Pilot Study Evaluating the Role of Histopathology Correlation in Treatment Planning
Phase: NA
Conditions: Prostate Cancer
Sponsor: Case Comprehensive Cancer Center

 
 CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
Study Number:  
 
CASE10814 
 
Clinicaltrials.gov#: 
NCT02681614 
 
Study Title:  
 
Pilot Study Evaluating the Role of Histopathology Correlation in 
Treatment Planning 
 
Principal Investigator:  
Bryan Traughber, M.D. 
 
 
 
Department of Radiation Oncology 
 
 
 
University Hospitals Cleveland Medical Center 
 
 
 
Case Western Reserve University 
 
 
 
11100 Euclid Avenue 
 
 
 
Cleveland, OH  44106 
 
 
 
 
 
 
 
 
Statistician: 
 
Pingfu Fu, Ph.D. 
 
 
 
Department of Epidemiology and Biostatistics 
 
 
 
11100 Euclid Avenue 
 
 
 
Cleveland, OH 44106 
 
 
 
 
 
 
 
 
Sponsor:   
       
Case Comprehensive Cancer Center 
 
Support: 
 
 
Invivo, Gainesville, FL,  
 
 
 
Philips Medical Systems, Cleveland, OH 
 
Supplied Device:        
Uronav biopsy guidance system 
 
IDE#: 
 
 
 
 
Protocol Date:  
 
06 February 2018 

 
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2 
SUMMARY OF CHANGES 
 
Protocol Date 
Section 
Change 
10.07.2015 
 
Initial IRB approval 
03.17.2016 
Cover 
page 
Updates to cover page  
4.3 
Changed Treating physician to Enrolling physician  
7.0 
Removed 3 month post MRI  
06.04.2016 
4.3 
Update clinical stage to be consistent with section 3.1  
6.1 
Update to virtual fiducial markers  
Remove reference to biopsy charge  
7.0 
Remove SOC items from study procedures 
7.1 
Add “routine treatment data” to information collected  
01.04.2017 
Cover 
page 
Changed PI to Bryan Traughber, removed list of co-
investigators  
4.3.3 
Replaced “hormonal therapy, radiotherapy, surgery” with 
“prostate cancer” 
3.9.2017 
7.0  
Change screening from 15 days to 60 days. 
7.0 
Add “blood pressure and pulse rate” to vitals 
7.1 
Clarified follow-up times 
9.1  
Clarified safety assessment times 
4.18.2017 
Cover 
Page 
PI changed from Traughber to Kumar 
2/6/2018 
Cover 
page/ 
footer 
PI Change:  Kumar back to Traughber 
Footer date revised to 02.06.2018 

 
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Table of Contents 
 
1.0 
Introduction 
1.1 
Study Conduct 
1.2 
Background 
1.3 
Preclinical Data 
1.4 
Clinical Data to Date 
2.0  
Study Objectives 
3.0  
Study Design  
3.1 
General Design 
3.2 
Primary Study Endpoints 
3.3 
Secondary Study Endpoints 
3.4 
Primary Safety Endpoints 
4.0 
Subject Selection and Withdrawal 
4.1 
General Characteristics of the Proposed Subject Population 
4.2 
Anticipated Number of Research Subjects 
4.3 
Inclusion Criteria 
4.4 
Exclusion Criteria 
4.5 
Subject Recruitment and Screening 
4.6 
Inclusion of Women and Minorities 
5.0 
Registration 
5.1       Early Withdrawal of Subjects 
6.0 
Study Biopsy Procedures 
6.1 
Description 
7.0 
Study Procedures 
7.1 
Follow-up Procedures 
   8.0 
Correlative/Special Studies (n/a) 
9.0 
Safety and Effectiveness Assessments 
9.1 
Safety Assessments 
9.2 
Effectiveness Assessments 
9.3 
Other Response Parameters 
10.0 
Statistical Plan 
10.1 
Sample Size Determination 
10.2 
Statistical Methods 
10.3 
Interim analysis 
11.0 
Risk Analysis 
11.1 
Anticipated Risks 
11.2 
Adverse Event Definitions 
11.3 
Expectedness  
11.4 
Attribution 
11.5 
Reporting of Adverse Effects and Unanticipated Problems 
11.6 
Reporting Adverse Events to the Responsible IRB 
11.7 
Stopping Rules 
12.0 
Data Reporting 
13.0 
Regulatory Considerations 
13.1 
Written informed consent 

 
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14.0 
Auditing and Inspecting 
15.0 
Ethics 
16.0 
Conflict of Interest 
17.0  Publication Plan 
 
References 
 
APPENDICES  
 
APPENDIX A 
 
ECOG Performance Status Criteria 

 
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1.0   Introduction 
 
1.1   Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB), and according to Good Clinical Practice standards. No deviation from the 
protocol will be implemented without the prior review and approval of the IRB except where it 
may be necessary to eliminate an immediate hazard to a research subject. In such case, the 
deviation will be reported to the IRB according to its policies and procedures.  
 
1.2   Background  
Despite many advances in imaging and therapy, prostate cancer remains the second most common 
cause of cancer-related death of men in the United States (1). Over one million men undergo 
prostate biopsies annually in the US. These biopsies have routinely been blind bilateral biopsies 
of the gland based on transrectal ultrasound guidance to assess tissue from representative section 
of the gland.  The standard practice continues to evolve, and has progressed biopsies from 
unlabeled location of the right and left gland to routine biopsy of up to 12 labeled regions of the 
prostate including both medial and lateral locations from the base, mid, and apical regions(2, 3). 
By obtaining an increased number of biopsy locations, the percentage of detected cancers has 
been shown to increase. The potential disadvantages to increasing the number of biopsies 
however include increased patient discomfort and risk of complications as well as increased cost. 
It may also increase the number in clinically insignificant cancers that are detected, thus placing 
the patient at an increased risk of harm from treatment of tumors with a low risk of becoming life 
threatening such as low volume low grade disease (4). Most recently the introduction of MRI to 
guide and track biopsy location has been developing. 
 
The use of MRI imaging has become increasingly more prevalent in the guidance of prostate 
biopsies both in the United States and internationally. Studies have confirmed that the use of MRI 
imaging to help direct the location of biopsies has increased both the frequency of diagnosing 
cancer, but even more importantly diagnosing clinically significant higher grade disease (5, 6 ). 
Several commercially available devises have come to market that aid in the ultrasound guidance 
of prostate cancer in patients that have had an MRI obtained prior to the biopsy (7). These devises 
may be designed for either transrectal or transperineal guided biopsy. Almost all of these 
manufactures have relied on the ability to use image fusion to align a real time transrectal 
ultrasound image of the prostate to the previously acquired MR image. By using segmentation 
tools to define high risk volumes likely to harbor cancer, these systems aid in the placement of a 
biopsy needle to the site of a suspected tumor foci. One such system, Uronav, developed by a 
subsidiary of Philips Medical, InVivo, has been FDA approved for routine use in transrectal 
guided biopsies of the prostate gland using an electromagnetic (EM) sensory system to help guide 
the biopsy needle tip to within 2 mm of the desired biopsy target defined by MRI. They have 
developed an additional version for transperineal biopsy as well and seek a validation trial to 
assess this platform. 
 
Routinely all patients at University Hospitals schedule to receive prostate brachytherapy treatment 
undergo a 3T MR imaging of the pelvis and prostate to plan prostate brachytherapy. At the time 
of the brachytherapy procedure a transrectal ultrasound probe is used to image the prostate, and a 
commercially available computer planning system, Symphony (MIM Software, Beachwood, 

 
CASE 10814  
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6 
Ohio) is used to align the MR image to the live ultrasound image to assist in needle placement 
and brachytherapy source delivery. During the procedure typically 20 to 35 needles are placed 
transperineally to deposit the brachytherapy sources per the computerized plan. Regions that are 
found to be suspicious for harboring cancer within the prostate volume are routinely planned to 
received a higher dose of radiation than the whole gland by placing additional radioactive sources 
at these locations at the time of the implant, however without a biopsy confirming the image 
findings it is unknown if these radiographic findings represent the biopsy proven disease site 
within the patients, or if these lesions may harbor higher grade disease or are false positive 
findings. 
 
Hypothesis:  Multiparametric MRI with histopathological correlation will improve the 
segmentation of the target volumes to treat sub-volumes of the prostate with focal dose escalation 
in low- and intermediate-risk patients beyond the use of imaging alone using standard T1 and T2 
MRI and the addition of functional MRI sequences. 
 
1.3   Preclinical Data 
The use of the electromagnetic guidance system employed by Uronav was developed at the NCI. 
Funding was partially supplied by Philips to develop the system platform originally labeled 
Percunav. Non-animal phantom studies were followed by animal studies to provide the initial 
validation and safety profile for FDA approval in human subjects (8).  
 
1.4   Clinical Data to Date 
The NCI went on to complete a human trial using the electromagnetic guidance system to 
compare MRI directed biopsies versus routine sextant biopsies in a series of 101 patients with a 
known diagnosis of prostate cancer. The data confirmed the transrectal ultrasound guided biopsy 
of the fused ultrasound and MR images yielded a higher rate of positive biopsies and also 
increased the yield for positive biopsies of high Gleason grade disease than routine ultrasound 
imaging directed biopsy alone (6). Limitations for the transrectal system include difficulty in 
placement of biopsy needles into regions seen in the anterior gland or transitional zone, as well as 
the increasingly prevalent risk of post procedural infections or rectal bleeding presumably related 
to the transrectal needle placement (9, 10). 
 
2.0   Study Objectives 
Specific Aim 1: Evaluate final pathology post-operatively for histopathology confirmation of 
multiparametric MRI targets detected during treatment planning. This will be accomplished by 
using transperineal biopsies obtained prior to interstitial brachytherapy during the procedure, 
while under anesthetic just prior to the placement of the brachytherapy needles and sources.  
 
Specific Aim 2: Evaluate the ability of the Uronav system in a transperineal setting to guide 
biopsy needle placement using the electromagnetic guidance system and transperineal ultrasound 
probe stabilization device and stepper.  
 
 
 
 
 

 
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3.0   Study Design 
 
3.1   General Design 
This 1-year pilot study will include 6 patients with a clinical diagnosis of prostate cancer (clinical 
stage T2a or T1cN0M0), Gleason score ≤7 (4+3), with a PSA ≤15ng/mL and routine pelvic 
screening with MRI of the prostate and pelvis for staging and treatment planning who have 
elected to undergo prostate brachytherapy as definitive treatment.  
 
Only patients who have clinically detectable intraprostatic findings on the MRI will be eligible to 
participate, and will be screened from the routine population of patients undergoing prostate 
brachytherapy at University Hospitals. 
 
3.2   Primary Study Endpoints 
The primary endpoint will be to report correlation of biopsy tissue histopathology with 
intraprostatic MRI findings. A total of 12 to 15 tissue samples will be obtained from each subject 
using standard sextant biopsies in addition to targeted biopsies of intraprostatic MRI findings. 
Assuming 14 specimens are sent for histopathology analysis in 6 subjects we will use the 84 
biopsy sites to report sensitivity and specificity for the MRI findings along with positive and 
negative predictive values. 
  
3.3   Secondary Study Endpoints 
3.3.1 We will report the post-operative radiation dose coverage for the prostate, organs at risk, 
and targeted lesion for each case. The coverage for the brachytherapy implant will be reported for 
the V100, V150, and V200, i.e. volumes of the prostate receiving 100, 150, and 200% of the 
prescribed dose. The dose delivered to the targeted lesion or lesions will be reported as a V100, 
V150, V200 as well to evaluate the ability to target the dose escalation prospectively, though 
again is per routine and not as part of a therapeutic trial design at this time. Additionally, the D90, 
i.e. dose to 90 percent of the prostate volume will be reported. Doses to the bladder, rectum and 
urethra will also be calculated for evaluation in the study. 
 
3.3.2  An additional secondary endpoint for the study will be to report the incidence of successful 
completion of the transperineal biopsy procedure using the Uronav system which is provided by 
Philips Medical as part of the support for this study. The Symphony biopsy system will be 
available in the operating room (OR) as a back-up to complete the biopsies if needed. It is, 
however, anticipated that the combined DynaCAD computer for processing the MR images and 
Uronav systems supplied for the study to integrate with our standard transperineal ultrasound 
system will be 100% successful in obtaining the required biopsies. We will also report on any 
unanticipated complications or infections.  It is anticipated that the risk of infection should be 
substantially diminished by avoiding transrectal biopsies. However, the risk for prostate edema 
and urinary obstruction may be increased due to the additional transperineal needle placement as 
the biopsy will be followed by routine prostate brachytherapy. Patients may therefore be asked to 
maintain a Foley catheter overnight to allow edema to resolve, and avoid acute obstruction the 
following day. Assuming the Uronav system is capable of completing biopsies on all patients and 
no more than 1 patient acquires a post-operative infection this pilot study will be deemed a 
success, and further investigation may be warranted. 
 

 
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8 
3.4   Primary Safety Endpoints 
The primary safety endpoint for the study will be the rate of infection or hospital admission 
within 30 days that are felt to be directly related to the procedure.  
 
4.0   Subject Selection and Withdrawal 
 
4.1   General Characteristics of the Proposed Subject Population 
The subject population will be screened from males with low to intermediate risk prostate cancer 
Gleason score < 7(4+3) with PSA below 15 ng/mL who are consented for prostate low dose rate 
brachytherapy. They will qualify for the study if the planning MRI used for screening and 
brachytherapy source planning shows at least one region within the prostate that is reported as 
probable for malignancy by a Diagnostic Radiologist. Treatment planning will be preformed per 
routine, and thus this trial is deemed non-therapeutic as it will not alter treatment. The patient’s 
Urologist will consent them if desired for this study, and will perform the biopsies in the OR prior 
to proceeding with the prostate brachytherapy procedure as routinely preformed with Radiation 
Oncology and the biopsy locations will be tracked with virtual fiducial markers using the Uronav 
system in addition to gold fiducial markers. The cost for the additional histopathology will be 
covered by the study along with required supplies. 
 
The goal for this pilot study is to show feasibility to track histopathology location correlated to 
standard and functional MR imaging with the possible implication to translate to a therapeutic 
trial design in subsequent studies to use the combined histopathology data and imaging 
correlation to direct radiotherapy using either brachytherapy of other forms of radiotherapy such 
as intensity modulated photon or proton therapy. Post-operative dosimetry will be reported for the 
whole gland as well as the targeted lesions per routine. The standard goal is to provide 150% of 
prescribed dose to the region defined as high probability for containing tumor at the time of the 
brachytherapy implant. As many patients do undergo a combination of both external beam 
radiation and brachytherapy as a boost dose, the implications could yield a secondary therapeutic 
trial in higher risk patients where the brachytherapy implant could be completed prior to the 
external beam therapy, and image guided intensity modulated radiotherapy (IMRT) could be 
designed to paint dose on the prostate gland following the implant to optimize target coverage. 
For example if the histopathology confirms cancer, but the post operative dosimetry defines a 
region that was not fully escalated to 150% of prescribed dose, one can envision using dose 
painting to target further dose to that region, or conversely if the implant post operative dosimetry 
shows high doses near any organ at risk such as the rectum or bladder, this area could be dose de-
escalated in the additional 25 routine fractions of IMRT. 
 
4.2   Anticipated Number of Research Subjects 
The pilot study is designed to include only 6 subjects for testing of feasibility to obtain 
transperineal tissues and report correlation to MRI image findings. 
 

 
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4.3   Inclusion Criteria 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. The checklist must be 
completed for each patient and must be signed and dated by the treating physician.  
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date __________ 
 
Enrolling Physician [Print] ____________________________________________________ 
 
Enrolling Physician Signature: ________________________________ Date __________ 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
_____4.3.1 Patients must have histopathology confirmed prostate cancer that is Gleason score  
                   <7(4+3) clinical stage < T2aN0M0 with a PSA below 15 ng/mL. 
 
 
 
 
 
_____4.3.2 Patients must have MRI findings reporting intraprostatic lesions suspicious for  
                   malignancy. 
 
 _____4.3.3 Patient must not have had any prior treatment for prostate cancer 
 
_____4.3.4 Age >18 years.  
                   Because no dosing or adverse event data are currently available on the use of Uronav                
                   in patients <18 years of age, children are excluded from this study. 
 
_____4.3.5 ECOG Performance status < 2 [See Appendix A].  
 
 
_____4.3.6 Subjects must have an International Prostate Symptom Score of < 15. 
 
_____4.3.7 Subjects must have the ability to understand and the willingness to sign a written  
                   informed consent document. 
 
4.4   Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment. 
 
_____4.4.1 Gleason score of > 8(4+4)  
 
_____4.4.2 PSA > 15 ng/mL. 
 
_____4.4.3 Clinical stage >T2b or evidence of nodal  
 
 
_____4.4.4 Patients who are on anticoagulants or high dose aspirin therapy that cannot be safely   
                   stopped for greater than 10 days prior to treatment should be excluded to limit     

 
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10 
                   increased risk for urinary obstruction. 
 
_____4.4.5 Patients with uncontrolled intercurrent illness including, but not limited to ongoing or  
                   active infection, symptomatic congestive heart failure, unstable angina pectoris,   
                   cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance  
                   with study requirements.  
 
 _____4.4.6 HIV-positive patients on combination antiretroviral therapy are ineligible because of  
                    the unlikely risk of prostate cancer being life threatening in this population.  
 
4.5   Subject Recruitment and Screening 
Subject will be screened from the practice of the Principle Investigator in men who have 
consented for prostate brachytherapy. 
 
4.6   Inclusion of Women and Minorities  
Women are excluded from participating in this study. Men of all races and ethnic groups are 
eligible for this trial. 
 
5.0   Registration  
All subjects who have been consented are to be registered in the OnCore Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through University Hospitals Cleveland Medical Center and will be 
provided a study number by calling the study coordinator listed on the front page. 
 
5.1   Early Withdrawal of Subjects 
 
5.1.1   Criteria for Removal from Study 
Subjects may withdraw from the study at anytime prior to the procedure. They will be replaced by 
an additional subject to maintain 6 subjects in the cohort. 
 
5.1.2   Follow-up for Withdrawn Subjects 
Subjects who withdraw from the study will be followed per departmental routine policy if they 
proceed with the prostate brachytherapy or elect external beam radiation. They may otherwise 
elect to be followed by their urologist. As noted above, subject may be replaced to maintain 
adequate cohort numbers to complete the study. 
 
6.0   Study Biopsy Procedures 
 
6.1   Description biopsy procedure 
All biopsies will be completed in the outpatient setting in the ambulatory OR prior to routine 
prostate brachytherapy under general anesthesia. Patients will be prepped in a dorsal lithotomy 
position with insertion of a Foley catheter. The perineum will be shaved as needed, and cleansed 
with antiseptic solution, and the scrotum will be elevated with a towel roll to expose the 
perineum. The FDA approved DynaCAD and Uronav system will be used to localize the 
diagnostic MRI findings within the prostate. The 510K approved tranperineal Uronav system will 

 
CASE 10814  
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11 
be used to perform transperineal biopsy with electromagnetic alignment of the transrectal probe 
and stepper system attached to the perineal biopsy guide 17 gauge template.  
 
Specimens will be sent to anatomic pathology office of: 
Dr. MacLennan in separate cassettes at room 215A institute of pathology  
2085 Adelbert Rd  
Cleveland Ohio 44106  
 
They will be received by Liwei Jia, MD, PhD.  
 
Each specimen will be sent separately and identified by location in the prostate (1-12 a or p to 
identify the involved portion of the gland divided in 12 sextants and either anterior or posterior to 
midline of the coronal plane) along with PIRADS classification of the lesion in MRI report. The 
proximal and distal end of the sample will be dyed for orientation in the OR at the time of 
acquisition of each sample, or at a minimum noted if it is from the proximal, mid or distal 1/3 
portion of the biopsy cavity to correlate with the same region of the virtual fiducial marker placed 
at the site of the biopsy. 
 
Standard stains will be used to identify tumors within the specimen with photos taken after 
processing is completed to allow localization relative to the virtual fiducial marker placed at the 
site of the biopsy using the Uronav system. The pathology evaluation will be provided through 
Greg MacLennan, MD. 
 
Biopsy samples will be obtained by hand using direct visualization of the live transrectal 
ultrasound image with fusion to the mapping MRI obtained preoperatively. The Urologist and 
Radiation Oncologist will obtain the tissue samples using either an 18 gauge biopsy gun with a 25 
cm needle, or additionally may use a FDA approved 17 gauge needle as a trocar to be placed 
across the perineum and allow for readjustment between biopsies to reduce the number of needle 
placements and acquire additional biopsy samples using this trocar to reposition the tip to the 
desired biopsy location (note this step is per part of a pending patent application applied for by 
UH and the managing PI). The preoperative MRI images obtained prior to the procedure will be 
reviewed by the investigators, including Radiology, Urology, and Radiation Oncology, to 
determine the target volume for biopsy using the DynaCAD system, with transfer of the DICOM 
RT dataset and images to the Uronav system for image guided biopsy. The Uronav and its 
associated electromagnetic guidance system will be positioned adjacent to the patient in the 
operating room while the patient is in a dorsal lithotomy position under general anesthesia. The 
stepper/stabilizing devise associated with the Uronav system will be attached to the B&K 
Flexfocus ultrasound unit after placing the biplanar transrectal probe into position to visualize the 
prostate gland. Calibration of the encoders on the stabilization unit with the electromagnetic 
guidance system will be commissioned and maintained by Radiation Physics.  
 

 
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7.0   Study Procedures 
Study Procedures 
Screening (within 
60 
 days of biopsy) 
Biopsy 
Visit 3 
~2 weeks Post 
Visit 4 
1 month Post 
Visit 5 
3 months Post 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
X 
X 
Height and Weight 
X 
 
 
X 
X 
Vitals1 
X 
 
 
X 
X 
Concomitant Med Assessment 
X 
 
 
X 
X 
ECOG Status 
X 
 
X 
X 
X 
Adverse events assessment 
X 
X 
X 
X 
X 
Uronav Guided Biopsy  
 
X 
 
 
 
Pathology  
 
X 
 
 
 
1. Including blood pressure and pulse rate 
 
7.1   Follow-up Procedures  
Patients will be followed for safety assessments at post-operative day 1, and at visits 3, 4, and 5. 
Data collection will include routine treatment data, assessment of urinary obstruction requiring 
Foley catheter placement as well as signs or symptoms of infection requiring additional 
antibiotics or hospital admission felt to be directly related to the procedure.    
 
8.0   Correlative/Special Studies 
N/A 
 
9.0   Safety and Effectiveness Assessments 
 
9.1   Safety Assessments 
Laboratory values obtained as part of the routine pre-surgical evaluation for prostate 
brachytherapy will be assessed prior to the procedure including: Basic Metabolic panel, CBC, 
Glomerular Filtration Rate, Coagulation Screen, and Urinalysis. Any abnormal labs will be 
reviewed by the Urologist and/or the Radiation Oncologist to determine clinical significance and 
the possible need for a reasonable delays or cancellation of the procedure. Any abnormal 
laboratory values will be repeated prior to proceeding with the procedure in such an event. 
 
9.2   Effectiveness Assessments 
Effectiveness will be analyzed by the rate of urinary obstruction beyond 7 days or infection 
directly related to the procedure, in addition to the analysis for the correlation of the biopsy 
samples with preoperative MR imaging. Statistical analysis of effectiveness is not anticipated due 
to the limited number of subjects in this exploratory initial analysis. 
 
9.3   Other Response Parameters 
The dose to the targeted lesion will be planned to be 150% of the prescribed peripheral dose to the 
prostate gland. The post-operative dosimetry and intraoperative dosimetry values will be 
recorded. In addition we will report the biopsy results for each targeted lesion to confirm 
correlation of the imaging with histopathology. There however will not be any therapeutic 
treatment alteration to be made based on the results for this study. 
 
 

 
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10.0   Statistical Plan 
 
10.1   Sample Size Determination 
Sample size justification: This is a hypothesis-generating pilot study with enrollment of 6 
patients. Each patient is expected to have 12 to 15 tissue samples using standard sextant biopsies 
in addition to targeted biopsies of intraprostatic MRI findings. Assuming 14 specimens are sent 
for histopathology analysis in 6 subjects we will use the 84 biopsy sites. Based on the report in the 
literature [6], we expect the cancer lesion detection rate of 22% using multiparametric MRI/US 
fusion vs. 11% under current standard care.  Ignoring the potential correlation of multiple lesions 
from the same patient, 6 patients (84 lesions) will have 82% power to detect in 11% improvement 
of detection rate using 2-sided one-sample chi-square test with a significance level of 0.05.  
 
10.2   Statistical Methods 
Statistical analysis: The correlation of biopsy tissue histopathology with intraprostatic MRI 
findings will be estimated using binomial evaluation for True Positive, False Positive, True 
Negative, False Negative values to report Sensitivity, Specificity, and Positive as well as Negative 
Predictive value for parametyric MRI findings relative to correlated histopathology. These data 
will be used for reporting the study results in regards to Specific aim 1, The infection rate and 
hospitalization rate within 30 days due to the procedure will be collected for expected acute events 
(AE’s) and these data will be used for reporting the study results for specific aim 2 evaluation the 
transperineal use of Uronav to determine if the transperineal biopsy approach results in a reduced 
rate of infection or hospitalization compared to standard transrectal biopsies.  
 
Any deviations from the previously described statistical plan will be described and justified in a 
protocol amendment. 
 
10.3   Interim Analysis 
Patients will be continuously monitored for safety and toxicity as we enroll up to 6 patients for the 
study. A stopping point will be enforced if 2 or more subjects develop infections requiring IV 
antibiotics or require hospitalization. 
 
11.0   Risk Analysis  
Clinical information from subjects will be recorded onto Case Report Forms and subsequently 
transferred into OnCore.  Patients who additionally consent to a separate Urology Registry will 
have their data added to the Urologic Oncology & Minimally Invasive Therapies Database for 
UHHS Faculty. 
 
Should any unanticipated adverse events occur during the course of the study, the clinical 
research coordinator will ensure that they are documented by the investigator and reported to the 
appropriate IRB per its then-current guidelines. If the determination is made that an unanticipated 
adverse event presents an unreasonable risk to subjects, the clinical evaluation will be paused, or 
if deemed appropriate (to enable further investigation), the subject will be withdrawn as soon as 
safely possible.   
 
Adverse events, grade 2 and above, will be captured in OnCore and will be reported in accordance 
with the Data and Safety Monitoring Plan (DSMP) that is approved by the Cancer Center Protocol 

 
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Review and Monitoring Committee (and aligned with the NCI-approved plan).  All monitoring 
and reporting will be compliant with policies presented in the most current version of the 
CCCC Clinical Trials Operations Manual, so that an independent assessment can be made of 
study activities.  The study will be updated to remain compliant with any changing rules/policies 
of the CCCC. 
  
Accrual reports will be provided to the PRMC and Cancer Center leadership.  In addition, all 
active patients will be assessed for toxicity, SAE reports, completeness of data collection, and 
protocol violations. Early stopping toxicity endpoints, accrual goals and safety, and whether 
consent form modifications need to be made will also be reviewed. 
 
11.1   Anticipated Risks 
The Phillips Medical’s Uronav device poses no significant risk, however, any unanticipated 
complications or infections will be reported as stated below. The risk for prostate edema and 
urinary obstruction may be increased due to the additional transperineal needle placement as the 
biopsy will be followed by routine prostate brachytherapy. In this event, patients will be asked to 
maintain a Foley Catheter overnight to allowed edema to resolve, and to avoid acute obstruction 
the following day.  
 
11.2   Adverse Event Definitions 
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 the subject.  
 
11.3   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. Expected acute events in this study would be an infection requiring additional 
antibiotic treatment beyond the standard postoperative antibiotic given for the prostate seed 
implant, or readmission to the hospital for pain, infection, or obstruction as a result of the 
biopsies. 
 
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.  
 
 

 
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11.4   Attribution  
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 Definite – The AE is clearly related to the study devise or procedures. 
 Probable – The AE is likely related to the study devise or procedures. 
 Possible – The AE may be related to the study devise or procedures. 
 Unlikely – The AE is doubtfully related to the study devise or procedures. 
 Unrelated – The AE is clearly NOT related to the study devise or procedures. 
 
11.5   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 adverse events for 3 months after the 
Uronav guided 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.   
 
The investigator will provide the following for all adverse events: 
 
Description of the event 
 
Date of onset and resolution 
 
Grade of toxicity  
 
Attribution of relatedness to the investigational devise or procedures 
 
Action taken as a result of the event 
 
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.  
 
Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring that is attributed to the 
research devise that results in any of the following outcomes:  
 Results in death.  
 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 

 
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16 
the event.  It does not refer to an adverse event which hypothetically might have caused 
death if it were more severe.  
 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: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o 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 reportable as a serious adverse 
event dependant on clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
 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. 
 Is a congenital anomaly/birth defect.  
 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 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. The development of a new cancer is always considered an 
important medical event. 
 
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported as 
instructed below. The electronic FDA SAE reporting forms should not be used.   
 
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur on or after 
Biopsy through Visit 5. Adverse events, both serious and non-serious, and deaths that occur 
during this period will be recorded in the source documents. All SAEs should be monitored until 
they are resolved or are clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness(es). Related AEs will be followed until resolution to baseline or grade 1 or 
stabilization.  
 
 
SAE Reporting Requirements 
 The Site Principal Investigator will review the SAE and report the event to the FDA, 
external collaborator(s), and IRB as applicable. 
 It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL serious 
adverse events that occur on the study (e.g. ALL SAEs that occur at each enrolling 
institution) are reported to all participating sites. 

 
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Institutional Review Board Reporting Requirements: 
 Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events.  
 
SAEs and OnCore 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 
 
11.6   Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or 
external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to the sponsor and/or other 
regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC 
Data and Safety Monitoring Plan. 
 
11.7   Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.   
 
11.8   Stopping Rules 
A stopping point will be enforced if 2 or more subjects develop infections requiring IV antibiotics 
or infections that require hospitalization if felt to be related to the procedure (i.e for example gram 
negative sepsis) within 30 days of the procedure. 
 
12.0   Data Reporting  
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer Center, to 
provide data collection for both accrual entry and trial data management. OnCore is a Clinical 
Trials Management System housed on secure servers maintained at Case Western Reserve 
University. OnCore properly used is compliant with Title 21 CFR Part 11. Access to data through 
OnCore is restricted by user accounts and assigned roles. Once logged into the OnCore system 
with a user ID and password, OnCore defines roles for each user which limits access to 
appropriate data. User information and password can be obtained by contacting the OnCore 
Administrator at oncore-registration@case.edu. 
 
OnCore is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case Report 
Form completion in the OnCore database. A calendar of events and required forms are available 
in OnCore. 
 
13.0   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.  

 
CASE 10814  
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13.1   Written Informed Consent  
Provision of written informed consent must 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 must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided.  
 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
13.1.1   Subject Data Protection 
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. 
 
13.1.2   Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations.  
 
14.0   Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the Research 
Quality Assurance Office, IRB, the sponsor, and government regulatory bodies, of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.). The investigator will ensure the capability for inspections of applicable study-
related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
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. 
 
15.0   Ethics 
This study will be conducted in compliance with the protocol approved by the IRB, the relevant 
federal regulations, and IRB policies and procedures and according to Good Clinical Practice 
standards. No deviation from the protocol will be implemented without the prior review and 
approval of the IRB except where it may be necessary to eliminate an immediate hazard to a 
research subject. In such case, the deviation will be reported to the IRB according to its policies 
and procedures. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 

 
CASE 10814  
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19 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of all subjects will be sought using the IRB-approved consent 
form. Before a subject undergoes any study procedure, an informed consent discussion will be 
conducted and written informed consent obtained with a consent form signed by the subject or 
legally acceptable surrogate if applicable. An investigator-designated research professional will 
obtain written informed consent from subjects. 
 
16.0   Conflict of Interest 
One or more of the Investigators conducting this study serve as consultants for Philips, the 
company that makes the Uronav system, which is the device being used in this study.  These 
financial interests are within permissible limits established by the Case Conflict of Interest 
Policy.  
 
17.0   Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study will be obligated to provide the sponsor with complete test 
results and all data derived from the study. An abstract and/or manuscript is anticipated to be 
reported as a result of the completion of the study, and images are to be provided to the sponsor 
for their use in research or marketing of the device.  
 

 
CASE 10814  
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20 
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Appendix A 
ECOG Performance Status Scale 
Grade 
Description 
0 
 
Normal activity. Full active, able to carry on all pre-disease 
performance without restriction.  
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% if waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead.