Role of Magnetic Resonance Fingerprinting and Quantitative MR Imaging in Assessment of Response to Neo-Adjuvant Chemotherapy in Breast Cancer
Phase: NA
Conditions: Breast Cancer
Sponsor: Case Comprehensive Cancer Center

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Study Number: CASE 3118
ClinicalTrials.gov#: NCT03650803
Protocol Date:  September 1, 2020
Study Title: Role of Magnetic Resonance Fingerprinting and Quantitative MR Imaging in 
Assessment of Response to Neo-Adjuvant Chemotherapy in Breast Cancer
Principal Investigator:
Holly Marshall, MD
Department of Radiology 
University Hospitals Cleveland Medical Center
Co-Investigators (University Hospitals/ Case Western Reserve University):
Research Personnel: 
See Personnel Table in SpartaIRB
Study Contacts (Radiology): 
See Personnel Table in SpartaIRB
Statistician:
Support/Funding: 
Study Site(s):
University Hospitals Health System 

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TABLE OF CONTENTS
1. INTRODUCTION
2. PRELIMARY STUDIES
3. OBJECTIVES/ HYPOTHESIS
4. RESEARCH PLAN
      
4.1   Recruitment 
      
4.2   Inclusion/Exclusion Criteria
4.3   Vulnerable Populations
      
4.4   Methods 
            
4.4.1  Breast MRI
4.4.2 Study Procedures
            
 
5. STUDY PARAMETERS/ DATA COLLECTION
6. STATISTICAL CONSIDERATIONS
7. POTENTIAL RISKS
             7.1   Breast MRI
 7.2   MRI contrast agent
 7.3  Confidentiality
8.  BENEFITS
9. ADVERSE EVENTS
             9.1    Serious Adverse Events
             9.2    Expectedness
 9.3    Reporting Procedures for all Adverse Events
 9.4    Reporting Procedures for all Serious Adverse Events
10. RECORDS/ DATA TO BE KEPT
             10.1    Regulatory Consideration
             10.2    Written Informed Consent 
             10.3    Subject Data Protection
             10.4    Accessing Electronic Medical Records for University Hospitals Health System
             10.5    Retention of Records
             10.6    Audits and Inspections
             10.7    Data Safety and Monitoring Plan
11. REFERENCES 

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Version 
date/#
Section #/page
Description of change (s)
Rationale for change
V1.4, 
4/15/20
Section 11  
Compensation
Patient stipend increase: 
visit 1  from $20 to $100
visit 2  from $20 to $150
visit 3 from $20/100 to $50/100
Increased enrollment
V1.5 
5/21/2020
Visit 2: addition of anatomical 
imaging-no additional time
Anantomical images as 
reference for 3D MRF
09/01/2020
Section 3: 
Objective/Hypothesis
Section 4: 
Recruitment
Section 4.4.2 Study 
procedures
Addition of single pre-therapy 
scan for patients with low 
Mammaprint scores
Patients with low 
Mammaprint scores will not 
undergo chemotherapy, but 
will provide a useful genetic 
control group to compare 
with the existing cohort of 
breast cancer patients.  
9/24/2020
Section 4.3 
vulnerable 
populations
Rescinded previous attempt to 
include non-english speaking 
individuals 
translated documents and 
translators not available
1. Introduction
There has been a growing trend towards using quantitative MRIs for early response assessment in 
oncology1. Methods already utilized clinically for measuring treatment response in breast cancer 
include 1) size criteria, 2) diffusion weighted imaging (DWI) with calculation of Apparent 
Diffusion Coefficient and 3) Contrast-enhanced dynamic contrast enhanced MRI (DCE-MRI)2-4. 
While these techniques assess various tumor properties such as volume, cellularity and perfusion, 
these techniques have their own individual limitations. For example, a change in size requires at 
least 2-3 cycles of chemotherapy to be measurable and have a predictive value5.  Waiting till at 
least 2-3 cycles or mid-therapy to detect non-response implies that patients might be subjected to 
unnecessary cycles of ineffective treatment. Thus earlier measures of treatment response are 
essential. While DWI and DCE-MRI in combination have shown to be useful for early prediction 
of treatment response6,7, DWI is hampered by low signal-noise-ratio in breast imaging and the 
measured ADC is highly dependent on MR system parameters and b-values used8. DCE-MRI 
requires administration of contrast and quantitative analysis of DCE-MRI is complex and time-
consuming. Moreover, the results from DCE-MRI are affected by physiological factors, 
acquisition technique and post-processing pharmacokinetic modeling used for analysis2,9,10. 
On the other hand, T1 and T2 relaxation times represent intrinsic tissue properties in MRI. 
Relaxometry, i.e. measurement of T1 and T2 relaxation times can also provide objective and 
reproducible information about pathology. Older studies showed that relaxation times differed 
between healthy breast tissue and breast cancers11,12 and could potentially be used to predict early 
response to chemotherapy13-15.  However, relaxometry as a response assessment technique has not 
yet crossed the translational gap because it is technically difficult in breast and there is very limited 
evidence on breast relaxometry for response assessment.  We developed a novel 3D Breast 

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Magnetic Resonance Fingerprinting (3D MRF) technique, which allows simultaneous estimation 
of both T1 and T2 relaxation times in a clinically feasible manner and in less than 6 minutes of 
scan time16.  This is a volumetric acquisition technique that generates co-registered quantitative 
maps to characterize breast tumor and peritumoral and contralateral breast tissue.
 
2. Preliminary Studies:
Our preliminary work on 3D breast MRF has shown that there are significant differences in T1 
and T2 relaxation times between tumor and normal breast tissue16, 17.  We scanned 12 women 
with biopsy proven breast cancer and the tumor T1 and T2 relaxation were longer compared to 
normal breast tissue (mean ± SD, Tumor T1: 1156 ± 200 ms, Normal breast T1: 846 ± 388 ms, 
Tumor T2: 72 ± 14 ms, Normal breast T2: 48 ± 12 ms, p = 0.039 for T1, p < 0.001 for T2). In 
addition, we performed a repeat 3D MRF scan after one cycle of chemotherapy in 7 patients and 
patients with decrease in tumor size showed significant decrease in tumor T1 and T2 relaxation 
times while non-responders showed only a negligible change in tumor T1 and T2 relaxation 
times17 (Table 1). Figure 1 shows representative 3D breast MRF maps from one patient who was 
scanned before and after one cycle of chemotherapy. Thus we hypothesize that 3D MRF before, 
during and after chemotherapy can provide additional quantitative information about changes 
during treatment and may predict early response to chemotherapy.
Table 1: Pilot data showing greater % decrease in T1 and T2 relaxation times in patients showing 
treatment response after one cycle of chemotherapy compared to non-responders
Patient 
No
Baseline 
tumor size  
(cm)
%Δ Size
after one 
cycle of 
treatment
%Δ 
Tumor T1 
after one 
cycle of 
treatment
%Δ 
Tumor T2 
after one 
cycle of 
treatment
Response status by 
surgical pathology 
staging or RECIST 
criteria
1
3.6
-25
-43
- 20
Responder (pCR)
2
3.0
-20
-13
-22.5
Responder (pCR)
3
2.0
-45
-26
-27
Partial Response 
(RECIST)
4
2.3
-39
-23
-54
Partial Response 
(RECIST)
5
3.6
-11
3.6
-5
Non-Responder 
(pT2N2)
6
3.3
58.00
6
-2
Progressive Disease 
(RECIST)
7
1.5
-13
0
5
Stable Disease 
(RECIST)
Figure 1: Representative T1 (A,C) and T2 (B,D)  MRF color maps of tumor before and after one 
cycle of chemotherapy in a patient who was treatment responder. Pre-treatment T1 and T2 were 
1087 ms and 60 ms respectively while post treatment T1 and T2 were 619 ms and 47 ms 
respectively 

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3. Objectives/ Hypothesis

To assess the utility of quantitative MRI in assessment of response to neo-adjuvant 
chemotherapy in breast cancer

MR Fingerprinting based relaxometry allows quantification of T1 and T2 relaxation 
times of tumor and normal breast tissue. Response to chemotherapy is associated 
with measurable changes in these properties and may be used to predict treatment 
response earlier than conventional MRI.  

We hypothesize that 3D MRF before, during and after chemotherapy can provide 
additional quantitative information about changes during treatment and may predict 
early response to chemotherapy.

We hypothesize that MRF-based T1 and T2 maps will be significantly different for 
breast cancer patients with low and high MammaPrint scores before therapy. This 
will provide additional capability to differentiate low grade and high grade breast 
cancer and potentially eliminate the need for invasive biopsy.
4.  Research Plan
     
4.1  Recruitment 
Patients will be identified from clinical visits to UH Breast Surgery/Hematology-Oncology 
Clinics and Radiology and the MRI inpatient/outpatient schedules.  Patients will be recruited for 
two different study cohorts:

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1.  Patients with biopsy proven cases of breast cancer who will undergo chemotherapy treatment.  
These subjects will receive 3 MRI scans: 1 before chemotherapy, Scan 2 one week to ten days 
after the first round of chemotherapy, Scan 3 after completion of chemotherapy.  
2.  The range of scores for MammaPrint is -1 to +1.  Any score above 0 is considered low risk.  
Any patients who have scores 0.355 or above are considered Ultra Low Risk.  Patients with 
biopsy proven cases of breast cancer who have had a low MammaPrint assessment will not be 
treated with chemotherapy prior to surgery as per clinical standard of care. These subjects will 
receive only one MRI scan before clinically indicated surgery and/or therapy.
We propose the following pathways for patient recruitment: 

for patients first seen at the Clinics, the treating physician (breast cancer surgeon/breast 
oncologist) will introduce the study and a flyer with key information about the study may 
be given to the patient. If the patient shows willingness to participate, the patient’s MRN 
will be sent via UH email to the Radiology Research Coordinator for actual study consent 
on the day of the baseline diagnostic MRI at UHCMC. 

if the patient has already had a diagnostic scan elsewhere before visiting the Clinic and is 
still interested in participating in the study, they will be scheduled for a research only 
non-contrast MR Fingerprinting scan at UHCMC before starting chemotherapy. 

alternatively, for patients who are first scheduled for breast MRI at UHCMC Radiology 
department, consenting will be directly done on the day of MRI without a referral from 
the breast clinic. 
We are requesting a HIPAA waiver to identify eligible patients before approaching them to 
participate in the study. To confirm study eligibility, we will access the Physician Portal to get 
information about the breast cancer diagnosis and pathology results.
Request for waiver of HIPAA authorization and waiver of consent: We are requesting a waiver 
of HIPAA authorization and waiver of consent for identifying and contacting patients in person 
and not a waiver of the consent for the research study as such. We intend to identify patients 
from physician portal, inpatient/outpatient MRI schedule and/or referred by treating physician 
for a clinically indicated breast MRI and contact them in person. There will be no improper use 
of or disclosure of PHI under this waiver. The investigator will take precautions to protect the 
subject’s privacy and the confidentiality of the data pertaining to his/her participation in this 
research study.  Only the research staff will access the PHI for above described purpose. The 
patient identifiers accessed under this waiver of HIPAA authorization will not be retained. The 
identifiers will be destroyed on the same day once the purpose of contacting the patients in 
person is complete. We assure that the PHI will not be reused or disclosed to (shared with) any 
other person or entity, except as required by law, for authorized oversight of the research study, 
or for other research for which the use or disclosure of the PHI would be permitted under the 
Privacy Rule. We are requesting a waiver of HIPAA authorization for contacting the patients in 
person and not a waiver of informed consent process for the study itself. For this purpose, the 
waiver of HIPAA authorization and waiver of consent is necessary for recruitment. We will not 
be able to meet our recruitment goals without this waiver.

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Inclusion and exclusion criteria will be assessed for each potential study patient, and written 
informed consent will be obtained by qualified study personnel in a private setting at UHCMC.  
We will also obtain contact information of the patients to schedule them for follow-up scans for 
assessing tumor response. We hope to get at least one-two eligible patients per week and recruit 
patients over the first eighteen months. Since the chemotherapy regime takes about 4-6 months to 
complete followed by surgery, we hope to get the complete information for the last patient 
recruited within 2 years of initiating the study
4.2  Inclusion/Exclusion Criteria
Inclusion Criteria:
1.
Biopsy proven cases of breast cancer
2. 
Women ages 18 and over
Exclusion Criteria
1.
Patients with only benign lesion 
2.
Patients with only ductal carcinoma in situ (DCIS)
3.
Patients with recurrent/ residual breast cancer in same breast
4.
Pregnant women
5.
Lactating Women
6.
Patients with ferromagnetic or otherwise non-MRI compatible aneurysm clips.
7.
The presence of an implanted medical device that is not MRI-compatible, 
including, but not limited to: pacemaker, defibrillator 
8.
Patients with contraindications for MRI due to embedded foreign metallic objects.  
Bullets, shrapnel, metalwork fragments, or other metallic material adds 
unnecessary risk to the patient.
9.
Known history of severe claustrophobia.
10.
Patients under the age of 18
11.
For patients with known history of allergic reaction to MR contrast material or 
abnormal kidney function (GFR < 40 mL/ min), a contrast enhanced exam will 
not be performed; however, a non-contrast exam may be performed in these 
patients.
4.3 Vulnerable Populations
Illiterate individuals may be enrolled by having a witness present at the time of consent. The 
consent form will be read to the participant and they will sign the consent by making their mark in 
the signature section. A witness will be present to confirm the consent process has taken place; the 
witness will sign the consent document. We will not actively recruit students and employees of 
UH and CWRU, however, they will not be excluded from participation. UH/CWRU students and 
employees who may consider participation will be informed that their decision to participate will 
in no way influence their job or status in any way and study results will not be reported to their 
supervisor. We will not actively recruit student or employee populations, but they will not be 
excluded if they otherwise meet enrollment criteria.

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Prisoners and many other vulnerable populations will be excluded from this study; these 
populations will not provide any unique information to the study and will not benefit from 
participation. 
4.4  Methods
4.4.1 Breast MRI:
This is a prospective, longitudinal study comprising of pre-treatment baseline scan, interim scan 
after one cycle of chemotherapy and end-of-chemoetherapy scans. The research sequence being 
evaluated is 3D MR Fingerprinting sequence. This is a painless technique that takes about 6 
minutes to perform and does not have any risks or discomfort other than those associated with 
regular breast MRI. 3D MR Fingerprinting technique is also a non-contrast technique and 
generates quantitative information about MR-visible tumors without having to administer 
contrast. Since we propose to add 3D MR Fingerprinting sequence to regular clinical MRI scans 
ordered as part of standard of care, this would only add approximately 20 minutes to overall scan 
time.  For patients who undergo research only 3D MR Fingerprinting scans, the entire scan time 
would be approximately 30 minutes, less than the time taken for regular clinical MRIs. All 
patients would be screened for MR Safety and Eligibility to eliminate any risks of undergoing 
MRI, For patients getting contrast (Gadavist®) for research purposes, the eGFR would be 
checked from patient records and contrast would only be administered to patients who have a 
documented eGFR > 40 ml/min/1.73 m2 within the previous 3months. 
4.4.2  Study procedures:
Radiology study personnel will obtain consent in the Radiology department prior to performing 
3D MR Fingerprinting scans. Consent to participate will be obtained prior to performing any 
research scans:
Visit 1: 3D MR Fingerprinting images will be added to the clinical MRI scan before start of 
chemotherapy or before surgery for the MammaPrint cohort. The additional research images will 
take less than 20 minutes to acquire.
Visit 2: Patients receiving chemotherapy will be scheduled for a research only non-contrast 3D 
MR Fingerprinting and anatomical MRI scans 7- 10 days after the first cycle of chemotherapy. 
Acquisition of images will take approximately 30 minutes.
Visit 3: For patients receiving chemotherapy, if the treating physician orders a clinical MRI scan 
within 1 month of end of chemotherapy treatment, we will add a 3D MR Fingerprinting sequence 
to the clinical scan. The additional research images will take less than 20 minutes to acquire.  
If the patient is not scheduled for a clinical scan within 1 month of end of chemotherapy 
treatment, we will contact the patient to schedule a research only 3D MR Fingerprinting scan. 
Breast cancer is hard to visualize on MRI post treatment, so we would like to administer IV 
gadolinium contrast for research purposes.  Patients will be reconsented prior to the research 
only scan to determine whether or not they will receive IV contrast.  If the patient declines 

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administration of contrast for the post treatment scan, we will perform a non-contrast scan.  
Acquisition of images will take 30-45 minutes.
Criteria for response assessment
Final surgicopathology results would be used for response assessment. Thus pathology reports 
with pT0N0 would be designated as pathological complete response while pT0 but with residual 
nodal deposits on pathology would be considered as primary tumor response for analysis purpose. 
Presence of any residual tumor on pathology would be considered as non-responder.
In the sub-group of patients who fail to undergo surgery at the end of treatment due to reasons 
beyond the control of study researchers, RECIST version 1.1 criteria would be considered as 
surrogate criteria for response (1). Thus no visible tumor and nodes at end of treatment scan will 
be considered complete response,  >30% decrease in long-axis diameter (LAD) compared to 
baseline will be partial response, > 20% increase in LAD will be progressive disease while < 30% 
decrease/ > 20% increase in LAD will be considered stable disease. 
All categories of response would be considered independently for analysis.
5.   STUDY PARAMETERS/ DATA COLLECTION
Data may be extracted from UH patient medical records by UH research-credentialed 
(CREC/CITI-certified) or UH employees and recorded onto UH Radiology password-protected 
computers.  Data will be collected and stored in REDCap or in a password protected folder on the 
secured UH s:drive in order to correlate image findings with patient progress/care.  Data will 
include the following:

Name

MRN

Age

Email

Phone number

Date of last menstrual period

Date of biopsy

Biopsy results

TNM status/cancer stage

Pathology report with hormone receptor status

MammaPrint score

Chemotherapy schedule and treatment regime

Date of surgery

Type of surgery (mastectomy or breast conserving surgery)

Final surgical pathology 

MRI images 

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6.  STATISTICAL CONSIDERATIONS
1.
From the 3D MR Fingerprinting maps, T1 and T2 relaxation times will be obtained 
for tumor, and peritumoral and normal breast tissue at all three scans.
2.
From routine MRI scans, the tumor size and tumor ADC will be obtained.
3.
Changes in all quantitative measurements will be compared between responders 
and non-responders based on final surgical pathology and the predictive value of 
3D MR Fingerprinting as compared to existing techniques would be assessed using 
appropriate t-tests and logistic regression analysis.
Sample Size Calculation: Based on our pilot data, we expect a 25% change in T1 and T2 
relaxation times in responders and less than 7% change in non-responders with an effect size of 
18% (0.18). At a significance level of 0.05 and power of 80%, the expected sample size is 62. 
Based on our pilot data, we also expect an attrition and drop-out rate of 50%, and thus total number 
of subjects recruited will be 124. 
7.  POTENTIAL RISKS
7.1   Breast MRI
Certain metals are not safe to go into an MRI scanner. Prior to all MRI exams (standard 
clinical or research), stringent safety checklists will be used to determine if an MRI study 
can be performed on each patient. All patients will be receiving an MRI exam as part of 
the standard of care at baseline. This study will add several minutes to the duration of this 
baseline exam, but will not need any additional administration of contrast agents or drugs. 
7.2  MRI Contrast Agent
If the referring physician schedules a standard-of-care MRI exam within 1 month of 
completion of chemotherapy, MRI contrast agent will not be administered for research 
purposes. 
However, if the referring physician does not schedule a standard-of-care MRI exam within 
1 month of completion of chemotherapy treatment (for visit 3), a research only exam will 
be performed. This exam will include administration of MRI contrast agent unless the 
subject declines contrast administration. If contrast is administered for research only 
purposes in this subset of patients, the following risks are present:
Potential risks of IV contrast agents are allergic reaction. Gadolinium-based contrast agents 
(dyes) may increase the risk of a rare but serious disease called nephrogenic systemic 
fibrosis in people with poor kidney function with drastically decreased glomerular filtration 
rate (GFR) below 30ml/min, Chronic kidney disease, CKD 4 and 5). To exclude the risk 
of Gadolinium induced nephropathy, we will exclude all patients with a GFR below 40 
ml/min. This threshold is considerably higher than the current clinical threshold of GFR 
below 30.
Over 300 million doses of Gadolinium based contrast agents (GBCAs) have been 
administered since the introduction of these medications in the mid 1980s. The known and 

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proven adverse effects of these drugs are the possibility of allergic reactions (rare and 
idiosyncratic), and the development of the extremely rare disease Nephrogenic Systemic 
Fibrosis (NSF) with the administration of contrast agents in patients with severe renal 
dysfunction. NSF has been virtually eliminated upon not administering GBCAs in patients 
with end stage renal disease. Additional precautions such as minimizing use of GBCAs 
associated with NSF, and elimination of simultaneous administration of double/triple doses 
of agents, have also contributed. While all GBCAs are known to deposit in neural and other 
tissues, no harmful effect of this deposition has been documented18.
7.3 Confidentiality
Finally, there is a risk of a breach of confidentiality. To lower this risk, information will be 
de-identified by a co-investigator trained in the protection of PHI (Protected Health 
Information). A unique study code will be assigned to every study subject. This code will 
be used instead of identifiable information to describe which study subject is which when 
cases are discussed among study personnel.
 8.  BENEFITS
There may be no direct health benefits for participation in this study. Participation in this study 
will help the investigators determine whether these MRI techniques are useful, and may provide 
benefit to patients undergoing MRI examinations in the future. 
9.  ALTERNATIVES TO PARTICIPATION
Patients may choose not to participate in this study and clinical care will not be affected.  
10.  COST TO RESEARCH PARTICIPANTS
The study will pay for all procedures that are directly associated with this research study.
Procedures or drugs that are considered standard of care will be the responsibility of the patient 
and their insurance company.
11.  COMPENSATION
Visit 1:  Subjects will receive $100 for research scan
Visit  2:   Subjects will receive $150 for non-contrast research scan 
Visit 3: Subjects will receive $50 for non-contrast research scan or $100 for contrast research scan
   9. ADVERSE EVENTS
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments. Adverse events may be the result of the 
interventions and interactions used in the research; the collection of identifiable private 
information in the research; an underlying disease, disorder, or condition of the subject; and/or 
other circumstances unrelated to the research or any underlying disease, disorder, or condition of 

12
the subject. In general, adverse events that are at least partially the result of (a) or (b) would be 
considered related to the research, whereas adverse events solely related to (c) or (d) would be 
considered unrelated to the research.
The significance of an adverse event is used to describe the patient/event outcome or action criteria 
associated with events that pose a threat to a patient’s life or functioning (i.e., moderate, severe or 
life threatening). Based on the National Cancer Institute Guidelines for the Cancer Therapy 
Evaluation Program, severity can be defined by the following grades of events:
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical intervention; 
asymptomatic laboratory findings only; marginal clinical relevance)
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention;  
non-
invasive intervention; transfusion; elective interventional radiological procedure; therapeutic 
endoscopy or operation).
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation).
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life 
threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, 
sepsis; life–threatening physiologic consequences; need for intensive care or emergent invasive 
procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation).
Grades 5 are fatal adverse event resulting in death.
9.1 Serious Adverse Events
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:
1. Results in death.
2. Is a life-threatening adverse experience. The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time 
of the event. It does not refer to an adverse event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient hospitalization or prolongation of existing hospitalization. Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as serious, UNLESS at least one of the following expectations is met:
4. The admission results in a hospital stay of less than 12 hours OR
5. The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the 
start of the study) OR
6. The admission is not associated with an adverse event (e.g., social hospitalization for 
purposes of respite care. However it should be noted that invasive treatment during any 
hospitalization may fulfill the criteria of “medically important” and as such may be 

13
reportable as a serious adverse event dependent on clinical judgment. In addition where 
local regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.
7. Results in persistent or significant disability/incapacity. The definition of disability is 
a substantial disruption of a person’s ability to conduct normal life’s functions.
8. Is a congenital anomaly/birth defect.
9. Is an important medical event. Important medical events that may not result death, be 
life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
9.2 Expectedness
Adverse Events can be Expected or Unexpected.
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.
9.3 Reporting Procedures for All Adverse Events
All participating investigators will assess the occurrence of AEs throughout the 
subject’s participation in the study. Subjects will be followed for AEs for 30 days 
after biopsy or until death, whichever occurs first. The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. The investigator is responsible 
for ensuring that all adverse events observed by the investigator or reported by the 
subject which occur after the subject has signed the informed consent are fully 
recorded in the subject’s case report form, subject’s medical records, and/or any 
other institutional requirement. Source documentation must be available to support 
all adverse events.
A laboratory test abnormality considered clinically relevant (e.g., causing the 
subject to withdraw from the study), requiring treatment or causing apparent 
clinical manifestations, or judged relevant by the investigator, should be reported 
as an adverse event.

14
The investigator will provide the following for all adverse events:
1. Description of the event
2. Date of onset and resolution
3. Grade of adverse event
4. Action taken as a result of the event
5. Outcome of event
In this study, descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 available at 
http://ctep.cancer.gov will be utilized for AE reporting.
Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.
9.4  Reporting Procedure for Serious Adverse Event
Serious adverse events that occur beginning with the signing of the informed consent form, 
or within 30 days of the individual undergoing prostate biopsy must be reported to the 
University Hospitals Principal Investigator.
10.  RECORDS/DATA TO BE KEPT
10.1 Regulatory Considerations
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws.
10.2  Written Informed consent
Provision of written informed consent will be obtained prior to any study-related 
procedures.  The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects will also 
be notified that they are free to discontinue from the study at any time.  The subject 
will be given the opportunity to ask questions and allowed time to consider the 
information provided.
The consent will take place at the clinical practices of the listed co-investigators in a 
private location.  The patients will be evaluated a second time for MR safety prior 
entering the magnet prior to each MRI examination.
The original, signed written Informed Consent Form will be kept with the Research 
Chart in conformance with the institution’s standard operating procedures.  A copy of the 
signed written Informed Consent Form will be given to the subject.
10.3  Subject Data Protection

15
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history.
10.4 Accessing Electronic Medical Records for University Hospitals Health      System
This study will access electronic medical records systems to obtain medical information 
for the subjects enrolled in this study. We seek a HIPAA waiver to identify eligible patients 
and check whether patients meet inclusion criteria before approaching them for the study 
(see Recruitment section 4.1).
In order to ensure patient safety, investigators and study personnel must have up-to-the 
minute health information for subjects enrolled to this study. Therefore, electronic 
medical records must be utilized to obtain medical information in a timely manner. The 
following electronic systems will be used: IDX program to access scheduling 
information; UH Physician Portal/EMR/AEMR to access lab results and physician notes; 
PCOSS LITE as necessary to locate archived medical records; COPATH to locate 
archived pathology records; PACS to access radiological imaging results; and 
MySecureCare (Sunrise Clinical Manager) to access some or all of the above 
information when this application is fully functional.
Access to these systems is required for the life of this research study.  Information obtained 
from electronic systems will be copied into the research chart and/or printed (lab results, 
physician notes, etc.) and stored in the research chart. Research charts are kept secure and 
destroyed according to UH policy.
The PI, co-investigators, study coordinator, and/or data manager for this study via 
password-protected login will obtain study data.  The coordinator will be assessing EMR 
to obtain spontaneous adverse events.  All study personnel involved in this research will 
adhere to the UH policies regarding confidentiality and Protected Health Information.
Patient MRI images will be de-identified to protect personal information and will only 
referred to by a unique number identifier.
Research MRI and MRF images may be reconstructed or analyzed in either an online or 
offline manner. If images are reconstructed online, it is possible to share these images with 
referring physicians or radiologists using the PACS database. If requested and available 
online, these images may be shared via PACS. However, there may be no direct benefit of 
sharing these research images.
10.5  Retention of records

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The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, case report forms, source documents, 
records of study drug receipt and dispensation, and all IRB correspondence for as long as 
needed to comply with national and international regulations and the institution in which 
the study will be conducted, or for the period specified by the sponsor, whichever is 
longer.  No records will be destroyed until the Principal Investigator confirms destruction 
is permitted.
10.6 Audits and inspections
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform 
audits or inspections, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.
10.7  Data Safety and Monitoring Plan
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI regulations.
 
The group of investigators, including the principal investigator, and the research support 
staff will carry out the Data and Safety Monitoring Plan. Adverse events will not be 
submitted to an external Data and Safety Monitoring Board or Committee for assessment; 
instead, there will be an ongoing review of the aggregate data each month to ensure that 
the study can continue without undue risk to participants. Data will be reviewed to ensure 
that they are accurate, complete, and that data collection is in compliance with the protocol.
 
There will also be a continual assessment of the risks and benefits through the review of 
individual adverse events and other safety parameters as they occur throughout the study 
to determine whether individual participants can safely continue to participate. Serious 
adverse events, should any occur, will be reviewed within 48 hours of occurrence with a 
determination made for medically appropriate follow-up for the subject involved. Adverse 
event reporting will be strictly performed in compliance with IRB rules for reporting.
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