al. 
published similar findings, reporting a 6.5 times higher odds of leptomeningeal disease in patients 
who were treated with surgical resection prior to SRS.32 A recently published abstract by Prabhu 
et al. describes a “nodular” pattern of leptomeningeal spread associated with surgery followed by 
SRS that is distinct from the classic “sugarcoated” pattern of leptomeningeal carcinomatosis 
described in other settings.29 The authors also reported more favorable survival with the nodular 
pattern and that SRS may be a feasible option for focal treatment of nodular leptomeningeal 
disease.29 Adjuvant WBRT may offset the risk of leptomeningeal disease some degree, although 
this does not address the entire volume of CSF circulation.9,32 
 
1.7 Study Rationale 
 
Given the increased risk of leptomeningeal failure with surgery followed by SRS, as well as the 
risk of radiation necrosis, new paradigms in therapy delivery and sequencing are being 
explored.29,33-35 Areas of investigation include optimization of target volume, marginal expansion, 
multifractionation, timeliness of SRS after surgery, and delivery of SRS prior to surgical 
resection.33,34 In theory, advantages of preoperative SRS include better target delineation, 
sterilization of tumor cells prior to surgical disruption of the tumor, vascular supply, and CSF 
spaces, and resection of tissue that would otherwise be at risk of radiation necrosis.29,34,35  
 
In 2014, Asher et al. reported that the use of neoadjuvant SRS prior to surgery was both safe and 
effective (even for metastases >3 cm) with no reported leptomeningeal recurrences or radiation 
necrosis.34 More recently, Patel et al. performed a retrospective comparison of preoperative 
versus postoperative SRS and reported no difference in local control, distant brain failure, or 
overall survival. Furthermore, the authors reported significantly lower rates of leptomeningeal 
carcinomatosis and radiation necrosis with preoperative SRS.29,36  
 
Huff et al. recently published a protocol for a phase II prospective trial designed to compare 
outcomes using preoperative SRS versus historically cited outcomes for postoperative SRS.28 
Our current pilot study mirrors this design and aims to confirm study feasibility and to assess local 
control, CNS progression-free survival, overall survival, rates of leptomeningeal spread, rates of 
radiation necrosis, and quality of life measures with the use of preoperative SRS.  
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS 
Our hypothesis is that preoperative GK-SRS is feasible and results in greater local control than 
postoperative radiosurgery to the resection cavity. 
2.1 Primary Objectives 
1. To assess feasibility of preoperative GK-SRS in patients with brain metastases treated 
with preoperative GK-SRS.   
2. To assess local control in patients with brain metastases treated with preoperative GK-
SRS.   
 

 
 
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2.2 Secondary Objective(s) 
1. To assess survival (CNS progression-free survival and overall survival) for patients 
undergoing preoperative SRS and surgical resection.  
2. To document rates of leptomeningeal carcinomatosis for patients undergoing preoperative 
SRS and surgical resection.  
3. To record incidence of radiation necrosis in patients undergoing preoperative GK-SRS 
and surgical resection.  
4. To document quality of life measures using preoperative GK-SRS and to compare to 
historically cited rates using postoperative GK-SRS.  
 
2.3 Primary Endpoint 
1. Feasibility for this study will be defined as 50% of enrolled study subjects undergoing the 
surgical resection as per the protocol. 
2. Measure rate of local control at the resection cavity any new tumors by post-treatment 
MRI. 
 
2.4 Secondary Endpoint(s) 
1. CNS progression-free survival and overall survival will be evaluated at six, 12, and 18 
months following surgical resection. 
2. Rates of leptomeningeal carcinomatosis using preoperative GK-SRS will be documented 
and compared to historically cited rates for postoperative GK-SRS.  
3. Incidence of radiation necrosis will be measured by post-treatment MRI. 
4. Quality of life measures will be collected and will be compared to historically cited data. 
3 STUDY DESIGN 
3.1 General Description 
This is a single-arm, single-center, pilot study in which 10 completed patients with one to four 
brain metastases diagnosed on brain MRI within the past 30 days will be evaluated for study 
eligibility and enrolled as appropriate.  
3.2 Design of the Current Study 
Enrolled patients will receive GK-SRS to all metastases followed by surgical resection of 
resectable metastases within one to10 days following GK-SRS. Pathologic specimens will be 
analyzed, and the patient will enter a standard pattern of surveillance (brain MRI every three 
months for two years).  
Quality of life will be assessed every three months, and neurocognitive evaluations will be 
performed every six months. These parameters will be compared to baseline testing performed 
at the time of enrollment. Local control, CNS progression-free survival, overall survival, rates of 
leptomeningeal carcinomatosis, rates of radiation necrosis, and steroid requirements will also be 
documented and compared with historically reported rates. 

 
 
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3.3 Estimated Time for Completion of Study Enrollment 
Approximately two years. 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND 
WITHDRAWAL   
 
MCW must follow all MCW IRB requirements and policies regarding subject participation, found 
here: 
 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
 
4.1 Subject Status 
 
Subject statuses throughout the trial are defined as follows:   
 
x 
Prescreening: pre-consent (subject considering trial or study staff considering patient for 
the trial per institutional recruitment methods). 
x 
Screening: period after consent, but prior to eligibility confirmation. 
x 
Consented: consented, prior to eligibility confirmation. 
x 
Eligible: the local investigator confirms all eligibly criteria apply. 
x 
On study/enrolled: date eligibility is confirmed. 
x 
On arm: date of enrollment. 
x 
On treatment: first day treatment was given to the last day treatment was given. 
x 
Off treatment: the last day treatment was given. 
x 
On follow-up: from last day of treatment to the end of follow-up period. 
x 
Off study: follow-up period completed, with no additional data gathered. 
x 
Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off study by the local principal investigator. 
 
4.2 Prescreening and Screening Log 
 
The MCW study principal investigator regularly reviews screen failure reasons to understand 
barriers to accrual and consider amending eligibility criteria. Screen failures are defined as 
participants who were considered for the trial to participate in the clinical trial with or without 
consent but are not subsequently assigned to the study intervention or enrolled in the study. 
MCWCC CTO will follow its SOPs regarding prescreening and screening tracking. 
 
4.3 Consent  
 
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians, and/or other IRB-approved 
recruitment methods. No study conduct, including subject prescreening, can occur until after IRB 
approval. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 

 
 
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assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
4.4 Screening Procedures 
 
Refer to the study calendar of events. 
Visit procedures that were performed as standard of care prior to consent (without the specific 
intent to make the subject eligible for the trial), may count toward screening tests and eligibility if 
they are within the screening window. 
 
 

Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
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4.5 Eligibility Confirmation 
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
 
No waivers of protocol eligibility will be granted. When clinical factors relating to an eligibility item 
are unclear or questionable, the study PI (Michael Straza, mstraza@mcw.edu) can only provide 
guidance or clarification on eligibility.  
 
Inclusion Criteria 
 
1. Voluntary written consent must be given before performance of any study-related 
procedure that is not part of standard medical care, with the understanding that consent 
may be withdrawn by the subject at any time without prejudice to future medical care. 
2. English speaking. 
3. Female or male subject’s  18 years old at the time of informed consent. 
4. Radiographically confirmed solid tumor brain metastases. 
5. Criteria for surgical resection of at least one metastasis per neurosurgeon discretion. 
6. Stereotactic radiosurgery candidate per radiation oncologist discretion. 
7. A diagnostic MRI brain or CT head demonstrating the presence of one to four solid 
tumor brain metastases and lesion to be resected no more than 5 cm in any direction, 
performed within 30 days prior to stereotactic radiosurgery.  
8. For known and unknown primary, ds-GPA estimated median survival no less than six 
months. 
9. Surgical resection able to be performed within one to 10 days after radiosurgery. 
10. Patients currently on cytotoxic chemotherapy or immunotherapy are eligible, not 
including anti-VEGF therapy. 
11. Female subjects who: 
a. Are postmenopausal for at least one year before the screening visit, OR 
b. Are surgically sterile, OR 
 
If they are of childbearing potential: 
i. 
Agree to practice one highly effective method and one additional effective (barrier) 
method of contraception, at the same time, from the time of signing the informed 
consent through four months after the last study Intervention (female and male 
condoms should not be used together), OR 
ii. 
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)  
 
 
 
CRC Initials: ___________                                                            Date: _______________ 
 
 
 
Investigator/Enrolling Physician Initials: ___________                  Date: _________________ 
 
 
 

Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
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12. Male subjects, even if surgically sterilized (i.e., status post-vasectomy), who: 
a. Agree to practice effective barrier contraception during the entire study treatment 
period from the time of signing the informed consent through and through four 
months after the last study intervention (female and male condoms should not be 
used together), OR 
b. Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, postovulation methods for the female partner] withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception.) 
 
Exclusion Criteria 
 
1. Patients who received anti-VEGF therapy within six weeks prior to enrollment, as there is 
increased risk of fatal brain hemorrhage with surgical resection. 
2. Non-English speaking. 
3. 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 
surveillance. 
4. Patients with more than four brain metastases on MRI brain. 
5. Lesion to be resected is more than 5 cm in any dimension. 
6. Patients with leptomeningeal metastases documented by MRI or CSF evaluation. 
7. Previous whole-brain radiation therapy. 
8. Previous radiation therapy to the lesion to be resected. 
9. Planned adjuvant focal therapy including additional radiation therapy to the brain. 
10. Not a surgical candidate per neurosurgeon discretion. 
11. Not a stereotactic radiosurgery candidate per radiation oncologist discretion. 
12. Surgery unable to be performed between one to 10 days after radiosurgery. 
13. Women who are pregnant or nursing as treatment involves unforeseeable risks to the fetus 
or child. 
14. Patients who have a known or unknown primary and have an estimated median survival 
of less than six months per ds-GPA. 
 
 
 
 
 
“I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible.” 
 
 
_______________________________________         
          _______________ 
                   (CRC Signature)                                                          
     (Date) 
 
 
 
_____________________________________         
 
 
_______________ 
(Investigator/Enrolling Physician Signature)                                           (Date)

 
 
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4.6 Discontinuation of Study Treatment, Withdrawal, and Compliance 
Discontinuation from the study treatment does not mean discontinuation from the study. Subject 
will be considered in follow-up; study procedures should still be completed as indicated by the 
study protocol and AEs/SAEs will continue to be reported according to this protocol. 
 
In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
x 
Disease progression.  
x 
General or specific changes in the subject’s condition renders the subject 
unacceptable for further treatment in the investigator’s judgment.  
x 
Intercurrent illness that prevents further treatment administration. 
x 
Subject decides to withdraw from the study.  
x 
The subject has significant noncompliance with the protocol (see below).   
x 
Unacceptable adverse event(s) and/or dose level reduction beyond requirements as 
detailed in this protocol.  
x 
Study stopping rules are met. 
 
Subjects who sign the informed consent form, and are enrolled and receive the study intervention, 
but subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced. 
 
Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow its IRB of 
record’s SOPs regarding consent withdrawal.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
x 
Full consent withdrawal with no study follow-up. 
x 
Selective consent withdrawal from interventional portion of the study but agree to 
continued follow-up of associated clinical outcome information. 
 
Investigator-initiated Withdrawal 
 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject’s request to 
end participation, a subject’s noncompliance or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
 
 
4.7 Lost to Follow-up 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit and/or is unable to be reached for follow-up: 
 

 
 
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x 
The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
x 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
o Three telephone calls (at least one day apart) from the study team are unanswered  
AND  
o A letter to the participant’s last known mailing address goes unanswered (refer to 
Appendix 2). 
AND 
o These contact attempts must be documented in the participant’s medical record or 
study file.  
x 
Update OnCore® (follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
x 
If a subject is considered lost to follow-up, but subsequently contacts the participating site 
study team, the subject should be considered in follow-up again. 
 
4.8 Accrual Suspension and Closure 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
x 
OnCore® tracks accrual throughout the study. 
x 
If the study must be suspended, OnCore® is updated to a “suspended” status. 
x 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.9 End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the calendar of events 
or has been discontinued. 
 
4.10 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW study principal investigator, DSMC, sponsor, 
and/or IRB). Written notification, documenting the reason for study suspension or termination, will 
be provided by the suspending or terminating party to study participants, investigator, funding 
agency, and regulatory authorities. If the study is prematurely terminated or suspended, the MCW 
principal investigator (PI) will promptly inform the MCW Institutional Review Board (IRB) and 
sponsor and will provide the reason(s) for the termination or suspension. Study participants will 
be contacted, as applicable, and be informed of changes. 
 
 
 

 
 
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5 TREATMENT PLAN 
5.1 Intervention Description 
Guidelines for treatment based on tumor diameter (in cm) 
Maximum Tumor Diameter 
Prescribed Dose 
 2 cm 
20–24 Gy 
2.1–3.0 cm 
18 Gy 
3.1–5.0 cm 
15 Gy 
 
SRS followed by surgery within one to 10 days. 
x 
A typical SRS dose of 20 Gy applied to one to four brain metastases provides 
local control of approximately 90%.  
x 
15 Gy to 18 Gy = threefold increase in local failure compared to 24 Gy. 
 
5.1.1 Stereotactic Radiosurgery 
  
SRS will be delivered utilizing Gamma Knife®. Target volume and isocenter determination will be 
based on a brain MRI with the patient’s head in the stereotactic frame or face mask. SRS will be 
delivered to each lesion that has not previously undergone treatment. Due to the volumetric 
summation constraint for the remaining metastases, no single, non-resected lesion greater than 
5 cm will be allowed in the study. 
If any two lesions are within 0.8 to 2 cm of each other, the intervening midplane dose will not 
exceed 15 Gy. This may require treating each respective target with a lesser dose than dictated 
by the above dosing criteria to minimize toxicity. The dose to the critical structures, including optic 
pathway, brainstem, cochlea, and medulla, must meet constraints as determined by the radiation 
oncologist.  If the above constraints cannot be met utilizing the prescribed radiosurgery dose, then 
the highest dose to the target volume will be used such that constraints can be met. This will be 
considered a minor deviation. 
Possible Side Effects Related to Stereotactic Radiosurgery (SRS) 
 
Common, Some May Be Serious 
In 100 people receiving SRS, more than 20 and up to 100 may have: 
Temporary (short-term) pain from with the head frame placement (if a head frame is used). 
 
Occasional, Some May Be Serious 
In 100 people receiving SRS, from four to 20 may have: 
x 
Headache 
x 
Localized hair loss which may be permanent  
x 
Nausea 

 
 
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x 
Vomiting 
x 
Allergic reaction to the local anesthesia (rash, itching, nausea, or difficulty breathing)  
x 
Bleeding and/or infection around the head frame (if a head frame is used) 
x 
Swelling of the brain in the treated area which may require treatment with steroids 
x 
Severe local damage to or death of normal brain tissue, which may require surgery to 
remove 
 
Rare and Serious 
x 
In 100 people receiving SRS, three or fewer may have: 
x 
Decreased brain function such as motor function (coordination/movement) 
x 
Hardening of the arteries in the brain which rarely may lead to strokes many years after 
stereotactic radiosurgery 
x 
A second new cancer caused by radiation, in the brain or nearby organs which rarely may 
occur many years after stereotactic radiosurgery 
x 
Damage to vision tracts (eye damage) with the possibility of permanent blindness 
 
Long-term effects of the radiation or radiosurgery used in this study include an increased risk of 
developing other cancers. 
 
5.1.2 Surgical Resection 
At least one of the four lesions must be either larger than 3 cm or symptomatic to meet the surgical 
resection criteria. One to 10 days after radiosurgery, the dominant lesion(s) will be maximally 
resected and labeled tissue will be sent to the neuropathology department for clinical diagnosis 
and radiobiological correlative studies. If for safety concern or other considerations, gross total 
resection is not reached, the residual disease in the setting of subtotal resection will be closely 
observed given that it has been treated with a definitive dose of SRS, reserving salvage local 
therapy for cases of progression.  
 
Possible Side Effects Related to Surgical Resection 
 
Common, Some May Be Serious 
In 100 people receiving neurosurgery 20 to up to 90 patients may have: 
x 
Pain 
x 
Headache 
x 
Nausea 
x 
Vomiting 
 
Occasional, Some May Be Serious 
In 100 people receiving neurosurgery, 15 to up to 20 patients may have: 
x 
Bleeding 
x 
Infection 
 
Rare and Serious 
In 100 people receiving neurosurgery, less than five patients may have: 
x 
Stroke 
x 
Permanent injury, i.e., arms and legs not functioning properly, issues with speech 
x 
Complications from anesthesia, i.e., heart or lung problems 
 

 
 
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6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING 
REQUIREMENTS 
 
6.1 Definitions 
 
6.1.1 Adverse Event 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonisation [ICH], E2A, E6). 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0, located on the CTEP web site: 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures. 
 
6.1.2 Serious Adverse Event (SAE)  
 
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
x 
Death. Results in death. 
x 
Life-threatening. Is life-threatening (refers to an AE 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). 
x 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
x 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
x 
Pregnancy 
x 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
 

 
 
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6.1.3 Attribution of an Adverse Event 
An assessment of the relationship between the adverse event and the medical intervention, using 
the following categories:  
 
Definitely Related: The AE is clearly related to the intervention. There is clear evidence to 
suggest a causal relationship, and other possible contributing factors can be ruled out.  
 
Probably Related: The AE is likely related to the intervention. There is evidence to suggest a 
causal relationship, and the influence of other factors is unlikely.  
 
Possibly Related: The AE may be related to the intervention. There is some evidence to suggest 
a causal relationship (e.g., the event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have contributed to the event (e.g., 
the subject’s clinical condition, other concomitant events).  
 
Unlikely: The AE is doubtfully related to the intervention. A clinical event, including an abnormal 
laboratory test result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after administration 
of the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant treatments).  
 
Unrelated: The AE is clearly NOT related to the intervention. The AE is completely independent 
of study drug administration, and/or evidence exists that the event is definitely related to another 
etiology.  
 
6.1.4 Expectedness of an Adverse Event 
 
Study investigator or treating physician will be responsible for determining whether an AE is 
expected or unexpected as indicated in the protocol, informed consent form and/or drug 
information brochure. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is NOT consistent with the risk information previously described for the study 
intervention. 
 
6.2 Collection and Reporting Requirements for Adverse Events and Serious Adverse   
      Events 
 
6.2.1 Collection of Adverse Events 
 
All grade 3, 4, and 5 adverse events (including all SAEs) must be recorded in OnCore® and/or an 
adverse event log. All AEs required to be collected must be graded according to the CTCAE v5. 
When possible, signs and symptoms indicating a common underlying pathology should be noted 
as one comprehensive event. Investigator’s or treating physician’s assessment of AE attributions 
must also be documented.  
 
AEs will be collected from the time the subject signs the consent form through 30 days post last 
dose of study drug(s). AEs will be tracked and followed until resolution, subject withdraws 
consent, or is lost to follow-up (including subjects who discontinue early). All adverse events 
collected per the protocol will be followed with appropriate medical management until they are 
resolved, if they are related to the study treatment, or until the investigator deems the event to be 
chronic.  

 
 
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Please see section 6.2.2 and table 2 to identify the adverse events that need to be reported.  
 
 
6.2.2 Reporting of Adverse Events and Serious Adverse Events 
 
Please refer to table 2 below to identify adverse events that meet reporting requirements.  
 
All serious adverse events (SAEs) that occur after the subject has signed the consent form 
through 30 days post last dose of study drug(s) will be reported. All SAEs will be followed until 
satisfactory resolution, or until the investigator deems the event to be chronic. 
 
All serious adverse events (SAEs) must also be documented in OnCore®. 
 
Table 2 
 
1. Guidance on Adverse Event Reporting to the IRB is available online at MCW IRB Policies 
and Procedures.  
2. For expedited DSMC reporting, study coordinator/research nurse must notify the DSMC via 
email including the subject ID, date of event, grade, relatedness, expectedness, and a short 
narrative. DSMC will review data entered into OnCore®.  
3. For routine reporting, the events will be reported to IRB as part of the annual continuing 
progress report and the DSMC will review data entered into OnCore® at the time of scheduled 
monitoring. 
 
6.3 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website.  
 
 
Attribution 
SAE 
AE 
Grade 1, 2 & 3 
Grade 4 and 5 
Grade 3 
Grade 4  
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 
Unrelated 
Unlikely 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
DSMC2- 
Routine 
Review3 
 
DSMC2- 
Within 5 
calendar 
days 
DSMC2- 
Within 5 
calendar 
days 
 
Possible 
Probable 
Definite 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 

 
 
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6.4 Subject Complaints 
 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
 
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can call the 
Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. 
This information is provided to the subject in their consent.  
 
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who identify 
a potential product complaint situation should immediately contact the drug manufacturer and 
report the event. Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a drug manufacturer representative. 
Product complaints in and of themselves are not reportable events. If a product complaint results 
in an SAE, an SAE form should be completed. 
7 STATISTICAL CONSIDERATIONS 
7.1 Power Calculations 
The primary objective of this study is to demonstrate feasibility. With about 10 patients, assuming 
a local control of rate of 85% (in line with observed local control rates in the literature in 2014, 
Asher et al. and 2016, Patel et al.), 34,36 we will be able to estimate a 95% confidence interval with 
width not exceeding 0.40, that is about 47% of the assumed 85% local control rate. 
 
7.2 Methodology of comparisons between groups 
Descriptive statistics, including means, medians, and ranges will be reported wherever 
appropriate. For the primary hypothesis, the estimated rates of local control and its 95% 
confidence interval using an exact binomial method will be computed. For the secondary 
objectives, appropriate Kaplan Meier progression-free survival estimates will be computed.  
 
All calculations will be performed using the SAS and the R language for statistical computing. 
Unless explicitly mentioned, all analysis will use a type I error rate of 0.05 and 95% confidence 
intervals. 
 
7.3 Missing data and interim stopping 
If patients do not complete the follow-up period, patients will be considered lost to attrition and 
their data will not be used for the primary or secondary objectives, except possibly for 
demographic descriptions. No missing data imputation or specific analysis is planned for this 
study. Since the primary objectives of this study are to study feasibility rather than evaluate 
efficacy or futility – early stopping is not meaningful in the present context. No stopping rules or 
interim evaluations are planned for this study. 

 
 
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8 DATA AND SAFETY MONITORING PLAN (DSMP) 
Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data and Safety Monitoring Committee (DSMC) and 
the MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal investigator 
of the study with safety and progress reports submitted to the DSMC.  
The DSMP for this study will involve the following entities: 
8.1 Study Team 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist and the study biostatistician. While subjects are on study, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to review 
study status. This review will include but not be limited to reportable SAEs and UPIRSOs and an 
update of the ongoing study summary that describes study progress in terms of the study schema. 
The appropriateness of further subject enrollment and the specific intervention for a next subject 
enrollment is addressed. All meetings, including attendance, are documented.  
8.2 Quality Assurance  
This protocol was classified as high risk and will be reviewed internally by the MCW Cancer Center 
Clinical Trials Office Quality Assurance Staff according to the MCWCC Data and Safety 
Monitoring Plan and current version SOP, 6.5.2 Internal Quality Assurance Reviews. 
 
8.3 Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
8.4 DSMC 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at MCW 
includes a plan for safety and data monitoring. 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
 
Review the clinical trial for data integrity and safety.  
 
Review all DSM reports.  
 
Submit a summary of any recommendations related to study conduct.  
 
Terminate the study if deemed unsafe for patients.  
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained 
in the study research file and updated as membership changes. The committee will review reports 

 
 
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from the study PI twice annually (review frequency may change based on study risk per DSMC 
discretion) and provide recommendations on trial continuation, suspension or termination, as 
necessary.  
Any available DSMC letters will be submitted to the IRB of record as required. 
9 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
9.1 Ethical Standard 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
9.2 Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
9.3 Prestudy Documentation 
Prior to implementing this protocol at MCWCC, the protocol, informed consent form and any 
other information pertaining to participants must be approved by the MCW IRB.  
9.4 Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the MCW Institutional Review Board. Prior to obtaining MCW approval, the protocol must be 
approved by the Medical College of Wisconsin Cancer Center Scientific Review Committee. The 
initial protocol and all protocol amendments must be approved by the IRB prior to implementation.  
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 

 
 
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Potential subjects will be told, and a statement will be included that this study is designed to 
determine both safety and effectiveness. The consent forms will include the approved MCW IRB 
template language. 
Consent forms will be IRB approved and the subject (and legally authorized representative, if 
necessary) will be asked to read and review the document. The treating physician or the 
investigator will explain the research study to the subject and answer any questions that may 
arise. The study coordinator may complete the consenting process. In accordance with 46 CR 
46.111, the subject will sign and date the informed consent document prior to any procedures 
being done specifically for the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (i.e., “Although not required, the 
subject’s spouse was present during the consenting process and signed as the witness.” Or 
“Although not required, hospital staff was present for consenting process and signed as a 
witness.”) 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Patients who require reconsenting will be defined in the IRB-approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. The MCWCC CTO will follow the 
MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency or limited literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent 
was given to the subject. The original consent is kept with the subject’s study file, and a copy of 
the consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed 
consent to be scanned into EPIC, the legal medical record. 
9.5 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, and the sponsor. This confidentiality includes the clinical information 
relating to participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator. 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects.  

 
 
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One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the information 
and keep it confidential, but it is possible that an unauthorized person might see it. Depending on 
the kind of information being collected, it might be used in a way that could embarrass the subject 
or affect his/her ability to get insurance. 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject’s data/PHI are stored in the locked clinical research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the case report forms contain the study identifiers, subject initials, date of birth and date of 
service.  
Personal identifiers, such as name and medical record number, will be removed from 
accompanying lab reports and test results. Any data/PHI that are not stored for the purposes of 
the study are shredded in the Clinical Trials Office. 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site in order to keep an accurate record of screened and 
enrolled subjects for the sponsor and potential audit purposes only specific for this study.  
9.6 Protection of Human Subjects 
9.6.1 Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject’s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately 
and clearly communicates the nature of the research to be done and its associated risks and 
benefits. 
9.6.2 Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be asked to sign informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed document.  
9.7 Changes in the Protocol 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
investigator must then notify the IRB in writing within five working days after implementation.  

 
 
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The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
9.8 Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
10 DATA HANDLING AND RECORD KEEPING 
10.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data is 
protected from physical damage as well as from tampering, loss or theft. This project’s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
10.2 Data Management Responsibilities 
10.2.1 Principal Investigator 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication and investigational 
product(s), measurements, exams, evaluations and adverse events; c) corrections are applied to 
clinical research data according to principles of good research practice (i.e., single-line delete, 
date and initial). He or she will ensure that there is correlation between the case report forms and 
the source documents.  
10.2.2 Research Coordinator  
A research coordinator creates, collects and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
 
10.2.3 Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events and compliance to study procedures. 
10.2.4 Biostatistician 

 
 
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The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
10.3 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test 
reports, etc.) are maintained in the patient’s clinical file.  
All source documents will be written following ALCOA standards:  
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when made, 
chronology should be recorded. Acceptable amount of delay 
should be defined and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
10.4 Case Report Forms 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific case report forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs, 
in accordance with the study calendar, using single data entry with a secure access account. The 
clinical research coordinator will complete the CRFs as soon as possible upon completion of the 
study visit; the investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 

 
 
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approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
10.5 Study Record Retention 
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on everyone 
administered the investigational intervention or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed and 
dated consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 

 
 
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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
predisease performance without 
restriction 
100 
Normal, no complaints; no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
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 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self but unable to carry on 
normal activity or to do active work 
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 
Requires occasional assistance but 
is able to care for most of personal 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
Capable of only limited self-
care; confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled; requires special care and 
assistance 
30 
Severely disabled; hospitalization 
indicated although death not 
imminent 
4 
Completely disabled; 
cannot carry on any selfcare;  
totally confined to bed or chair 
20 
Very ill; hospitalization indicated 
Although death not imminent 
10 
Moribund 
5 
Dead 
0 
Dead 
 
 
 

 
 
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APPENDIX 2. LOST TO FOLLOW-UP LETTER 
 
Date: ___________________________________ 
 
 
Dear ___________________________________, 
 
 
The research study team has been unable to contact you regarding the clinical trial (A Pilot Study 
Analyzing Pre-Operative Stereotactic Radiosurgery (SRS) With Gamma Knifeט (GK) IconTM for 
Brain Metastases) in which you participated. 
 
We would like to discuss how you are doing and if we may continue contacting you. 
 
 
 
Please contact us at 
_____________________________________________________________ 
 
 
Sincerely, 
 
 
___________________________________ 
 
 
 
 
 

 
 
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APPENDIX 3. RESPONSE CRITERIA FOR CNS METASTASES 
PROPOSED BY RANO-BM37 
 
 
Complete 
Response 
Partial response 
Stable disease 
Progressive 
disease 
Target lesions 
None 
30% decrease 
in sum longest 
distance relative 
to baseline 
<30% decrease 
relative to baseline 
but <20% increase 
in sum longest 
distance relative to 
nadir 
20% increase in 
sum longest 
distance relative to 
nadir* 
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 does 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 con¿rm there is de¿nitely 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 to 
do not de¿ne progression. 
 
 ‡Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration. 
 

 
 
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