Utility of PET/MR in Surgical Planning for Breast Cancer Treated With Neoadjuvant Chemotherapy
Phase: NA
Conditions: Breast Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
Title: Utility of PET/MR in Surgical Planning for Breast Cancer Treated with 
Neoadjuvant Chemotherapy 
 
NCT number: NCT04149353 
 
Date: 07/06/2017  
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC 1716: Utility of PET/MR in Surgical Planning for Breast Cancer Treated with 
Neoadjuvant Chemotherapy 
 
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) 
Kandace Mcguire, M.D., Surgery 
Cherie Kuzmiak, D.O., Radiology  
Terence Wong, M.D., Ph.D., Radiology 
Carey Anders, M.D., Medicine – Oncology 
Siobhan O’Connor, M.D., Pathology and Laboratory Medicine 
 
Biostatistician 
Donglin Zeng, Ph.D. 
Department of Biostatistics 
3103-B Mcgavran-Greenberg Hall, CB #7420 
Chapel Hill, NC 27599-7420 
Phone: (919) 966-7273 
Email: dzeng@email.unc.edu 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: Lineberger Comprehensive Cancer Center Pilot Grants 
 
Version Date: 07/06/2017 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
LCCC 1716: Utility of PET/MR in Surgical Planning for Breast Cancer Treated with 
Neoadjuvant Chemotherapy 
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: 07/06/2017 
Version Date: 07/06/2017 
David S. Lalush

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 

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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 
 

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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 chemotherapy and surgical 
treatment decisions for operable breast cancers. Adult patients with operable breast 
cancer that are being treated at UNC with neoadjuvant chemotherapy followed by 
potentially curative surgical resection will be identified through the 
Multidisciplinary Breast Tumor Board.  Patients who are being treated with 
neoadjuvant chemotherapy followed by surgical resection and for whom pre- and 
post-treatment MR imaging is part of planned treatment will undergo additional 
pre-treatment and post-treatment PET/MR. The response to treatment will be 
assessed at post-treatment by evaluating change in tumor size from MRI, change in 
response to dynamic contrast enhanced (DCE) MRI, and 18F-fluorodeoxyglucose 
(18F-FDG) avidity from PET.   Patients will then undergo surgery. Their pathology 
will be reviewed for treatment effect as assessed by residual cancer burden (RCB) 
score. Patients will be followed and assessed for recurrence. 
 
This study is designed to provide preliminary information on the progression of 
tumor size, DCE-MRI response, and FDG avidity during and after treatment in 25 
patients diagnosed with operable breast cancer. The primary objective is to evaluate 
the capabilities of MRI/PET in prediction of RCB score as compared to standard-
of-care MRI alone.  A secondary objective will be to quantify the progression of 
PET- and MRI-based quantitative metrics at pre-, and post-treatment time points, 
and correlate these quantitative measures with RCB score.  
 
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 be used in determination of which patients are candidates for 
breast-conserving surgery versus mastectomy.  Existing studies point to the 
possibility of this combined imaging information enabling more patients to be 
candidates for breast-conserving surgery with no impact to recurrence rate. 
 
1.2 
Background 
Simultaneous PET/MR imaging [1]–[7] offers exciting opportunities to visualize and 
quantify soft-tissue tumors [2]. MRI offers superb soft-tissue contrast for anatomical 
information as well as a flexible suite of other techniques providing functional and 
physiological information.  PET offers sensitive molecular imaging via radioactive 
tracers, and is widely used for assessment of tumor glucose metabolism. Together, 
the two modalities provide complementary, synergistic information. Because of 
MRI’s superior soft-tissue contrast, it is considered a much better anatomical guide 
for PET quantitative analyses for tumors in soft tissue regions as compared to 
standard-of-care PET-CT.  Simultaneous PET-MR also provides inherently-aligned 
PET and MR, efficient simultaneous acquisition, and the opportunity for new 
approaches to PET quantitative analysis guided by detailed MR images.  

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The primary treatment for non-metastatic breast cancer is excision, but neoadjuvant 
chemotherapy has been shown to convert significant numbers of patients from 
mastectomy candidates to breast-conserving surgeries without impacting rates of 
local recurrence [8]. It also frequently reduces tumor size and therefore enhances 
cosmetic outcomes in lumpectomies [8].  Neoadjuvant chemotherapy has been 
shown to result in high correlation between pathologic complete response and long-
term outcomes [8]. 
The decision of whether to pursue mastectomy or breast-conserving surgery is based 
on several sources of information, including biopsy and imaging.  MRI is part of the 
standard of care for some of these cases.  Assessment of the effect of neoadjuvant 
treatment by measuring morphological and perfusion changes from pre-treatment to 
post-treatment offers an important, but incomplete picture of the status of the tumor 
prior to surgery.  PET imaging is generally not part of the standard-of-care regimen, 
but 18F-FDG-PET has been shown in several studies to be correlated with risk of 
recurrence [9]–[11] as well as with treatment response in neoadjuvant chemotherapy 
[12], [13].  Additional information on the response to neoadjuvant therapy and 
metabolic status of the tumor prior to surgery offers a better-informed decision 
environment for risk-assessment.  It may ultimately reduce the need for multiple 
operations to remove residual tumor and could potentially lead to a level of imaging 
accuracy where surgery could be omitted in those with a complete imaging response.   
One of the key barriers to the use of PET in breast imaging is the difficulty of 
aligning a conventional PET-CT image with a separately-acquired MRI image, given 
that each imaging modality will use different positioning systems and the breast is 
highly deformable.    An integrated PET-MR system inherently solves this problem, 
since the PET and MRI images can be acquired simultaneously with perfect 
registration between the two.  Also, with the excellent soft-tissue contrast of MRI, 
the system has the potential for greater anatomical detail to guide interpretation of 
FDG activity. UNC has one of the few PET-MR scanners in the country, making it 
one of few centers in the US capable of conducting this study. 
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 chemotherapy in operable breast cancer.  There are no 
prior studies evaluating combined, simultaneous PET-MR for this purpose, 
although there are studies evaluating each modality individually.  These studies 
suggest our guiding hypothesis: that simultaneous PET and MRI, acquired at pre- 
and post-treatment time points, will offer image metrics that are predictive of 
response to neoadjuvant chemotherapy. If so, in the future, application of PET-
MRI may result in conversion of more patients to breast-conserving surgery (as 
opposed to full mastectomy) without impacting re-excision rates and long-term 
outcomes. 
 
We propose that the change between PET/MR studies from pre- to post-therapy 
will accurately predict response to neoadjuvant chemotherapy.  We will enroll 
patients with breast cancer deemed by the Multidisciplinary Breast Tumor Board 
to require neoadjuvant chemotherapy due to need for tumor downstaging in the 
breast to facilitate breast conservation or to otherwise optimize cancer 

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care.  Patients enrolled will be limited to those who will have pre- and post-
treatment clinical MRI as part of their planned treatment.  These clinical scans will 
be performed on hospital MRI scanners as normally done.  Patients in our study 
will receive additional PET/MRI scans at each time point on the Biograph mMR 
combined PET-MRI scanner at the Biomedical Research Imaging Center.  The 
PET-MRI scans will be evaluated retrospectively and will not be used in the 
determination of treatment.   
These patients will receive pre-treatment imaging and then proceed through their 
course of neoadjuvant chemotherapy followed by post-treatment imaging.  Next,  
patients will receive curative intent surgery and be followed in the usual fashion 
and assessed for local and/or distant recurrent disease.  The pathology results will 
be consulted to obtain the Residual Cancer Burden (RCB) score. 
 
Quantitative measures from PET and MRI will be computed: the change in PET 
tumor-mean standardized uptake value (SUV), change in tumor size as assessed 
by MRI, and quantitative measures from DCE-MRI from pre- to post-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 To compare MRI-PET with standard-of-care MRI in early prediction of response to 
neoadjuvant chemotherapy at pre-treatment and post-treatment time points;  
 
2.2 
Secondary objectives 
 
2.2.1 To estimate the correlation between changes from pre-treatment to post-treatment 
in the Metabolic Tumor Volume metric from PET acquired on the PET-MRI 
scanner and the Residual Cancer Burden score from the pathology report; 
2.2.2 To evaluate metrics combining multiple features from simultaneous positron 
emission tomography (PET maximum SUV, metabolic tumor volume, total lesion 
glycolysis) and magnetic resonance imaging (MRI tumor size, DCE quantitative 
measures) in early prediction of response to neoadjuvant chemotherapy at pre-
treatment and post-treatment time points. 
 
 
 
2.3 
Exploratory Objectives 
 
2.3.1 None 

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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 clinical T1-3, N0-3, M0 disease.  All phenotypes are acceptable.. 
 
3.1.4 Must have surgically curable disease as evaluated by the UNC Multidisciplinary 
Tumor Board. 
3.1.5 Must have pre- and post-treatment MRI imaging as part of the treatment plan. 
3.1.6 Must be able to meet size restrictions for the PET-MR scanner: chest depth and 
abdominal depth less than 27 cm (approximately the smallest 55% of women will 
meet this), as measured on imaging or with physical template. 
3.1.7 Must be in acceptable health to undergo chemotherapy and curative intent surgery 
as assessed by Multidisciplinary Tumor Board. 
3.1.8 Must be able to understand and comply with study procedures for the entire length 
of the study. 
3.1.9 Must receive their chemotherapy and curative intent surgery at UNC Hospitals.  
3.1.10 If patient has a history of prior malignancy, including melanoma, patient must 
be cancer-free for three or more years.  Non-melanoma skin cancers will be 
included even if not cancer-free for three years.  
3.1.11 Women of childbearing potential must have a negative serum or urine pregnancy 
test performed within 7 days prior to each 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 Chronic severe renal insufficiency or renal dysfunction due to hepato-renal 
syndrome 
 
3.2.5 Body Mass Index (BMI) > 35 
 
3.2.6 Patient receiving neoadjuvant endocrine therapy (due to low likelihood of complete 
response) 

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3.2.7 Pregnancy or lactating female 
 
3.2.8 Substance abuse, medical, psychological, or social conditions that may interfere 
with the patient’s participation in the study 
3.2.9 Evidence of distant disease on physical exam or initial imaging 
3.2.10 Medical conditions precluding chemotherapy or curative intent surgery 
3.2.11 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 Multidisciplinary Breast Tumor Board at UNC.  
Once identified, the patients will be recruited and addressed at the clinics of the 
surgical oncologists, and/or medical 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. Body measurements may be taken with a physical template to 
verify that patient will meet size restrictions for PET-MR scanner. The study 
coordinator will verify that the planned treatment is still consistent with inclusion 
criteria. Enrollment and informed consent will be facilitated by the 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 DCE-MRI scan, they will be required to have a blood draw at UNC 
Hospitals for creatinine before their DCE-MRI scan visit.  This is the normal 
procedure for performing DCE-MRI on the clinical scans, and so these blood 
values can also be used for DCE-MRI performed on the PET-MRI scans. 
 
4.4 
FDG-PET-MRI 
All patients will undergo a MRI scan with simultaneous acquisition of [18F] 
Fludeoxyglucose Positron Emission Tomography (FDG F18- PET) at the two 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. 

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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 
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 two 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 upon completion of the second PET-MRI as 
compensation for their time. 
 
4.5 
Duration of Study Intervention 
The study intervention is complete once the patient receives their last (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. 
 

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5.0 
TIME AND EVENTS TABLE 
5.1 
Time and Events Table 
 
Baseline 
0 weeks 
Treatment 
+0 to +6 
months 
Post-
treatment 
+6 
months 
Surgery 
+7 
months 
Pathology 
+7 to +8 
months 
Long-
term 
follow-
up2 
>+8 
months 
Screening 
 
 
 
 
 
 
Informed 
Consent 
 
 
 
 
 
 
Pregnancy 
test1 
 
 
 
 
 
 
Clinical MRI 
 
 
 
 
 
 
PET-MRI 
 
 
 
 
 
 
Chemotherapy  
 
 
 
 
 
Surgery 
 
 
 
 
 
 
Pathology 
 
 
 
 
 
 
Monitoring 
 
 
 
 
 
 
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 

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UNIVERSITY OF NORTH CAROLINA 
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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. 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 she is free to stop at 
any time, for any reason. 
 
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 1.1 rem for 
each scan for a total of 2.2 rem for the full set of two 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 7.3 years 
from natural background radiation for participants completing two 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 44 % 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 

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UNIVERSITY OF NORTH CAROLINA 
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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. 
 
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 
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, liver; 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. 
 
Experimental MRI Breast Coil 
The PET-MRI scan will use a non-FDA approved experimental breast coil for MRI 
imaging.  While the manufacturer offers a FDA-approved coil for this device, it is 
quite expensive and beyond the means of this pilot study.  Future funding resulting 
from this pilot study will hopefully include the FDA-approved coil.  The 
experimental coil is intended only to assist in this pilot research project.  It is not 
intended for clinical use and therefore will not require FDA approval.  Further, a 
coil passing manufacturer-recommended safety testing (described below) 
represents a non-significant risk to the patient and therefore does not require an 
Investigational Device Exemption. 
 
This coil is intended to position the patient comparable to the coil used for clinical 
MRIs and to provide image quality comparable to the clinical MRIs.  The coil is a 
passive detection device, so it does not carry significant electrical current and is not 
considered an electrical hazard.  The primary risk is of surface heating.  Prior to 
patient imaging, extensive thermal studies will be conducted to verify that the coil 
will remain in a safe temperature range for the MRI sequences to be applied in this 
study. 
 
The PET-MRI system manufacturer provides a detailed procedure for safety testing 
of new coils.  The experimental breast coil will be tested with this procedure and 
must pass all tests before use with subjects in the study.  Failure of any test will 
require adjustment and/or redesign and retesting of the complete procedure.  This 
procedure requires (1) no electrical parts exposed to possible patient contact; (2) no 
sharp edges; (3) fuses or passive circuits for coils > 10 cm diameter; (4) 
measurement and calibration of specific absorption rate (SAR) monitoring to 
ensure accurate estimation of energy applied to tissue during coil use; (5) change 

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UNIVERSITY OF NORTH CAROLINA 
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in surface temperature due to gradient eddy currents must be less than 4 oC; (6) 
change in surface temperature due to transmit signal must be less than 4 oC. 
 
The experimental breast coil will also be tested on five normal volunteers under a 
separate protocol before use with cancer patients.  These tests are intended to verify 
that the coil offers suitable image quality for purposes of this study.  If the custom 
breast coil fails to provide adequate image quality in the separate normal-volunteers 
protocol, we will proceed on this study using the built-in FDA-approved scanner 
volume coil for MRI detection.  In that event, the experimental coil housing will be 
used merely as a positioning aid and not as a detection device. 
 
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, assessing response to neoadjuvant chemotherapy in breast cancer.  
The overall design is to image patients with PET-MR at two time points, pre-
treatment and post-treatment, and to compare results from PET-MR with those from 
standard-of-care MRI in the prediction of residual tumor volume.  Also, secondary 
objectives correlate both individual and combined quantitative measures from 
imaging with results of pathology to determine if the PET-MR scan provides 
information that predicts response to chemotherapy.  The primary endpoint is to 
compare PET-MR with standard-of-care MRI as predictors of Residual Cancer 
Burden (RCB) score.  The secondary endpoints will address the effectiveness of the 

LCCC XXXX 
PI: David Lalush, PhD  
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UNIVERSITY OF NORTH CAROLINA 
16 
 
 
PET metric Metabolic Tumor Volume (MTV) as a predictor of RCB and the 
development of a prediction model for response from combined quantitative PET-
MRI measures.  
 
Patients will be identified at the Multidisciplinary Breast Tumor Board at UNC. 
Patients will be breast cancer patients that are to be treated with neoadjuvant 
chemotherapy followed by curative intent surgery, and for whom pre- and post-
treatment MRI scanning is to be part of the treatment plan.  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 a study 
coordinator 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 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 around the same time 
as clinical MRI and proceed to neoadjuvant chemotherapy per the direction of the 
oncologist.  After therapy the patient will undergo a post-treatment PET-MR around 
the same time as their clinical MRI, and proceed for curative intent surgery 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 10 mCi 18F-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 DCE sequences, and the Dixon PET-MR attenuation-
correction sequence. 
 
The PET-MRs at each time point will be evaluated retrospectively 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), additional PET metrics 
(metabolic tumor volume (MTV) and total lesion glycolysis (TLG)), 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 PET/MRs will be evaluated by UNC breast radiologists and nuclear medicine 
specialists as to the size of the lesion, the FDG activity as measured by SUVmax and 
SUVmean, 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 breast cancer as to (1) the size of the 
primary tumor, (2) the proportion of invasive carcinoma within the primary tumor 

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bed, (3) the number of axillary lymph nodes involved, and (4) the size of the largest 
metastasis in an axillary lymph node.  These four quantities will be used to compute 
the RCB score1. Again, all data will be stored on a secured, password protected 
server. 
1http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3 
 
To address the primary endpoint, image metrics from the MRI component of PET-
MRI and clinical MRI will be evaluated.  The principal metric to be examined is the 
change in tumor size from pre- to post-treatment.  The change in tumor size will be 
correlated with RCB scores reported by the pathologist.   
 
For the secondary endpoints, quantitative imaging measures (mean SUV, 
maximum SUV, MTV, TLG, MRI-based tumor volume, MRI DCE imaging 
parameters) will be compounded for all patients.  The fractional change from pre-
treatment to post-treatment will be computed for all quantities.   
 
 
7.2 
Sample Size and Accrual 
The study will enroll 33 eligible patients that are being treated at UNC Hospitals; of 
these, 25 are expected to complete the study based on completion rates from previous 
PET-MR pilot studies at UNC.  
 
 
7.3 
Data Analysis Plans 
For the primary endpoint, each subject’s change in tumor size will be correlated with 
the primary outcome (RCB score) and correlation estimated using the Pearson 
product-moment correlation coefficient.  Confidence intervals on the correlation 
coefficient will be estimated using the Fisher transformation. 
 
For secondary endpoint 2.2.1, the change from pre- to post-treatment in metabolic 
tumor volume (MTV) from PET imaging will be correlated with RCB score using the 
Pearson product-moment correlation coefficient.  Confidence intervals on the 
correlation coefficient will be estimated using the Fisher transformation. 
 
For secondary endpoint 2.2.2, each subject’s set of quantitative measures will be 
compiled and an optimal linear regression between the image metrics and the outcome 
measure (RCB score) will be derived.  Prediction performance will be evaluated using 
a leave-one-out cross-validation strategy. 
 
For correlating individual metrics with RCB scores, with n = 25 subjects, we will 
have approximately 73% 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. 
 
 
  
 
7.4 
Data Management 

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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 
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 “BR_001”. This identifier will be used 

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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. 
 
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. 

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• 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 
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 

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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 
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