Utility of PET/MR in Assessing Response to Neoadjuvant Radiation Therapy in the Treatment of High Grade Sarcomas
Phase: NA
Conditions: Sarcoma
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER  
CLINICAL ONCOLOGY RESEARCH PROGRAM  
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC XXXX: Utility of PET/MR in Assessing Response to Neoadjuvant Radiation 
Therapy in the Treatment of High Grade Sarcomas 
 
Principal Investigator  
David S. Lalush, PhD  
Department of Biomedical Engineering 
CB #7575, 152 MacNider Hall 
Chapel Hill, NC 27599-7575 
 (919) 513-7671 (PHONE) 
(919) 513-3814 (FAX) 
Email: dlalush@email.unc.edu 
 
Co-Investigator(s) 
Hong-Jin Kim, M.D., Surgery 
Shachar Laks, M.D., Surgery 
Jacqueline Carr, M.D., Surgery 
Joel Tepper, M.D., Radiation Oncology  
Robert Esther, M.D., Orthopaedics  
Terence Wong, M.D., Ph.D., Radiology 
Daniel Nissman, M.D., Radiology 
Leslie Dodd, M.D., Pathology and Laboratory Medicine 
 
Biostatistician 
Naim Rashid, Ph.D. 
Lineberger Comprehensive Cancer Center, Rm 20-016 
CB #7295 
Chapel Hill, NC 27599-7295 
Phone: (919) 966-8150 
Email: naim@unc.edu 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: UNC TRACS Institute 
 
Version Date: 6/20/2016 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
LCCC XXXX: Utility of PET/MR in Assessing Response to Neoadjuvant Radiation 
Therapy in the Treatment of High Grade Sarcomas 
 
 
Principal Investigator  
David S. Lalush, PhD  
Department of Biomedical Engineering 
CB #7575, 152 MacNider Hall 
Chapel Hill, NC 27599-7575 
 (919) 513-7671 (PHONE) 
(919) 513-3814 (FAX) 
Email: dlalush@email.unc.edu 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Principal Investigator (PI) Name: David S. Lalush, PhD 
 
 
PI Signature:   
 
 
Date: 07/05/2016 
 
 
 
 
Version Date: 6/20/2016 
 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ...................................................................1 
1.2 
Background ...........................................................................................................1 
1.3 
Purpose and Rationale ...........................................................................................3 
2.0 
STUDY OBJECTIVES/AIMS AND ENDPOINTS .............................................4 
2.1 
Primary objective ..................................................................................................4 
2.2 
Primary Endpoint ..................................................................................................4 
3.0 
PATIENT ELIGIBILITY ......................................................................................4 
3.1 
Inclusion Criteria ...................................................................................................4 
3.2 
Exclusion Criteria ..................................................................................................5 
4.0 
STUDY PLAN .........................................................................................................6 
4.1 
Schema ..................................................................................................................6 
4.2 
Patient Identification and Consent .........................................................................6 
4.3 
FDG-PET-MRI ......................................................................................................7 
4.4 
Removal of Patients from Protocol .......................................................................8 
4.5 
Abstraction of Medical Records ............................................................................8 
5.0 
TIME AND EVENTS TABLE ...............................................................................9 
5.1 
Time and Events Table ..........................................................................................9 
6.0 
EXPECTED RISKS/UNANTICIPATED PROBLEMS ......................................9 
6.1 
Assessment of Safety .............................................................................................9 
6.2 
Expected Risks ......................................................................................................9 
6.3 
Unanticipated Problems .......................................................................................10 

LCCC XXXX 
PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
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7.0 
STATISTICAL CONSIDERATIONS .................................................................10 
8.0 
STUDY MANAGEMENT ....................................................................................13 
8.1 
Institutional Review Board (IRB) Approval and Consent ...................................13 
8.2 
Required Documentation .....................................................................................13 
8.3 
Registration Procedures .......................................................................................13 
8.4 
Adherence to the Protocol ...................................................................................14 
8.5 
Amendments to the Protocol ...............................................................................15 
8.6 
Record Retention .................................................................................................15 
8.7 
Obligations of Investigators .................................................................................16 
9.0 
REFERENCES ......................................................................................................17 
 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Study Synopsis 
The purpose of the study is to assess the utility of combined, simultaneous positron 
emission tomography (PET) and magnetic resonance imaging (MRI), collectively 
called PET-MR, in assessing response to neoadjuvant radiation therapy in the 
treatment of high grade sarcomas. Adult patients with potentially curable high 
grade sarcomas that are being treated at UNC with neoadjuvant radiation therapy 
followed by potentially curative surgical resection will be recruited through the 
Department of Surgery.  Patients who are being treated for potentially curable high 
grade sarcomas with neoadjuvant radiation therapy followed by surgical 
resection will undergo pre-treatment, mid-treatment, and post-treatment PET/MR 
and the response to treatment will be assessed at mid-treatment and post-treatment 
time points by evaluating change in tumor size from MRI and 18F-
fluorodeoxyglucose (18F-FDG) avidity from PET.   Patients will then undergo 
curative intent resection.  Their pathology will be reviewed for treatment effect as 
assessed by percent necrosis, size, and resection margins. Patients will be 
followed and assessed for recurrence. 
 
This study is designed to provide preliminary information on the progression of 
tumor size and FDG avidity during and after treatment in 30 patients diagnosed with 
potentially curable high-grade sarcomas. The primary objective is to evaluate the 
capabilities of PET and MRI, individually and combined, in early prediction of 
patients who will and will not respond to neoadjuvant radiation therapy.  A 
secondary objective will be to quantify the progression of PET- and MRI-based 
metrics at pre-, mid-, and post-treatment time points.  
 
Information from this study may be used to estimate effect size for power 
calculation and sample size considerations for possible future studies in the use of 
combined PET-MR to predict, at a mid-treatment time point, which sarcoma patients 
will respond to, and therefore continue with, neoadjuvant radiation therapy, and 
which patients will not respond and should be spared additional time and radiation 
dose before proceeding to surgery. 
 
1.2 
Background 
The only curative treatment for non-metastatic sarcomas is complete surgical 
resection.  Nonetheless, most patients who undergo curative intent surgery will have 
positive gross or microscopic margins.  Of those who are treated with complete 
resections, a large proportion will recur locally.  Radiation has been shown to 
improve the rate of complete resection, and improve local control rates. Neoadjuvant 
radiation has even been shown to improve 3 year overall survival in high grade 
extremity sarcomas. The utility of radiation in the treatment of sarcomas has been 
shown in multiple studies.  Still, utilization of adjuvant and neoadjuvant radiation in 
the United States remains low.  This is partially related to the large discrepancy 
within subtypes of sarcomas and varied response to radiation among different grades 
of sarcoma within the same subtype.  The underutilization of neoadjuvant radiation 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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is also partly in due to some controversy about which patients should undergo 
neoadjuvant radiation as opposed to adjuvant radiation versus no radiation at all. 
  
PET/CT and MRI are two modalities that are utilized in the diagnosis, treatment, and 
follow up of extremity soft tissue and retroperitoneal sarcomas.  PET activity has 
been shown to correspond with treatment response in many tumor types. MR has a 
specific advantage in imaging of soft tissues which is especially important in 
extremity and retroperitoneal sarcomas.  An integrated PET/MR system has the 
potential benefit of reducing patient time, and expenditures, as well as avoiding the 
ionizing radiation associated with CT.  Further the integrated system has the potential 
for greater anatomical detail in the context of FDG activity.  The University of North 
Carolina leads in the utilization of neoadjuvant radiation for sarcoma and has one of 
the few combined PET-MR imaging systems in the US. 
  
There exists a need to identify those patients with high grade sarcomas who will 
benefit from neoadjuvant radiation therapy.  This will enable us to focus our 
resources on delivering effective radiation therapy to those patients who will benefit 
from them and minimize the associated risks and consequences of radiation in those 
patients who will not benefit from them and allow those patients to move quickly to 
curative intent surgery. 
 
1.3 
Purpose and Rationale 
This is a prospective study of the use of combined PET-MR [1-7] for assessment 
of response to neoadjuvant radiation therapy in high-grade sarcomas.  There are no 
prior studies evaluating combined, simultaneous PET-MR for this purpose, 
although studies indicate that PET, at a mid-treatment time point, is predictive of 
response to neoadjuvant chemotherapy in sarcomas [8] and that PET and MRI, 
acquired separately, are correlated with response to neoadjuvant chemotherapy at 
a post-treatment time point [9].  These studies suggest our guiding hypothesis: that 
simultaneous PET and MRI, acquired at a mid-treatment time point, provide 
image-based quantitative measures that are associated with and predict response 
to neoadjuvant radiation therapy in high-grade sarcomas.  If so, in the future, 
application of PET-MRI at mid-treatment may be used to determine the course of 
treatment for patients at this stage, whether to continue neoadjuvant therapy, or to 
spare time, expense, and radiation dose for nonresponders. 
 
We propose that a PET/MR study at the midpoint of radiation treatment will 
accurately predict which patients will respond to neoadjuvant radiation 
therapy.  We will enroll patients with high-grade sarcomas as identified by 
preoperative biopsy that will be treated with neoadjuvant radiation into the 
study.  The standard of care for these patients is to receive MRI scans at pre-
treatment and post-treatment time points.  Patients in our study will receive their 
standard pre- and post-treatment imaging in the form of PET/MR, with PET 
conducted simultaneously with MRI, and within the context of the study they will 
also receive one additional PET/MR at the end of the second week of 
therapy.  These patients will then receive curative intent surgery and be followed 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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in the usual fashion and assessed for local and/or distant recurrent disease.  The 
pathology will be assessed for completeness of resection and percent of necrosis.  
On the basis of pathology, patients will be classified as responsive or non-
responsive to therapy.  Quantitative measures from PET and MRI will be 
computed: the change in PET tumor-mean standardized uptake value (SUV) and 
tumor size as assessed by MRI, from pre- to post-treatment, and from pre- to mid-
treatment.  The image-based quantitative measures will be correlated with the 
pathology outcomes to evaluate predictability of the image measures for treatment 
response.  Patients will be followed with the intent of further correlating image 
measures with clinical outcomes.  
 
2.0 
STUDY OBJECTIVES/AIMS AND ENDPOINTS 
2.1 
Primary objectives 
2.1.1 Determine whether there is a significant difference between response groups in 
PET mean SUV fractional change (baseline to mid-treatment). 
 
 
2.2 
Secondary objectives 
 
2.2.1 Determine whether there is a significant difference between response groups in 
MRI tumor size fractional change (baseline to mid-treatment). 
2.2.2 Determine whether there is a significant difference between response groups in 
PET mean SUV fractional change (baseline to post-treatment). 
2.2.3 Determine whether there is a significant difference between response groups in 
MRI tumor size fractional change (baseline to post-treatment). 
 
2.2.4 Assess the correlation in PET mean SUV change and MRI tumor size change 
from baseline to mid-treatment, in addition to baseline to post-treatment. 
 
 
2.3 
Exploratory Objectives 
 
2.3.1 To assess the utility of combined, simultaneous positron emission tomography 
(PET mean SUV) and magnetic resonance imaging (MRI tumor size), in early 
prediction of response to neoadjuvant radiation therapy in the treatment of 
high-grade sarcomas at mid-treatment and post-treatment. 
 
2.3.2 Examine the utility of using maximal SUV in place of mean SUV in prediction 
of response 
 
 

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PI: David Lalush, PhD  
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3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subject must meet all of the inclusion criteria to participate in this study: 
 
3.1.1 Age ≥ 18 years of age (no upper age limit) 
 
3.1.2 Signed, IRB-approved written informed consent 
3.1.3 Must have a biopsy-proven high-grade retroperitoneal or soft tissue extremity 
sarcoma confirmed by independent evaluation of a UNC sarcoma specialized 
pathologist. 
 
3.1.4 Must have surgically curable disease as evaluated by initial imaging by our UNC 
surgeons. 
3.1.5 Must be in acceptable health to undergo radiation therapy and curative intent 
surgery as assessed by UNC surgeons and radiation oncologist. 
3.1.6 Must be able to understand and comply with study procedures for the entire length 
of the study. 
3.1.7 Must receive their neoadjuvant radiation therapy and curative intent surgery at UNC 
Hospitals – Chapel Hill location.  
3.1.8 Women of childbearing potential must have a negative serum or urine pregnancy 
test performed within 7 days prior to first PET/MRI 
 
3.2 
Exclusion Criteria 
Any subject meeting any of the following exclusion criteria at baseline will be 
ineligible for study participation: 
 
3.2.1 Inability to tolerate MRI (e.g., inability to lie flat for >1 hour) 
 
3.2.2 Presence of pacemaker, intracranial aneurysm clip, bladder stimulator, cochlear 
implant or metal near eyes or near pelvis that would create excessive imaging 
artifact 
 
3.2.3 Poorly controlled diabetes mellitus 
 
3.2.4 Creatinine > 1.4 mg/dL OR GFR < 30mL/min 
 
3.2.5 Body Mass Index (BMI) > 35 
 
3.2.6 Active vaginal bleeding requiring packing and emergent radiation therapy 
 
3.2.7 Pregnancy or lactating female 
 
3.2.8 History of a prior malignancy within past 5 years are excluded unless they have 
been disease free for 3 or more years 
 
3.2.9 Substance abuse, medical, psychological, or social conditions that may interfere 
with the patient’s participation in the study 

LCCC XXXX 
PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
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3.2.10 Evidence of distant disease on physical exam or initial imaging 
3.2.11 Medical conditions precluding radiation therapy or curative intent surgery 
3.2.12 Previous radiation exposure precluding radiation therapy 
3.2.13 Incarcerated or otherwise institutionalized at time of enrollment 
 
4.0 
STUDY PLAN 
4.1 
Schema 
 
 
 
4.2 
Patient Identification and Consent 
Patients will be identified at the clinics of the surgical oncologists, orthopedic 
oncologists, radiation oncologists, and sarcoma multi-disciplinary conference at 
UNC.  Once identified the patients will be recruited and addressed at the clinics of 
the surgical oncologists, orthopedic oncologists, and/or radiation oncologists at 
UNC.  The recruitment will take place in the privacy of the UNC clinics in private 
rooms and guided by the subject’s treating physicians. Enrollment and informed 
consent will be facilitated by a study coordinator.  Patients will then proceed to 
treatment as determined by the multidisciplinary tumor board. 
 
4.3 
Blood Draw for Creatinine 
If subjects do not have a serum creatinine value within 30 days prior to a 
scheduled FDG-PET-MRI scan, they will be required to have a blood draw at 
UNC Hospitals for creatinine before their FDG-PET-MRI scan visit. 
 
4.4 
FDG-PET-MRI 
All patients will undergo a gadolinium enhanced MRI with simultaneous 
acquisition of [18F] Fludeoxyglucose Positron Emission Tomography (FDG F18- 
PET) at the three time points noted.  18F-FDG is a 
positron-emitting 
radiopharmaceutical used for diagnostic purposes.  It is a glucose analog that 
concentrates in cells relying upon glucose as an energy source 
or in cells whose reliance on glucose increases under pathophysiological 
conditions.  Diabetic patients may need stabilization of blood glucose levels on 
the day before and on the day of administration of FDG F18. 
 
Injection of gadolinium contrast agent will be performed in the usual manner and 
images simultaneously obtained with MRI.  Patients will have fasted for at least 6 
hours before intravenous injection of FDG.  To minimize radiation-absorbed dose 
to the bladder, patients should drink at least an 8 ounce glass of water prior to drug 

LCCC XXXX 
PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
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administration. Whenever possible, patients should take the following precautions 
for 12 hours after injection: used toilets should be flushed several times after each 
use, and hands should be washed thoroughly.  If blood, urine or feces soil clothing, 
the clothing should be washed separately. 
 
Each patient will be imaged at three time points as noted. For each visit, patients 
will be scheduled for PET-MRI imaging at Marsico Hall and will receive imaging-
day instructions from the study coordinator.  The study coordinator will meet the 
patient at the imaging facility and escort them to the imaging suite.  Women of 
childbearing potential will undergo repeat urine pregnancy test within 7 days prior 
to each PET/MRI. 
 
Patients will be paid $50 each as compensation for their time. 
 
4.5 
Duration of Study Intervention 
The study intervention is complete once the patient receives their last (8 weeks 
post-treatment) PET-MRI scan. The patient may be withdrawn from the study 
prior to this point if any of the following apply: 
 
• Inter-current illness prevents completion of imaging studies 
• Unacceptable adverse event(s) prevents completion of imaging studies 
• Patient decides to withdraw from the study, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for completion of study in the judgment of the 
investigator. 
 
4.6 
Duration of Follow Up 
Patients will be followed up via review of their medical records through disease 
recurrence or survival for up to 5 years. 
 
4.7 
Removal of Patients from Protocol 
Patients may be removed if they experience unanticipated claustrophobia causing 
intolerance to the MR. If patients require lorazepam in order to tolerate the MR, 
they will be withdrawn from study participation. 
 
4.8 
Abstraction of Medical Records 
De-identified records will be reviewed and data extracted for clinical outcomes. 
Treatment response will be documented based on pathology results, as well as 
any information on recurrence and survival.  Information collected may help to 
establish preliminary data for future studies. 
 
5.0 
TIME AND EVENTS TABLE 
5.1 
Time and Events Table 
 
Baseline Treatment Mid-
Treatment Post-
Surgery 
Pathology 
Long-

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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0 weeks 
+0 to +2 
weeks 
treatment 
+2 weeks 
+2 to +4 
weeks 
treatment 
+8 weeks 
+8 to 
+10 
weeks 
+10 to 
+12 
weeks 
term 
follow-
up2 
>+12 
weeks 
Screening 
 
 
 
 
 
 
 
 
Informed 
Consent 
 
 
 
 
 
 
 
 
Pregnancy 
test1 
 
 
 
 
 
 
 
 
PET-MRI 
 
 
 
 
 
 
 
 
Radiation 
Therapy 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
Pathology 
 
 
 
 
 
 
 
 
1If clinically applicable women of childbearing potential will undergo urine or serum pregnancy test within 7 
days prior to baseline scans; urine pregnancy test within 7 days prior to each subsequent PET/MRI. 
2Long-term follow-up will be restricted to abstraction of medical records for any data on recurrence and/or 
survival for up to three years post treatment. 
 
6.0 
EXPECTED RISKS/UNANTICIPATED PROBLEMS 
6.1 
Assessment of Safety 
In general, any patient enrolled on this protocol will be evaluable for 
adverse events. 
 
6.2 
Expected Risks 
 
6.2.1 
Risks of PET/MRI 
Emotional Distress 
Emotional distress is possible during MRI.  Technologists will ask subjects, before 
injection, if they are claustrophobic. Also, technologists will do their best to help 
comfort any subject who is claustrophobic but chooses to continue, by using a cloth 
over their eyes or a fan providing cool air to the subject. Technologists will hand 
subjects a squeeze ball alarm and instruct them to use it in case of any discomfort. 
The technologist will also inform the subject that he/she is free to stop at any time, 
for any reason. 
 

LCCC XXXX 
PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
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Radiation 
Radiation: The PET/MRI scans will expose study participants to controlled 
amounts of limited radiation.  The total dose of radiation from these tests is not 
anticipated to cause any adverse effects of any significance over that which they 
may experience over their standard of care diagnostic imaging and subsequent 
therapies.   Patients enrolled in this pilot study will receive an estimated dose of 
radiation as specified by the Radiation Safety Committee.  The amount of risk to 
this estimated dose will be equated to the annual radiation exposure limit for 
radiation workers in the informed consent.  This radiation exposure involves a 
small risk and is necessary to obtain the information desired. 
 
This research study involves exposure to radiation from radiotracer used for 
PET/MR scan. The radiation dose subjects will receive in this study is 1.32 rem 
for each scan for a total of 3.96 rem for the full set of three scans. For comparison, 
a person in the United States receives a radiation exposure of 0.3 rem per year 
from natural background sources. The radiation dose that subjects will receive in 
this study is equivalent to the radiation exposure that everyone receives in 13.2 
years from natural background radiation for participants completing three scans. 
For comparison, the people who work with radiation (radiation workers) are 
allowed to receive a radiation dose of 5 rem per year. The amount of radiation 
exposure received in this study is equal to 79 % of the annual radiation exposure 
limit for radiation workers.  This radiation exposure involves only a small risk and 
is necessary to obtain the research information desired. The radiation exposure 
described here is what subjects will get from this research study only. It does not 
include any exposure subjects may have received or will receive from other tests 
outside of this study that are a part of their medical care. 
 
FDG 
Information about FDG F18 was obtained from the Prescribing Information 
(August 
5 
2004); 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 
. 
According to this document , reviews of the oncology literature did not reveal 
reported adverse reactions when using 18F-FDG as a diagnostic in conjunction with 
PET.   In a subset (n=42) of a safety database of epilepsy patients (n=374), 4 patients 
had transient hypotension, 6 had hypo- or hyperglycemia and 3 had transient 
increases in alkaline phosphatase. 
 
Gadolinium 
An extremely rare disease called Nephrogenic Systemic Fibrosis (NSF) is 
associated with the use of gadolinium contrast agents in patients with chronic 
severe renal insufficiency or renal dysfunction due to hepato-renal syndrome or in 
the peri-operative liver transplantation period.  Exclusion criteria for this study are 
in compliance with the Food and Drug Administration’s advisory statements, and 
patients with creatinine clearance < 30 ml/min will be excluded from this study. 
 
As part of the MRl procedure subjects may receive a dye called gadolinium. 
Gadolinium makes it easier to see details on the MRI pictures. If subjects have any 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
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problems with their kidneys, they may be at risk for a condition called Nephrogenic 
Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy. NSF has been 
reported to occur between 2 days and 18 months following injection of gadolinium. 
There is no known treatment for NSF. Some people have even died from this. Signs 
and symptoms of NSF may include: burning, swelling, hardening or tightening of 
the skin, blood vessels and internal organs (heart, lungs, live; yellow spots on the 
white part of the eyes; joint swelling and stiffness; pain in the hip bones or ribs; 
muscle weakness. 
 
Subjects’ study doctor will check how well their kidneys work before they are given 
gadolinium. Depending on how well their kidneys work, they may be given a 
reduced dose or they may not be able to take gadolinium at all. NSF has not been 
reported in people with normal kidneys. 
 
6.3 
Unanticipated Problems 
 
6.3.1 Definition 
As defined by UNC’s IRB, unanticipated problems involving risks to study subjects 
refers to any incident, experience, or outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• 
Is related or possibly related to a subject’s participation in the research; 
and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
 
6.3.2 Reporting 
Any unanticipated problem that occurs during the conduct of this study and that 
meets at least the first two criteria listed in 6.3.1 must be reported to the UNC IRB 
using the IRB’s web-based reporting system. 
 
7.0 
STATISTICAL CONSIDERATIONS 
 
7.1 
Study Design/Study Endpoints 
The purpose of the study is to assess the utility of combined, simultaneous positron 
emission tomography (PET) and magnetic resonance imaging (MRI), collectively 
called PET-MR, in assessing response to neoadjuvant radiation therapy in the 
treatment of high grade sarcomas.  The overall design is to image patients with PET-
MR at three time points, pre-treatment, mid-treatment, and post-treatment, and 
correlate quantitative measures from imaging with results of pathology to determine 
if the mid-treatment PET-MR scan provides information that predicts response to 
radiation therapy.  The primary endpoint is to quantify the association between 

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PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
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pathology determination of response/nonresponse and image metrics from PET at 
midtreatment.  Exploratory aims will address the development of a prediction model 
for response mid-treatment change in PET and MR, and will evaluate the use of 
combined PET and MR metrics for prediction compared to each metric alone.  
 
Patients will be identified at the Multidisciplinary Sarcoma Board at UNC. Patients 
will be high-grade sarcoma patients that are to be treated with neoadjuvant radiation 
therapy followed by curative intent surgery.  Once patient identification occurs, the 
patient will be assessed for the study via the inclusion and exclusion criteria 
mentioned above. The patient will then be approached by either the PI, the sarcoma 
nurse navigator, the radiation oncologist, the surgeon, or a member of their team and 
the study protocol explained and all risks outlined. If the patient provides informed 
consent the patient will be enrolled.  Demographic data such as patient age, gender, 
comorbidities, and previous treatments, etc. will be collected. Tumor characteristics 
such as tumor subtype, grade, Ki-67 score, size, invasion into adjacent organs, etc. 
will be collected.  All data collected will be kept on a password protected, secured 
server, and all physical documentation will be stored in a locked cabinet.  All data 
will be collected by the PI and co-investigators. 
 
Patients will then be scheduled for a pre-treatment PET/MR and proceed to 
neoadjuvant radiation therapy per the direction of the radiation oncologist.  At the 
end of the second week of radiation therapy the patient will undergo a mid-treatment 
PET/MR. The patient will the complete their radiation therapy.  Four weeks after 
radiation therapy the patient will undergo a post-treatment PET/MR, and proceed for 
curative intent surgery at 6-8 weeks post radiation if they are still surgical candidates. 
 
For all PET scans, patients will be instructed to fast, and blood glucose levels will 
be measured prior to imaging.  Patients will be injected with 12 mCi 18-FDG, and 
then imaged starting 60 minutes post-injection for ten minutes each at one or two 
bed positions focused on the primary tumor site.  MRI sequences to be run will 
include conventional anatomic T1- and T2-weighted sequences, high-resolution T1 
pre- and post-contrast sequences, and the Dixon PET-MR attenuation-correction 
sequence. 
 
The PET/MRs at each time point will be evaluated by UNC radiologists as to the 
size of the lesion, the FDG activity as measured by tumor-maximum and tumor-mean 
standard uptake values (SUVs), the presence or absence of invasion to adjacent 
organs, and the presence or absence of metastatic or multifocal disease.  PET images 
will be evaluated with aligned anatomical MRI for guidance as well as determination 
of the tumor margins for computation of tumor-mean SUV. 
 
The UNC surgeons will record the resectability of the tumor, and the gross 
appearance of the resection (R0-grossly negative, R2-grossly positive), as well as 
any evidence of metastatic disease, presence or absence of invasion to surrounding 
organs, or multifocal disease.  The PET/MRs will be evaluated by UNC radiologists 
as to the size of the lesion, the FDG activity as measured by SUVmax and SUVmean, 

LCCC XXXX 
PI: David Lalush, PhD  
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
15 
 
 
the presence or absence of invasion to adjacent organs, and the presence or absence 
of metastatic or multifocal disease.  The pathological specimens will be evaluated by 
a UNC pathologist specialized in sarcoma as to the degree of necrosis (none, <10%, 
10-50%, 51-90%, >90%, 100%), status of margins (R0-negative margins, R1- 
microscopically negative margins, R2 – grossly positive margins), the presence and 
absence and number of affected lymph node involvement if applicable, and presence 
or absence of invasion to adjacent organs.  Again, all data will be stored on a secured, 
password protected server. 
 
7.2 
Sample Size and Accrual 
The study will enroll 30 eligible patients that are being treated at UNC Hospitals. To test for 
a difference in change scores between response groups at a given time point (for example, 
mid-treatment change from pre-treatment) we will utilize the non-parametric Wilcoxon Rank 
Sum test.  An advantage of using this nonparametric method is that the effect size is expressed 
in probabilistic terms, since the difference scores have been transformed into ranks, the 
statistical comparisons take place in this space, and the magnitude and variability of the 
difference scores are not needed. This means the power and sample size for each time point’s 
difference scores will be the same.  
 
 
Let X = x1, x2, …. xn represent a sample of size n difference scores for 
responders and Y = y1, y2, …. Yn represent a sample of size n difference scores 
non-responders. Now let p = P(X>Y), or the probability that a difference score in 
the responder group greater than the difference score in the non-responder group. 
Please note that we could just as easily frame the probability p = P(Y>X). 
Intuitively, one can see that a p=0.5 would mean that either X>Y and Y > X would 
be equally likely. This p would be the measure of the nonparametric or distribution-
free effect size. The Wilcoxon signed-rank method tests the null hypothesis that the 
distributions of the two samples are equal , which corresponds to a p=0.5. 
 
  Assuming 30 patients complete the study, we will have approximately 90% power 
assuming p = 0.82, with a Type I error rate of 0.05  and utilizing the Wilcoxon 
Rank Sum test [1] to test for a difference in PET mean SUV from pre-treatment to 
mid-treatment.  For correlating the fractional change in PET mean SUV with 
change in MRI tumor volume between time points, with n = 30 subjects, we will 
have approximately 82.5% power to detect a Pearson correlation of at least 0.5, 
assuming a two-sided Type I error rate of 0.05 and utilizing the correlation test. 
 
 
 
[1] Noether, G. E. (1987). Sample size determination for some common nonparametric 
tests. Journal of the American Statistical Association, 82(398), 645-647. 
 
 
 
 
 
7.3 
Data Analysis Plans 
Quantitative imaging measures (mean SUV, maximum SUV, MRI-based tumor 

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volume) will be compounded for all patients.  Difference scores including the 
fractional change from pre-treatment to mid-treatment (early response) and the 
fractional change from pre-treatment to post-treatment (late response) will be 
computed for all quantities.  Subjects will be classified into responders and non-
responders on the basis of degree of necrosis (>90% necrosis = good response; 
<90% necrosis = poor response).  Median, range, mean, and variance of each image 
measure will be computed for each response group.  Differences in all quantitative 
measures between the response groups will be assessed with the non-parametric 
Wilcoxon Rank Sum test, and correlations between quantitative measures will be 
determined using the non-parametric Spearman’s rank correlation coefficient and 
Pearson product-moment correlation coefficient.  To develop a predictive model 
for early response, we will train a logistic regression classifier on the binary 
response data utilizing various PET SUV and MRI-based imaging measures (in 
terms of change from pre-treatment to mid-treatment) as covariates.  All subsets 
selection with BIC will be used to determine the best combination of PET and MRI 
imaging measures to predict binary response, and empirical measures of predictive 
performance such as leave-one-out cross validation and Receiver-Operating-
Characteristic (ROC) curves ,(evaluated as to the area under the ROC curve) will 
be computed. 
 
7.4 
Data Management 
Image datasets will be stored on a secure server in the Biomedical Research 
Imaging Center with patient identifiers removed.  De-identified copies of these may 
be stored temporarily on password-protected computers or portable hard drives for 
use in data analysis.  Quantitative data extracted from the images and results of data 
analysis will be maintained on a secure server.  All data will be archived on a 
password-protected computer in the office of the PI and backed up with a RAID 
system.  Datasets will be maintained for at least five years from the close of the 
study. 
 
8.0 
STUDY MANAGEMENT 
8.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that the 

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patient understands the implications of participating in the study, the patient will 
be asked to give consent to participate in the study by signing a IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
 
8.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North Carolina. 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• CVs and medical licensure for the principal investigator and any 
associate investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
 
8.3 
Registration Procedures 
Once patients have consented to be a subject in this trial, they will be assigned an 
encoded false patient name/number, such as “SARC_001”. This identifier will be 
used throughout the study in the data analysis.  The study coordinator will have the 
key to relate the patient’s true name to the study identifier, and will coordinate the 
acquisition and de-identification of relevant clinical patient data so that study 
personnel not directly involved in patient care will not have access to any personally 
identifiable information.  The study coordinator will secure all information related 
to patient identifiers on a restricted-access, password-protected computer. 
 
All patients must be registered with a study coordinator at the University of North 
Carolina Biomedical Research Imaging Center before enrollment in the study. The 
Study Coordinator will verify that the patient meets all criteria to participate in the 
study before registration. 
 
8.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol. 
 
8.4.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC IRB 
approval. 
 
For any such emergency modification implemented, a UNC IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change. 
 

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8.4.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB. 
 
8.4.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that: 
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected 
• Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria: 
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®  (or 
other appropriate database set up for the study), and report to any sponsor or data 
and safety monitoring committee in accordance with their policies. Deviations 
should be summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems. 
 
Unanticipated Problems: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB (see section 6.3.1) must be reported by the Study Coordinator using the 
IRB’s web-based reporting system. 
 
8.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator at UNC.  It should also be noted that 
when an amendment to the protocol substantially alters the study design or the 

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potential risk to the patient, a revised consent form might be required. 
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation. 
 
8.6 
Record Retention 
Study documentation includes all Case Report Forms, 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. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until five years after the completion and final study report of this 
investigational study. 
 
8.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 
be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 

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9.0 
REFERENCES 
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M. R. Benz, J. Czernin, M. S. Allen-Auerbach, W. D. Tap, S. M. Dry, D. Elashoff, 
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[10] 
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Cancer Res, submitted, 2015.