MRI-Guided Active Selection for Treatment of Prostate Cancer: The Miami MAST Trial
Phase: NA
Conditions: Prostate Cancer
Sponsor: University of Miami



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TABLE OF CONTENTS
SCHEMA.......................................................................................................................................................4
1.
BACKGROUND....................................................................................................................................5
1.1
Study Disease .................................................................................................................5
1.2
Study Interventions..........................................................................................................6
1.3
Other Interventions
..........................................6
1.4
Rationale .........................................................................................................................6
1.5
Preliminary Studies........................................................................................................10
1.6
Quality of Life.................................................................................................................13
2.
HYPOTHESES................................................................................................................................14
3.
OBJECTIVES..................................................................................................................................15
3.1
Primary Objective ..........................................................................................................15
3.2
Secondary Objectives....................................................................................................15
4.
STUDY DESIGN .................................................................................................................................15
4.1
Accrual goal...................................................................................................................16
4.2
Duration of Study Participation ......................................................................................16
5.
STUDY ENTRY AND ENROLLMENT AND WITHDRAWAL .............................................................17
5.1
Study Entry....................................................................................................................17
5.2
Enrollment Procedures..................................................................................................17
5.3
Cancellation Guidelines.................................................................................................17
6.
PATIENT SELECTION/ELIGIBILITY CRITERIA................................................................................17
6.1
Inclusion (Eligibility) Criteria ..........................................................................................17
6.2
Exclusion (Eligibility) Criteria .........................................................................................18
6.3
Gender and Ethnicity.....................................................................................................18
7.
CLINICAL, RADIOLOGICAL AND LABORATORY EVALUATIONS ................................................18
7.1
Screening Evaluations...................................................................................................18
7.2
Evaluations During Intervention* ...................................................................................18
7.3
Early discontinuation of study participation....................................................................19
7.4
Multiparametric MRI ......................................................................................................20
7.5
Prostate Biopsy .............................................................................................................20
7.6
Biopsy Tissue Handling.................................................................................................21
7.7
Molecular Analyses of Blood and Urine ........................................................................22
7.8
Quality of Life and/or Outcomes ....................................................................................22
8.
ADVERSE EVENT REPORTING........................................................................................................23
9.
DATA AND SAFETY MONITORING PLAN .......................................................................................24
10.
STATISTICAL CONSIDERATIONS................................................................................................24
10.1
Primary Study Endpoints..............................................................................................25
10.2
Secondary Endpoints ....................................................................................................25
10.3
Sample size, accrual rate and study duration...............................................................27
10.4
Statistical Analysis........................................................................................................28
10.5
Interim monitoring..........................................................................................................28
 
        
 
 

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11.
INVESTIGATOR’S RESPONSIBILITIES........................................................................................28
11.1
Investigator Responsibility/Performance........................................................................28
11.2
Confidentiality................................................................................................................28
11.3
Informed Consent and Permission to Use Protected Health Information ......................29
11.4
Source Documentation and Investigator Files ..............................................................29
11.5
Recording and Processing of Data................................................................................29
11.6
Non-Protocol Research .................................................................................................30
11.7
Ethics ............................................................................................................................30
11.8
Essential documents for the conduct of a clinical trial...................................................30
12.
REFERENCES................................................................................................................................30
APPENDIX I: LIST OF STAND-ALONE DOCUMENTS............................................................................35
APPENDIX IIV: STUDY CALENDAR........................................................................................................36
 
        
 
 

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1.
BACKGROUND
1.1   Study Disease
Prostate cancer is the most common malignancy and second most common 
cause of cancer related death among men in the United States.1 Despite excellent 
cancer control for low-intermediate risk disease, treatment results in a significant 
detriment to health related quality of life.2-4 Since the advent of prostate cancer 
screening, many men are diagnosed with indolent tumors which are unlikely to become 
symptomatic or result in metastasis or mortality, questioning whether the risks of 
treatment outweigh the benefits.5,6 As a result, active surveillance (AS) has emerged as 
an attractive alternative to immediate treatment. This is a process in which a man 
defers immediate treatment, and undergoes monitoring with the intent of timely curative 
intervention at the point where a higher risk of tumor progression is indicated.7,8 
Research has shown active surveillance to be safe in carefully selected men allowing 
many men to defer treatment and its burden to quality of life for over 5 years.9-11 The 
preservation of quality of life is of primary importance, particularly for men in their 50’s 
and 60’s. However, since men in these age ranges have a long-life expectancy, it is 
imperative that they be carefully selected for active surveillance to ensure the window of 
opportunity for cure is preserved.
Despite a worldwide acceptance of active surveillance in men with low risk 
tumors, nearly a third of men will progress to requiring treatment within the first three 
years.7,12 Most active surveillance protocols select patients with low volumes of low 
grade tumor seen on diagnostic biopsy. However, unlike other solid tumors where a 
lesion is visualized on imaging and a needle is inserted directly into it, most methods of 
visualizing the prostate cannot reliably identify lesions that are localized to the prostate. 
As a result, the current standard for diagnosis involves visualizing the prostate via 
transrectal ultrasound and performing segmented biopsies of the gland for cancer 
detection because the tumor(s) is not usually identified clearly. Given the 
heterogeneous nature of prostate cancer, where both indolent and aggressive tumors 
may be found in the same gland and some tumors are located in regions of the prostate 
(e.g., anteriorly) not thoroughly sampled, this “sampling” approach may miss the 
dominant or high grade tumors, which are likely to be the drivers of progression.
This is confirmed by a 20-30% chance of seeing a higher grade or volume of 
tumor when a second biopsy is performed.13 Furthermore, data from surgical patients 
suggest that 20-30% of patients who appear to be good candidates for surveillance may 
harbor high-risk features within their prostates suggesting that their biopsy may have 
underestimated the aggressiveness or volume of tumor present.14,15 This highlights the 
need for serial biopsy, but also suggests that those patients who are likely to progress 
early are not truly progressing, but more likely to harbor higher risk tumors that were 
missed on initial biopsies; a process referred to as “reclassification”. Therefore, men 
choosing active surveillance must understand that the biopsy may not reflect the true 
biology of their disease, and there is some inherent risk involved that they may lose 
their opportunity for cure while their tumor is being monitoring.
The primary goal of active surveillance is to monitor tumors that are deemed not 
to require immediate treatment with the goal of timely intervention at the point of tumor 
 
        
 
 

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progression. However, without careful selection of patients for surveillance this approach
can compromise oncologic outcomes. Better tools are critically needed to improve risk
stratification in men choosing between surveillance and immediate treatment to allow 
improved outcomes in men who truly harbor aggressive tumors so they can be offered 
necessary treatment earlier, before outcomes can be compromised.
1.2
Study Interventions
Single arm therapeutic trial investigating the impact of MRI and MRI-US fusion 
biopsy to identify higher grade or volume tumors early on for better selection of patients 
for active surveillance versus immediate treatment. We suspect that use of MRI and 
MRI-US fusion biopsy will allow the detection of men who are not ideal candidates for 
observation (based on a higher grade or volume of tumor that was missed on initial 
diagnostic biopsy) earlier in the surveillance process, so they can be offered timelier 
treatment rather than initial observation with delayed therapy after the tumor has 
progressed. MRI–US fusion biopsy will include targeting of suspicious areas seen on 
MRI as well as segmented sampling of the remaining gland. Patients will undergo MRI 
and MRI-US fusion biopsy within 3 months of enrollment in the trial and have repeat 
MRI-US fusion biopsies every year to assess overall rates and the temporal distribution 
of progression. Serum, urine and prostate biopsy tissue will be serially collected to 
investigate the association between various molecular biomarkers and radiologic and 
histological progression.
1.3
Other Interventions
Currently, there are no urine, serum or tissue markers that have been validated 
to reliably discern between men who are ideal candidates for active surveillance and 
those who are not. Previous studies have suggested that post digital rectal exam 
expressed prostatic secretions for prostate cancer antigen 3 (PCA3) and 
TMPRSS2:ERG (gene fusion related to promotion of prostate cancer) had a modest 
effect at best in predicting patients who would not be suitable for active surveillance.16 
Various prostate specific antigen isoforms, which can be collected in the serum, have 
shown some association to helping predict patients who are likely to progress on active 
surveillance.17. Recently, new genomic signature panels performed on biopsy tissue has 
shown promising results in helping to stratify risk among patients selecting active 
surveillance.18 However, these tests still require further validation to evaluate their true 
benefit in treatment decision-making. Although each of these biomarkers may add 
some information regarding risk stratification, none of them can reliably guide or 
significantly facilitate treatment decision-making process. As a result, most protocols 
must rely on clinical (serum PSA) and histopathological factors on biopsy (Gleason 
score, percent of cores positive, percent of each core with cancer) to help select 
patients who may be suitable for active surveillance. However, as mentioned before 
there is an inherent risk in using these parameters as they will only be informative about 
the portion of the gland that was sampled.
1.4
Rationale
1.4.1
Rationale for Studying Active Surveillance Patients
 
        
 
 

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Radical prostatectomy and radiotherapy, the two most common and potentially
curative treatment options for prostate cancer come at a significant impact to health 
related quality of life.2-4 With earlier diagnosis from PSA screening, there may be as 
much as a 15 year lead time before the majority of patients progress and metastasize. 
Active surveillance has emerged as an appropriate and safe alternative to immediate 
treatment and is supported by both the American Urological Association and the 
European Urological Association.19,20 Our center has one of the largest active 
surveillance cohorts in the world. With a median follow up of 3 years about 30% of 
patients experienced progression of tumor. However, no patient in our series has 
developed metastasis or mortality. Given the success and emerging popularity of active 
surveillance, there is a consideration to expand the criteria for surveillance to allow 
intermediate risk patients to be considered eligible. However, some patients who 
undergo delayed surgery after initial surveillance have adverse histological findings that 
may portend worse outcomes or require further secondary treatments to establish 
cure.21,22 It is likely that many of these patients harbored higher risk disease that was 
missed on initial evaluation of their prostate. Therefore, any biomarker, predictive tool, 
or imaging modality that could identify these patients early would be a welcome addition 
to reduce the likelihood of an adverse outcome due to poor selection of suitable 
patients.
1.4.2
Multiparametric MRI and MRI-US fusion for Identifying Tumor Areas with 
Aggressive Characteristics
As mentioned before transrectal ultrasound has poor sensitivity and specificity in 
visualizing tumors within the prostate making it difficult to target areas of the gland that 
are likely to harbor the most aggressive lesions. Multiparametric MRI, when applied to 
the prostate, provides much better tissue resolution and improved sensitivity and 
specificity in detecting aggressive cancers of prostate.23,24 The individual parameters 
include T2 weighted images, which provides excellent depiction of prostatic anatomy 
with prostate tumors having a lower signal intensity than the surrounding tissue.25 
Diffusion weighted MRI (DWI) displays information on the diffusion of water molecules 
through the tissue and measures the resistance of the tissue using an apparent 
diffusion coefficient (ADC), which is often lower in higher Gleason score tumors.26,27 
Dynamic contrast enhanced (DCE)-MRI has also been applied to discriminate normal 
from malignant prostate tissues, with earlier and greater enhancement followed by 
washout seen in the latter. DCE-MRI measures vascularity and hence angiogenesis.
Both DWI and DCE have a relatively high sensitivity and specificity for prostate 
cancer.23,24
Due to its improved accuracy to detect aggressive tumors of the prostate, many 
groups have advocated for the use of MRI to select patients who may be suitable for 
active surveillance. A recent study of 298 men with low risk cancer on biopsy who 
underwent MRI prior to removal of the prostate found that those with a lesion on MRI 
were more likely to have a more aggressive or larger tumor then initially perceived, 
suggesting they would not have been good candidates for surveillance.28 Similarly, 
another study of 85 patients who qualified for active surveillance found that a suspicious 
lesion, lesion density and the number of lesions on MRI correlated with the likelihood of 
finding a higher grade or volume of tumor on repeat biopsy.29 These studies speak to
 
        
 
 

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the emerging role of MRI in selecting and following patients on active surveillance for
low risk tumors.
Despite the increased accuracy of MRI to detect suspicious lesions within the 
prostate, targeting these areas on MRI can be cumbersome since the patient will have 
to be in the MRI suite for a prolonged period of time. However, recent technology that 
fuses MRI images with real time transrectal ultrasound has allowed the clinician to 
target lesions seen on MRI using transrectal ultrasound, allowing the biopsy to be 
performed quickly in the office seting.30 Recent studies have revealed that MRI-US 
fusion biopsy results in a higher detection of cancers and significant cancers (that would 
exclude a patient from active surveillance) compared to the current standard of random 
biopsy using just transrectal ultrasound.31,32 A prospective, blinded study compared 
MRI-US fusion biopsy and random sampling of the prostate on transrectal ultrasound.33 
Among the 172 patients in the study, fusion biopsy was more often informative then 
random sampling by the standard approach with a higher detection of all prostate 
cancers and aggressive prostate cancers. This improved accuracy for detection was 
robust to all subgroups of patients, prostate sizes, and lesion sizes.
Our group has developed semi-automated tools for compartmentalizing the 
prostate into “habitats” based on the combined analysis of the multiparametric data 
from T2w, DCE and ADC maps. This new tool will be applied to our protocol patients to 
better direct prostate biopsies based on MP-MRI.
There is emerging data that the application of this technology to selecting 
patients for active surveillance will contribute to the earlier identification of patients who 
are not good candidates for such an approach.34 However, this data is in its infancy and 
requires further validation in larger prospective studies. Furthermore, due to the 
improved detection of more significant cancers with a fusion biopsy technique the 
histology is more likely to reveal higher grades and volumes of tumor compared to 
traditional biopsy methods. As a result, the grade and volume thresholds which 
currently serve as criteria for selection of active surveillance patients will have to be 
revisited.35 Finally, the role of MRI-US fusion biopsy and MRI alone in following patients 
on surveillance will require further investigation to see if certain features on MRI alone 
can predict the outcome of biopsy. Therefore, although MRI-US fusion technology 
provides a more accurate way of identifying risk within the prostate, its role in the 
selection and management of active surveillance patients requires further validation.
1.4.3
Radiomics to provide more Quantitative Risk Assessment in Active Surveillance 
Patients
“Radiomics” refers to the extraction and analysis of large amounts of advanced 
quantitative MP-MRI features using high throughput methods.36 Radiomics data are in a 
format that is amicable for building descriptive and predictive models relating image 
features to outcome, as well as gene–protein signatures. Resultant models may include 
imaging, molecular, and clinical data, and provide valuable diagnostic, prognostic or 
predictive information. Dr. Gillies’s group at Moffitt Cancer Center have pioneered the 
use of image texture features in CT of the lung that are prognostic of survival.37
These methods are semi-automated wherein the radiologist identifies the lesion 
and computer software proceeds to segment, render and generate a report of 
quantitative features. These reports are pertinent to the questions: Which features are
 
        
 
 

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informative (e.g. have a wide range and are measureable in all samples)? What is the
variance from one measurement to another and what are the critical sources of that 
variance? Are the features with largest dynamic range related to outcomes?
The use of image features has been elevated to a new level through the work of 
Kuo and colleagues, who have associated extractable features from MRI or CT to global 
gene expression patterns in glioblastoma multiforme (GBM) and hepatocellular 
carcinoma (HCC).38,39 In GBM, there are clear correlations between histopathology 
grade and MR imaging features.40 However, the diversity of MR phenotypes is greater 
than that of histology, e.g. tumors of similar histopathology can exhibit distinctly different 
MR imaging patterns.41 In HCC, Kuo quantified 138 features from contrast-enhanced 
CT images in a training set from 28 patients. These features were individually filtered 
by frequency in the datasets, interobserver agreement, and independence from other 
features, resulting in a subset of 32 highly informative features. A modified neural 
network was then used to identify 116 gene “modules” that contained sets of genes (out 
of 6732 total) whose variation was coherent. The algorithm then identified combinations 
of imaging features that were highly correlated with each gene module. This training set 
was then tested using a permutation of the original data and a completely independent 
data set. Only 28 of the imaging features were needed to explain all 116 gene modules, 
and 9 features could explain half of them. For each gene module, only 3-4 imaging 
features were needed. Thus, the CT feature data was predictive of global gene 
expression.
Gillies and Gatenby have recently pioneered the concept and practice of defining 
specific “habitats’ from radiological images, which we will use to facilitate applying 
radiomics to prostate cancer analysis.42 This approach requires the combination of co- 
registered images from multiple modalities, with each one contributing a piece of 
orthogonal information. For this reason, MRI is a technique of choice because multiple 
pieces of co-registered orthogonal data can be generated in a single exam. For 
example, DCE-MRI is a powerful method to identify regional distributions of blood flow, 
and lack of blood flow. The texture of these enhancements has proven to have 
significantly higher prognostic value than simple region-of-interest (ROI) measures.
Diffusion MRI measured ADCs is a powerful method to interpolate the density of 
diffusion barriers (i.e. cells) and hence provides information that may be biologically, but 
not physically, related to DCE. T2 is sensitive to microscopic perturbations in the 
magnetic field; this is affected by blood flow and cell density, but in a non-linear fashion. 
Hence, T2 information is not strictly orthogonal to DCE and ADC and this correlation is 
accommodated in habitat imaging as described below.
1.4.4
Biomarker Validation for Active Surveillance
Biomarkers, be they from blood, urine or tissue, have the potential to contribute 
meaningfully to the decision of whether to recommend treatment or AS, and perhaps 
when to convert to treatment for men undergoing AS. The most promising of these 
biomarkers include genomic signature panels that can be tested on biopsy tissue to 
provide important information on risk stratification and prognosis.18 Previous validations 
of these tissue markers have been performed using biopsy tissue from random 
sampling of the prostate. However, we plan to examine tissue biomarkers in two unique 
methods that may allow for a more enhanced prediction. First, we will be testing tissue
 
        
 
 

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attained from MRI-US-guided biopsies, which will sample suspicious regions of the
prostate most likely to harbor the dominant tumor. To the best of our knowledge, there 
have been no publications on biomarker assessment using tissue obtained from 
targeted biopsy. Biomarker testing from these tissue cores will be compared to cores 
from segmental sampling of the prostate to assess for any differences in risk 
assessment. Secondly, these biomarkers will be attained serially to assess the change 
over time in genomic risk assessment.
We have previously collaborated with GenomeDx who has developed techniques 
for the analysis of RNA-based gene expression in formalin fixed paraffin embedded 
(FFPE) tissues from prostate biopsy. Using their system, gene expression profiling will 
be performed using a high-density 1.4 million-feature expression microarray. Although 
previous genomic signatures have been limited in assessing risk among patients on 
active surveillance this study allows us to explore various combinations of genetic 
alterations seen in the tumor region most likely to be driving progression. Therefore, we 
can expand on previous findings43,44 and facilitate the development of other genomic 
alterations that may have more significant prognostic implications. We believe that the 
radiomic and genomic characterization of various regions within the prostate will 
complement each other as well as the histological assessment to help select patients 
who are likely to harbor tumors that will portend an unfavorable outcome on active 
surveillance.
Other biomarkers to be investigated include the Four-Kallikrein Panel or OPKO 
test. The test is an algorithm comprised of the quantitative measurements of four 
kallikrein protein markers that can be measured in the blood: total PSA, free PSA, intact 
PSA, and human kallikrein protein. The OPKO test is derived from the measurement of 
these proteins in the blood as well as the patient age and digital rectal exam findings.
The test provides a percent probability that the patient would have cancer, and high- 
grade cancer on prostate biopsy. Multiple studies have shown that the test improves 
the ability to discern between pathologically indolent versus aggressive tumors.45-47 
However, this test has not been validated in the active surveillance population to see 
whether it can improve the selection of patients who are unlikely to progress while 
monitoring their tumors.
Urinary PCA3 has emerged as another biomarker that assists in differentiating 
between patients with indolent versus aggressive tumors.48 PCA3 mRNA is detected in 
the first amount of urine after prostatic massage. Although initially used to help in the 
detection of prostate cancer, this test has expanded its role and has shown promising 
results in selecting patients who are well suited for active surveillance.16,49 While 
surveillance patients are at the extreme in terms of being favorable, we still may identify 
high risk patients not previously identified based on standard factors (Gleason score 
and tissue burden) and biomarker patterns that are associated with men in other stages 
of the disease. Finally, we will assess urine and serum based molecular markers to 
investigate their associations to tissue-based markers, radiological findings and 
histological progression.
1.5
Preliminary Studies
1.5.1 Experience with active surveillance
 
        
 
 

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The Department of Urology at the University of Miami has a significant
experience in active surveillance. Currently the clinical and histological criteria for 
surveillance include Gleason ≤ 6 (3+3), PSA ≤ 20ng/mL, and two or fewer biopsy cores 
with no more than 20% tumor present in each core. All patients had at least one 
confirmatory surveillance prostate biopsy. At diagnosis, the mean age of the AS 
patients was 62 years (range 33-79 years) with a mean PSA of 5.1 ng/mL. The mean 
follow-up for the cohort was 2.9 years (interquartile range (IQR) 1.4-24.0 years). On the 
first re-biopsy, 52% of the patients had no tumor. Only 7% of the AS patients had tumor 
progression (to some component of Gleason 4 disease) on first re-biopsy. In the 
second and third surveillance biopsies, 18% and 17% of the patients respectively 
progressed. Of the 249 men in the AS cohort as of this analysis in 2011, 64 (26%) 
demonstrated biopsy progression and 61 of them have been treated. No patient died of 
prostate cancer. Among the 61 treated patients, 32 had radical prostatectomy, 27 had 
interstitial or external beam radiation, and for 2 patients the type of treatment was 
unknown. Three men with an increase in tumor burden in follow-up biopsies elected to 
continue active surveillance despite the biopsy progression. However, the Miami criteria 
for active surveillance is very conservative and may exclude many men for whom 
surveillance would be acceptable. These criteria have been expanded in current clinical 
practice.
Similar outcomes have been reported in other cohorts of low risk patients on 
active surveillance.11 Given the global success of active surveillance in low risk men, 
there has been a growing body of literature supporting the expansion of active 
surveillance to men with higher tumor burden or intermediate risk features.8 As 
mentioned, we are also expanding our criteria in a similar fashion. Studies comparing 
intermediate and low risk patients on active surveillance have shown similar rates of 
progression between the two groups.9 Although follow up is shorter in the intermediate 
risk group of men, we are not seeing a higher rate of metastasis or mortality. However, 
a proportion of men placed on active surveillance harbor a high-risk tumor that was 
missed on initial sampling. For these men, cancer outcomes may be compromised by 
failure to recognize this high-risk tumor and offer immediate treatment. We believe the 
emergence of MRI targeted biopsy will allow detection of higher volumes and grades of 
cancer due to more accurate targeting of suspicious lesions. As a result, this 
proportion of men, who truly aren’t candidates for surveillance, will be reclassified earlier 
and be offered treatment before their oncologic outcomes can be compromised.
 
        
 
 

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demonstrate good internal reliability, with Cronbach’s alphas exceeding 0.80. The SF-
12 has been used extensively in cancer populations, and has been validated with 
prostate cancer patients.50 As an index of Prostate Cancer-Specific Anxiety, we will 
administer the Memorial Anxiety Scale for Prostate Cancer patients (MAX-PC). The 
MAX-PC is an 18-item instrument designed to detect symptoms of anxiety in prostate 
cancer patients. It is designed to evaluate three separate aspects of prostate cancer 
specific anxiety on 3 subscales: anxiety related to prostate cancer in general (prostate 
cancer anxiety subscale), anxiety specifically centered around PSA testing (PSA anxiety 
subscale) and fears of cancer recurrence (fear of recurrence subscale). The MAX-PC9 
demonstrated high internal reliability with a Cronbach’s alpha of 0.89, with subscale 
reliabilities between 0.59-0.90 and has been validated in prostate cancer patient 
samples.51 Finally, we will evaluate Prostate Cancer-specific Quality of Life. Prostate- 
specific QOL will be measured with the Expanded Prostate Cancer Index Composite 
(EPIC-SF12).52 Development of the EPIC was based on the widely used University of 
California Los Angeles Prostate Cancer Index and has been used extensively to assess 
post-treatment related dysfunction among prostate cancer patients. The EPIC has 
demonstrated excellent reliability (i.e., Cronbach’s >.91) across sexual function and 
sexual bother composites. The EPIC questionnaire will be used to measure changes in 
QOL over time. For this study, a combined EPIC-SF12 questionnaire will be used.
There has been a significant amount of research showing a link between lifestyle 
modifications pertaining to diet and exercise and improved prostate cancer outcomes. 
As a result, we would like to collect information on patient’s diet and exercise habits to 
see how changes in these modifiable factors can impact progression on active 
surveillance. For this purpose we will use the food frequency questionnaire (FFQ). The 
FFQ forms are optional for the patient and can be refused. All questionnaires will be 
available in English and Spanish.
2.
HYPOTHESES
1) Multiparametric MRIus-guided or direct MRI-guided biopsies will allow for 
more directed sampling of the tumors from compartments with distinct MP- 
MRI characteristics, termed habitats, that will increase the rate of 
“progression” on early (first and second) surveillance biopsies and decrease 
the rate of “progression” on late (third and further) surveillance biopsies 
compared to historic TRUS-guided biopsy rates.
2) Identifying higher risk tumor early on will reduce the proportions of patiens 
with poor response to delayed primary treatment
3) Radiomics signatures from MP-MRI will define patterns that are associated with 
progression
4) Genomic signatures based on RNA from tumor tissue will define patterns that 
are associated with habitats and radiomics signatures, as well as progression.
 
        
 
 

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3.
OBJECTIVES
3.1
Primary Objective
To determine if multiparametric MRI and MRI-US fusion biopsies increase the 
rate of progression (conversion to treatment) within the first two non-diagnostic biopsies 
after undergoing active surveillance as compared to historical cohorts using standard 
ultrasound guided biopsies.
3.2
Secondary Objectives
1) To identify whether earlier identification of progression with MRI and MRI-US 
fusion biopsy will portend improved outcomes of patients undergoing delayed 
primary surgery or radiation after initial surveillance at the University of Miami
2) To determine the effect of multiparametric MRI and MRI-US fusion biopsy on 
health related quality of life and cancer specific anxiety using patient reported 
validated questionnaires.
3) To determine the incremental benefit of mpMRI, genomic risk test, and 
molecular marker at baseline compared to NCCN risk class for predicting 
progression on Active Surveillance
3.3
Exploratory Objectives
1) To define radiomic signatures on multiparametric MRI that select regions of the 
prostate that are likely to harbor more aggressive disease.
2) To molecularly characterize tissue from the muliparametric habitat-directed 
prostate biopsies and develop genomic signatures of indolent versus 
progressing prostate cancer using a 1.4 million feature oligonucleotide 
microarray capable of global high throughput analysis of formalin fixed 
paraffin embedded specimens.
3) To relate radiomics and genomics signatures to existing urine, serum and 
tissue biomarkers that have been associated with prostate cancer diagnosis 
and/or progression.
4) To determine the incremental benefit of mpMRI, genomic risk testing, and 
molecular markers at baseline compared to NCCN risk class for predicting 
reclassification on confirmatory baseline biopsy.
5) To evaluate serial changes in mpMRI, genomic risk scores and molecular 
markers and relate them to progression on active surveillance.
4.
STUDY DESIGN
Single arm therapeutic trial investigating the impact of MRI and MRI-US fusion 
biopsy to identify higher grade or volume tumors early on for better selection of patients 
for active surveillance and improved outcomes for those undergoing delayed treatment 
after initial observation. MRI–US fusion biopsy will include targeting of suspicious 
areas seen on MRI as well as segmented sampling of the remaining gland. Patients will
 
        
 
 

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undergo MRI and MRI-US fusion biopsy within 3 months of enrollment in the trial and
have repeat MRI-US fusion biopsies every year to assess overall rates and the temporal 
distribution of progression. Serum, urine and prostate biopsy tissue will be serially 
collected to investigate the association between various molecular biomarkers and 
radiologic and histological progression.
Patients who are found to have cancer progression will undergo either radical 
prostatectomy or prostate dose escalated (EQD2 >78Gy) image guided radiotherapy of 
the prostate. Although patients will be encouraged to seek treatment at the University of 
Miami to continue follow up on trial, we understand that patients may select to be 
treated elsewhere and this would not be considered a deviation from the protocol. Men 
undergoing surgery will have their pathology specimen compared to men in the 
University of Miami active surveillance database who had surgery after initial 
surveillance without MRI. After surgery men will be followed every 3-6 months (+/- 2
months) for the first year, every 6-12 months (+/- 3 months) in the second year, and
annually (+/- 6 months) thereafter up to 5 years post surgery. Any adjustments to this 
schedule will be permitted under the discretion of the clinician. A PSA of 0.2 ng/ml with 
a repeat value showing the same or higher will be used to define biochemical 
recurrence post radical prostatectomy. For men undergoing radiation therapy, the 
method and dose of radiation that will be delivered will be left to the discretion of the 
treating physician. For men undergoing radiotherapy of the prostate, follow up serum 
PSA testing should occur every 6 months (+/- 3 months) for the first 3 years and then 
annually thereafter (+/- 6 months) for up to 5 years post treatment.
A PSA of 2 ng/ml above the nadir will be used to define biochemical failure post 
radiation. Rates of biochemical recurrence post surgery or radiation will be compared to 
historical data of men being treated after initial surveillance at the University of Miami.
The choice to use androgen deprivation therapy will be left to the discretion of the 
treating physician. Follow up and treatment protocols have purposely been made broad 
to allow enrollment on other interventional trials for which a patient may be eligible. If 
the patient enters a radiation oncology clinical trials, then the timing of PSA and other 
labs will be timed in accordance with the radiation treatment protocol.
The flow chart shown in Figure 1 illustrates the surveillance portion of the 
sequence that patients will go through if entered in the study. The post treatment flow 
chart for those who progress has purposely been left out to avoid prevention of patients 
enrolling on other intervention trials for which a patient may be eligible. Patients will be 
recruited for protocol participation from the pool of men seen for management of 
prostate cancer by physicians at the University of Miami. Those patients that sign an 
informed consent form for the study will be screened by the study investigators for 
fulfillment of eligibility criteria. Once the University of Miami Pathologic review is 
completed and all eligibility requirements are met, the patient will be registered in the 
study. Additionally, the patient will be asked to participate in the Urology Active 
Surveillance database for comparison with other active surveillance patients available in 
that database.
4.1
Accrual goal
The accrual goal for this study is 230 patients or approximately 46 patients per 
year for 5 years.
4.2
Duration of Study Participation
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Duration of study treatment will be a maximum of 60 months from enrollment and four 
biopsies for patients who do not progress. After the end of study, the patient will be 
followed, if consented, in the department of Urology active surveillance database as per 
their clinician’s standard of care.
5.
STUDY ENTRY AND ENROLLMENT AND WITHDRAWAL
5.1
Study Entry
Study entry, as used in this protocol, will be defined as a subject signing informed 
consent. Study enrollment, as used in this protocol, will be defined as the investigator’s 
confirmation of the subject’s eligibility by signing an eligibility checklist.
5.2
Enrollment Procedures
As per UM/SCCC Clinical Research Services policy, eligibility must also be 
reviewed by a CRS director or designee. The investigator or study coordinator will 
provide the following to a CRS representative:
1) Completed and signed protocol-specific eligibility checklist;
2) All pages of the original signed informed consent forms (ICFs), including 
HIPAA Form B;
3) Relevant source documents such as: subject medical history and physical 
exam, admission or discharge notes, diagnostic reports, pathologic 
confirmation of diagnosis, and relevant subject-specific written 
communication.
5.3
Cancellation Guidelines
The following are reasons for withdrawal of subjects from the study:

a subject does not meet the eligibility criteria, (the subject will be 
considered a screen failure).

a subject withdraws consent,

a subject dies during protocol participation or

a study investigator decides the subject should be withdrawn from the 
study (e.g. subject non-compliance)
Contact the CRS representative, or e-mail the information including the reasons 
for withdrawal as soon as possible, but no later than 48 hours after the event/decision.
6.
PATIENT SELECTION/ELIGIBILITY CRITERIA
Patients with low to low-intermediate risk prostate cancer are eligible for the 
study. Eligibility criteria for involvement in the study have been made broad enough to 
allow for most men who have relatively low volume Gleason score 6-7 disease to 
participate. Patients will be recruited from the pool of men seen for management of 
prostate cancer by physicians at the University of Miami.
6.1
Inclusion (Eligibility) Criteria
1) Biopsy confirmed adenocarcinoma of the prostate within 18 months prior to 
enrollment;
2) Pre-enrollment prostate biopsy must consist of at least 8 cores;
3) Biopsy reviewed by a University of Miami Pathologist;
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5) Age ≥35 and ≤85 years;
6) Ability to understand and willingness to sign a written informed consent
document;
7) Patients must agree to undergo serial multiparametric MRI and MRI-guided 
biopsy;
8) Patients must agree to fill out the longitudinal psychosocial questionnaires 
assessing health related quality of life.
6.2
Exclusion (Eligibility) Criteria
1) Greater than 4 cores positive, of any Gleason score, on the UM review,
2) Greater than 2 cores positive for Gleason 3+4 cancer,
3) Gleason 4+3 or higher cancer in any single biopsy core.
4) Extracapsular extension suspected on digital rectal exam with confirmation on 
MRI. Suspicion of extracapsular extension on MRI alone is not an exclusion 
for study enrollment.
5) Subject is not a candidate for multiparametric MRI with contrast. Some 
reasons may include (but are not limited to): renal insufficiency, foreign body 
or pacemakers.
6) No prior pelvic radiotherapy
7) No prior surgery to the prostate, other than transurethral procedures for 
benign prostatic hyperplasia (e.g., transurethral resection, green light laser 
treatment)
8)
No concurrent, active malignancy, other than non-metastatic skin 
cancer of any type, superficial bladder cancer, or early stage chronic 
lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma) 
or <stage IV follicular lymphoma. If a prior malignancy is in remission for ≥ 
3 years then the patient is eligible.
9) Bilateral hip replacement.
6.3
Gender and Ethnicity
Prostate cancer is a disease of adult men, with exceptionally few diagnosed at 35 
years of age. Therefore, women and children are not candidates for this protocol. Based 
on standard NIH definitions, we estimate that approximately 40% of patients will be White, 
24% African American, 35% Hispanic and 1% other at the University of Miami.
7.
CLINICAL, RADIOLOGICAL AND LABORATORY EVALUATIONS
7.1
Screening Evaluations

History and physical exam, within 12 months prior to protocol enrollment.

Serum PSA (+/-) 3 months of protocol enrollment.

Pathology review at the University of Miami of the outside biopsy material, 
prior to enrollment.
7.2
Evaluations During Intervention*

Multiparametric MRI obtained at the University of Miami (+/-) 3 months of 
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
MRIus-guided biopsies will be obtained at 0 to 3 months from enrollment 
(“initial biopsy”) and at 12, 24 and 36 month from initial biopsy.

History and physical at the discretion of the treating physician. Treating 
physician can be outside of UM..

Serum PSA will be done preferably every 6 months or at least once a year up 
to 36 months from the initial biopsy. If the subject progress, PSA should be 
done every 6 months (+/- 3 months) or at the discretion of the clinician for the 
first 3 years and then annually thereafter (+/-6 months) for up to 5 years post 
treatment.

If possible, plasma and/or serum (up to 5 tubes)) for research purposes 
(biomarkers) may be obtained at 0 to 3 months from enrollment and at 12, 
24, and 36 months from initial biopsy (optional - patient may refuse),

If possible, post prostate-massage urine (approximately 50 mL) may be 
collected for research purposes at 0 to 3 months from enrollment and at 
12, 24, and 36 months from initial biopsy (optional - patient may refuse). 
Urine research collection will not be done if research funds are not 
available.

Quality of Life surveys obtained 0 to 3 months after enrollment and every 12 
months from initial biopsy:
- Expanded Prostate Cancer Index Composite Questionnaire (EPIC+SF12)
- Memorial Anxiety Scale for Prostate Cancer patients (MAX-PC)
- Optional - Food Frequency Questionnaire (FFQ) will be collected only 
atbaseline.
* Follow-up evaluations and visits may occur ± 1.5 months around each scheduled 6- 
month timepoint. For example, for the 6 month follow-up, the patient may be seen anytime 
between 4.5 and 7.5 months from the time of the first prostate biopsy. For the 12-month follow- 
up, the patient may be biopsied between 10.5 and 13.5 months from the time of the first 
prostate biopsy. Since the first biopsy may be from between 0-6 months from the day the 
patient is enrolled, each subsequent calendar event is timed in reference to the time of that first 
biopsy.
7.3
Early discontinuation of study participation
Patients who experience protocol-defined progression will have attained the 
primary study outcome and will undergo treatment either with radical prostatectomy or 
whole gland image guided radiotherapy of the prostate at the University of Miami. Their 
histopathology (for surgery patients) and rates of biochemical recurrence will be 
followed and compared to historical series for comparison with cohorts not undergoing 
MRI guided selection for surveillance versus immediate treatment. However, those who 
refuse the recommendation for treatment will continue to be followed per active 
surveillance standard of care guidelines. Furthermore, those who seek treatment 
outside UM will be contacted for information on histopathology (for those undergoing 
surgery) and rates of biochemical recurrence. Patient refusal of the recommendation 
for treatment or further follow-up beyond progression will not be a protocol deviation.
Patients who are without progression upon completion of the third annual biopsy will be 
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7.4
Multiparametric MRI
Multiparametric MRI exam of the pelvis and prostate, including T2, T1 non- 
contrast, T1 DCE and DWI MRI scans will be carried out at the GE Discovery MR750 
3T MRI unit located at the University of Miami on 3T MRI at the University of Miami. 
The GE Discovery MR750 3T in the department of Radiation Oncology is preferred, but 
not mandated. Standard contraindications to MRI, such as ferromagnetic metal in 
body/eye, pacemaker, defibrillator, other mechanical device, or extreme claustrophobia 
(medication with anti-anxiety agents, such as Ativan, may be attempted) will prevent 
eligibility and will be applied for all protocol-related MRIs. Since the DCE-MRI scan 
involves the use of gadolinium, renal function should be assessed per routine policies.
A preparation procedure protocol has been developed to optimize the 
multiparametric MRI (see Appendix III) and will be recommended to the patient, but not 
mandated. A diet designed to reduce bowel gas will also be recommended to begin the 
day before the diagnostic MP-MRI. This protocol is a guide and slight variations are 
acceptable. Imaging parameters will be recorded on each patient in the CRFs. As a 
quality control measure, every MP-MRI will be reviewed by the study team within 45 
days for adequacy. If the MP-MRI is deemed inadequate, another MRI will be 
requested within 30 days. An inadequate exam at that point will be deemed a protocol 
deviation. De-identified data will be sent to Moffitt Cancer center for radiomics as 
described below.
7.5
Prostate Biopsy
Standard antibiotic prophylaxis of will be at the discretion of the physician 
managing the biopsy. Aspirin, anticoagulants and vitamin supplements will be 
temporarily discontinued at least one week prior to the procedure, per routine; these 
drugs may be restarted per standard practice for prostate biopsies (typically a day or 
two later if there is no bleeding). The typical and recommended procedure involves 
placement of the patient in the left lateral decubitus position. Immediately prior to the 
procedure, 10 cc of 1% Lidocaine may be injected into the periprostatic nerve plexus 
under ultrasound guidance, typically using a 22 gauge 7-inch needle. The syringe is 
aspirated before the lidocaine injection to prevent unintentional injection into the 
vascular compartment. An ultrasonographic wheal may be viewed in the sagittal plane 
between the rectal wall and base of the seminal vesicles.
Transrectal ultrasound biopsies will be performed on an FDA-approved device using 
standard techniques. Twelve to fourteen needle core biopsies are desired, but the 
managing physician may opt for fewer, if there are complications or other indications, or 
more, if an area of interest was felt to be inadequately biopsied (needle misdirection or 
other reason). The managing physician will be a co-investigator and will understand the 
protocol goal of 12-14 cores per prostate biopsy. The arrangement that is recommended 
(not mandatory) will be left lateral base (LLB), left lateral mid (LLM), left lateral apex (LLA), 
left medial base (LMB), left medial mid (LMM), left medial apex (LMA), right lateral base 
(RLB), right lateral mid (RLM), right lateral apex (RLA), right medial base (RMB), right 
medial mid (RMM) and right medial apex (RMA). Transition zone biopsies may be 
acquired. The MRIus biopsies will be performed in the same fashion, but corresponding 
needle cores will be targeted towards the suspicious areas (see Figure 6). During the 
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biopsy. If this is the case, or if gross blood is noted
at the urethral meatus, bladder catheterization and clot irrigation may be indicated, as 
determined by the urologist.
The procedure will be performed by an urologist in the Department of Urology 
(SP) at the University of Miami. For patients with MRI visible lesions, an MRI-US fusion 
biopsy will be performed in addition to the standard template (above). MRI-US fusion 
biopsies will be performed preferably using the Uro-Nav system from Invivo, Philips; 
although, the Artemis system is available in the department of urology and may be 
used.
7.5.1 MRI-Ultrasound (MRI-US) Registration for Targeted Prostate Biopsy
MRI-US fusion biopsy will be performed on an FDA approved platform (e.g., 
UroNav, In Vivo). The approach begins with multiparametric MRI of the prostate as 
described above. Expert radiologists will interpret the MRI with the assistance of in- 
house and/or commercially available software. Suspicious lesions will be determined 
based on multiple parameters and delineated on the MRI by a panel of expert 
radiologists with experience reading prostate MRI. Biopsy needle localization and 
tracking is recorded by an external magnetic field while the biopsy is performed using 
freehand transrectal ultrasound. Once the MRI is loaded onto the software platform, an 
initial transrectal ultrasound sweep of the prostate of the prostate is performed, and a 
rigid image fusion is performed allowing clinicians to see both the MRI and ultrasound 
images moving together in real time. The lesion on MRI is then targeted using 
ultrasound to ensure the correct depth and course of the needle to ensure the needle 
enters the suspicious area. By using freehand ultrasound, a technique familiar to 
urologists, the learning curve for the procedure is steep and the workflow preserved 
allowing a quick procedure for the patient.
7.6
Biopsy Tissue Handling
Immediately following each biopsy core, the tissues will be fixed in 10% formalin 
per routine. The formalin fixed tissues will be delivered to the Department of Pathology 
for paraffin embedding and sectioning.
The biopsies are to be placed in the tissue processor and processed routinely, 
and embedded in paraffin. Biopsies will be reviewed by a pathologist and the results 
(Gleason scoring and percent of tumor tissue) recorded in the patient’s record per 
routine. The remainder of the block will be stored per institutional policy in the 
Department of Pathology and requests for the biomarker analyses made at a time 
batched staining is possible (after a number of cases have been accrued).
When the tissue is sectioned for biomarker analyses, the slides will be labeled 
with a research ID number and will not contain patient information. Biomarker data will 
be entered into the Active Surveillance Database, which links the patient Medical 
Record number to a participant's Research ID number and in which data on each 
patient related to biopsies and treatments will be recorded. De-identified data will be 
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7.7
Molecular Analyses of Blood and Urine
The objectives are to identify and examine molecular and genomic biomarkers in 
blood products and the urine that predict for disease progression and see how they 
correlate with radiomic and genomic signatures from distinct regions of the prostate.
Blood may be collected at baseline, and at 12, 24 and 36 months after initial 
biopsy. Urine post prostate massage may be collected at baseline and 12, 1,24 and 36 
months after initial biopsy. Note that the collection of research fluids is optional – the 
patient can refuse the procedure. While these are exploratory studies, of key 
importance is to have such samples collected prospectively on a well-defined group of 
patients. Any urine or blood that is not used for specific biomarker testing will be stored 
for biomarkers development or validation.
7.8
Quality of Life and/or Outcomes
Psychosocial assessments will be conducted by a trained and fully-bilingual 
clinical coordinator/research nurse with experience in conducting psychosocial 
assessments in prostate cancer populations. We will make every effort to pair our 
psychosocial assessment visits with scheduled clinic appointments to reduce participant 
burden. The psychosocial battery will last between 30-40 minutes. All assessments will 
be conducted in private rooms in our clinics. All psychosocial data will be de-identified 
and only coded by participant number. Should a participant display any significant signs 
of distress (e.g., high levels of anxiety, depressed mood or spontaneous comments 
suggesting a need for psychosocial care), we will refer participants to appropriate 
psychosocial resources within our medical center.
7.9
Treatment
Men undergoing protocol defined progression will undergo for radical prostatectomy, 
prostate dose escalated (EQD2 >78Gy) image guided radiotherapy of the prostate, HiFu 
or any other prostate treatment. Although patients will be encouraged to seek treatment 
at the University of Miami to continue follow up on trial, we understand that patients may 
select to be treated elsewhere and this would not be considered a deviation from the 
protocol. Both treatment modalities are offered at the University of Miami and portend 
excellent cancer control in men with localized tumors. Patients will be counseled 
regarding with risks and benefits of both approach’s to allow for informed decision- 
making between the two options. Men undergoing surgery will have their pathology 
specimen compared to men in the University of Miami active surveillance database who 
had surgery after initial surveillance without MRI. After surgery men will be followed 
every 3-6 months (+/- 2 months) for the first year, every 6-12 months (+/- 3 months) in 
the second year, and annually (+/- 6 months) thereafter up to 5 years post surgery. Any 
adjustments to this schedule will be permitted under the discretion of the clinician. A 
PSA of 0.2 ng/ml with a repeat value showing the same or higher will be used to define 
biochemical recurrence post radical prostatectomy. For men undergoing radiation 
therapy, the method and dose of radiation that will be delivered will be left to the 
discretion of the treating physician. For men undergoing radiotherapy of the prostate, 
follow up serum PSA testing should occur every 6 months (+/- 3 months) for the first 3 
years and then annually thereafter (+/- 6 months) for up to 5 years post treatment. A 
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Rates of biochemical recurrence post-surgery or radiation will be compared to historical
data of men being treated after initial surveillance at the University of Miami. Androgen 
deprivation will be prescribed at the discretion of the treating physician. Men who 
decline treatment despite progression and recommendation for treatment will be 
followed as per standard of care active surveillance criteria. Men who desire to undergo 
their treatments at centers outside the University of Miami will be contacted to attain 
post treatment oncologic data, as described above. Patient refusal to undergo treatment 
based on the protocol will be follow as per the treated physician. If the patient chose to 
seek treatment elsewhere will be left to the clinician and patients discretion and will not 
be considered a deviation of the protocol.
If the patient enters a radiation oncology clinical trial, then the timing of PSA and 
other labs will be timed in accordance with the radiation treatment protocol.
8.
ADVERSE EVENT REPORTING
During the active surveillance part of the study, the only difference is the addition 
of a multiparametric MRI and MRI-US fusion biopsies in addition to random biopsy. The 
only adverse events expected from obtaining an MRI would include allergic reaction to 
the contrast, renal toxicity, or claustrophobia. Other than guidance by MRI, the prostate 
biopsy will be performed in the same fashion as standard biopsy of the prostate and 
therefore carries no increased risk from bleeding or infection. The addition of MRI 
guided biopsy has not been shown to increase the risk of infection or bleeding, 
compared to random biopsies alone.53 These procedures are standardized and the risks 
well-documented. In the unlikely event that a study patient experiences an adverse 
reaction to a study related procedure, this will be reported the University of Miami 
Institutional Review Board as per their policies and using the grading scales of the NIH 
CTCAE version 4.0.
If the patient progress and decide to undergo either radical prostatectomy or 
radiotherapy or any other procedure:
8.2.1
Recording Abnormal Findings
In any clinical assessment, a value outside the normal or reference range (such as 
a clinical laboratory, vital signs, imaging findings or EKG findings) will not be recorded or 
assessed as an adverse event unless that value is considered to be of clinical significance 
by the investigator
8.2.2
Recording Signs and Symptoms
Sign, symptoms, or procedures resulting from an underlying clinical diagnosis 
should be documented as one comprehensive adverse event. If no underlying clinical 
diagnosis can be identified, each sign and symptom should be recorded as a separate 
independent event.
However, a new or worsening event resulting from an underlying clinical diagnosis 
or a reaction to concurrent medications should be documented as a separate independent 
adverse event unless it is within the normal range of fluctuation for that patient.
 
        
 
 

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8.2.3
Recording Grade Changes
Adverse events will be recorded at the maximum grade/severity experienced 
for the duration of the event. Should one particular AE warrant further 
investigation, additional details may be collected at the discretion of the 
adverse event;
8.2.4
Reporting Period
Adverse Events relating to radical prostectomy and radiotherapy that are not 
related to MRI or MR biopsy, will not be documented in the adverse event log. 
Concominant medication will not be recorded after the subject progress.
8.2.5
IRB Reporting
All adverse events that are serious adverse events and are unexpected and are 
related or possibly related IRB within ten (10) working days of being made known to the 
Principal Investigator. Events that are more frequent than anticipated or more severe 
than expected must be reported to the IRB within ten (10) working days of being made 
known to the Principal Investigator.
All unanticipated deaths or life-threatening problems suspected as being a direct 
outcome or possibly an outcome of the study intervention must be reported to the IRB 
within 24 hours of being made known to the Principal Investigator.
For all SAE’s, the investigator is obligated to pursue and provide follow-up reporting 
information until the event has resolved or until an acceptable medical endpoint has 
been reached or the patient is lost to follow-up.
9.
DATA AND SAFETY MONITORING PLAN
The study investigators will report to the Sylvester Comprehensive Cancer 
Center Data and Safety Monitoring Committee (DSMC) to ensure data quality and 
subject safety. The investigators will conduct continuous reviews of the data and subject 
safety, keeping track of the number of subjects, significant toxicities in accordance with 
the protocol and observed responses, which will be discussed at DSMC committee 
meetings. All grade 3-5 adverse events will be entered into Velos and reviewed at 
DMSC meetings. In addition, all adverse reactions considered “serious” will be entered 
into Velos and reviewed by the DSMC on an ongoing basis. If an increase in the 
frequency of grade 3 or 4 adverse events is noted in the study, a report will be 
submitted to the DSMC at the time the increased rate is identified. If at any time the 
principal investigator stops enrollment or stops the study due to safety issues, the 
DSMC chair and manager will be notified within 1 business day and a formal letter will 
be sent to the DSMC to be received within 10 business.
10.
STATISTICAL CONSIDERATIONS
This is a single-arm trial with the primary objective of determining the rate of 
progression over 2 years in men undergoing AS who are managed with multiparametric-
 
        
 
 

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MRI and MRI-US fusion prostate biopsies, as compared to historical controls. The
primary study endpoint is the 24-month cumulative progression rate based on biopsy 
criteria.
10.1
Primary Study Endpoints
10.1.1 Progression
The main study endpoint will be the 24-month cumulative progression rate. In 
the context of this trial, progression refers to a repeat surveillance biopsy indicating any 
one of the following: (i) more than 4 positive cores involving any grade of cancer, (ii) ) 
three or more cores with Gleason 3+4 cancer, (iii) any single core with Gleason 4+3 
cancer or higher, (iv) a Gleason 3+3 at diagnosis that is upgraded to Gleason 3+4 or (v) 
undergoing treatment, regardless of histological progression. Although many existing 
active surveillance protocols incorporate volume of cancer in their definition of 
progression, these are based on random biopsy of the prostate. Critical volumes of 
cancer based on targeted biopsy have not been defined and will be explored in this 
analysis.
o
Progression rate will be estimated for each scheduled surveillance biopsy as the 
proportion of study patients without prior progression for whom the biopsy 
indicates progression.
o
Cumulative progression rate will be estimated for each of the four planned 
biopsies as the proportion of patients with progression among those having had 
all planned biopsies to date, or a previous biopsy indicating progression.
10.1.2 Histological progression
In the context of this trial, histological progression refers to a surveillance biopsy that 
indicates any one of the following: (i) more than 4 positive cores involving any grade of 
cancer, (ii) three or more cores with Gleason 3+4 cancer, (iii) a Gleason 3+3 at 
diagnosis that is upgrade to Gleason 3+4, or (iv) any single core with Gleason 4+3 
cancer or higher.
o
Histological progression rate will be estimated for each scheduled biopsy as the 
proportion of study patients without prior GS progression for whom the biopsy 
indicates GS progression.
o
Cumulative histological progression rate will be estimated for each scheduled 
biopsy as the proportion of patients with histological progression among those 
having had all planned biopsies to date, or a previous biopsy indicating Gleason 
score progression.
10.2 Secondary Study Endpoints
10.2.1 Time-to-Biochemical recurrence
Biochemical recurrence (BCR) is defined as PSA of 0.2 or higher on two or more separate 
measures after surgery or an increase of nadir + 2ng/ml or more after radiation. Time-to- 
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10.2.2 QOL scores 
Three contemporary instruments will be utilized to assess patient function and bother 
(Expanded Prostate Cancer Index Composite (EPIC), physical and mental health (SF12) 
and prostate cancer-specific anxiety Memorial Anxiety Scale for Prostate Cancer patients 
(MAX-PC). Each of these measures will be assessed via the specific scoring instructions 
for each instrument. Given that this is a single arm trial, we will compare patient reported 
quality of life to historical active surveillance cohorts to see if MRI and MR targeted biopsy 
of the prostate improves patient quality of life.
10.2.3 Area under ROC curves as predictive measure and incremental prediction improvement 
for progression
Patients will be categorized at baseline by NCCN risk class ranging from very low risk to 
intermediate risk and into those who progressed while on the trial and those who did not. 
Logistic regression will be used to model the association between NCCN risk class and 
progression using AUC for ROC curves. The incremental benefit of mpMRI, genomic 
testing and molecular markers compared to NCCN risk alone will be evaluated by 
comparing AUC using a likelihood ratio test. MRI will be categorized from 1-5 using 
PIRADS, while genomic test scores and molecular markers can be used as continuous 
scores or categorized into levels of risk (low/ intermediate/high).
10.3 Exploratory Study Endpoints
10.3.1 Radiomic signatures extracted from MP-MRI prostate exam
The MP-MRI prostate exam is composed of three modalities which represent 
anatomy, cellularity and blood flow. The contiguous regions across a modality based on 
a given criterion are referred to as habitats. Here we propose a computational method 
to connect three modalities (T2, DWI and DCE) to find regions of interest that will 
characterize the prostate beyond the tumor location. The three modalities are 
registered with MIM Software which provides high level of accuracy of alignment. Two 
Regions of Interest (ROIs): Prostate and Peripheral Zone (PZ) are manually contoured 
in MIM. The pixels within the prostate are classified in three groups based on the 
distribution of the pixel intensity. In our approach, the subpopulation obtained by the 
categorization will be called high, low and uncertain with respect to the pixel intensities.
Prostate biopsies will be placed in reference to the dominant and non-dominant SImTVs 
identified. The biopsy histopathologic results (i.e., percent core tumor tissue, Gleason 
score and percent Gleason grade 4) will then inform us on the relevance of the 
habitat(s).
10.3.2 Genomic signatures extracted from biopsy
493 genes in 16 pathways that include apoptosis, base excision repair, DNA 
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homologous end joining, hypoxia, p53 signaling, prostate cancer signaling, androgen 
receptor signaling, and cell cycle checkpoint (including G1/S, G2/M & mitotic spindle 
checkpoint) will be assessed using a 1.4 million feature oligonucleotide microarray by 
GenomeDx as discussed above. Some of these pathways might also be useful in 
determining response to treatment and it would be beneficial to understand the timing of 
gene expression changes occur during the AS period and how such changes relate to 
alterations in imaging features. We will develop a predictive model including 493 genes 
in 16 pathways.
10.3.3 Area under ROC curves as predictive measure and incremental prediction 
improvement for progression on baseline biopsy.
Patients will be categorized at baseline by NCCN risk class ranging from very low risk to 
intermediate risk and into those who progressed on the baseline biopsy and those who did 
not. Logistic regression will be used to model the association between NCCN risk class 
and progression using AUC for ROC curves. The incremental benefit of mpMRI, genomic 
testing and molecular markers compared to NCCN risk alone will be evaluated by 
comparing AUC using a likelihood ratio test. MRI will be categorized from 1-5 using 
PIRADS, while genomic test scores and molecular markers can be used as continuous 
scores or categorized into levels of risk (low/ intermediate/high).
10.3.4 Serial changes in markers related to progression
mpMRI, genomic scores and molecular marker scores will be assess and associated 
to the risk of progression on trial using mixed model repeated measures adjusted for 
relevant demographic and clinical factors.
10.4
Sample size, accrual rate and study duration
We plan to accrue approximately 55 patients per year for the first three years of 
the study; this assumes a 10% dropout rate. The power (97.3%), is based on 150 
patients, using a two-sided binomial test at the 5% significance level to detect an 
increase in the 24-month cumulative progression rate from 12.5%, as expected for AS 
historically, to 25% for MRI-AS. Enrollment will occur during the first 3.25 years.
Enrollment will be completed at < 3.33 years from the enrollment of the last patient.
 
        
 
 

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10.5
Statistical Analysis
Descriptive statistics will be done for patient demographics and baseline disease 
characteristics. Counts and percentages will be used to summarize the distribution of 
categorical variables while median, range, mean and standard deviation will be used 
for continuous variables. Baseline characteristics will include age, race/ethnicity, T- 
stage, Gleason score, PSA, PSAD and performance status. Continuous scores will be 
compared using ANOVA and linear regression controlling for common demographic 
and clinical variables.
For each scheduled surveillance biopsy session, we will tabulate patients and 
the following status categories: biopsy indicating progression, biopsy negative for 
progression, biopsy not performed for progression detected on earlier biopsy, biopsy 
not performed because patient refused, or biopsy not performed because patient 
dropped out of study.
Time to event endpoints such as progression and BCR will be analyzed by 
Kaplan-Meier (KM) or competing risk (CR) methods. Where the Kaplan Meier method is 
used, point estimates and two-sided 95% confidence intervals for rates will be reported 
for selected times using Greenwood’s variance and the log-log transform method.
Median survival time, if attained, will also be reported. We will report the progression 
rate and the cumulative progression rate for each surveillance biopsy. Taking the third 
scheduled biopsy at the end of 2 years as illustration, the progression rate at 24 
months is the proportion of biopsied patients indicating progression among the total 
number of biopsied patients over the 24 month period. The 24-month cumulative 
progression rate is the primary endpoint, which will include those who complete the first 
three biopsies or have progression from the first or second biopsy. The primary 
endpoint, 24-month cumulative progression rate, will be estimated and reported with 
corresponding 95% confidence intervals. Groups will be compared by the log rank test. 
In addition, we will report and plot the cumulative progression rates in each arm for the 
four scheduled surveillance biopsies. It is expected that the early difference with 
historical values and those obtained with MRI-guided biopsies will not be sustained; 
that is, the 36-month cumulative progression rates will be approximately equal. Similar 
estimation of time-specific and cumulative rates will be done for Histological 
progression.
For radiomic signatures, gene signatures, and other biomarkers such as 
Gleason score and percent positive tissue (PPT), descriptive statistics (counts and 
percents; median and range; mean and standard distribution) and box plots will be 
used to summarize the distribution of the variables. In particular, once the habitats are 
defined, imaging features may be extracted. These features describe characteristics of 
the image intensity histograms (e.g., high or low intensity), tumor shape (e.g. round or 
spiculated), texture patterns (e.g. homogeneous or heterogeneous), as well as tumor 
location. We will consider a two-stage feature selection approach. In the first step, we 
will filter out “radiomics” variables using standard t-test or ANOVA and in the second 
step; we will perform random forests to identify radiomics signatures of habitats in 
relation to risk groups. Genes will be selected using Significance Analysis of Microarray 
(SAM) in R package, which allow the determination of significantly differentially 
expressed genes between classes (HP-Risk 1-4) controlling the Benjamini-Hochberg 
false discovery rate (FDR). The augmented classifiers predictive model will be 
developed using multivariate ordinal logistic regression. We will use area under the
 
        
 
 

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receiver’s operating characteristic curve (AUC) with 10-fold cross-validation approach
to evaluate performance of prediction model. Radiomic profiles on multi-parametric MRI 
that suggest regions of the prostate that are suspicious for more aggressive prostate 
cancer will be correlated to histopathologic findings from biopsy of these regions.
Genomic profiles from tissue cores in each region will be correlated to radiomic profiles 
and histopathology from that region to see what each adds to improving the ability to 
predict patients who are likely to harbor more aggressive tumors that would portend 
poor outcome on active surveillance. Radiomic and genomic profiles from MRI 
targeted biopsies will be compared to segmental biopsies to see if profiles from 
targeted biopsies are more informative for risk assessment compared to segmental 
biopsy using longitudinal analysis approach. We will also assess how these profiles 
change over time in serial imaging and biopsy and see if/ how these profile changes 
correlate to change in histopathology. We will also relate genomic and radiomic profiles 
of the prostate to common serum and urinary markers that have been used predict 
progression on active surveillance. For continuous outcomes, association between 
outcome and other covariates will be examined using linear regression model and 
correlation coefficient. For binary outcomes and time-to-event outcomes, logistic 
regression and Cox proportional hazards regression will be used, respectively. All tests 
will be two-sided and statistical significance will be considered when p<.05 after 
multiplicity adjustment.
10.6 Interim monitoring
Since this is a single arm trial, we do not propose any planned interim analysis or 
early stopping guidelines.
11.
INVESTIGATOR’S RESPONSIBILITIES
11.1 Investigator Responsibility/Performance
The investigator will ensure that this study is conducted in accordance with all 
regulations governing the protection of human subjects.
The investigator will ensure that all work and services described in or associated 
with this protocol will be conducted in accordance with the investigational plan, 
applicable regulations, and the highest standards of medical and clinical research 
practice.
11.2 Confidentiality
The investigator must ensure that each subject’s anonymity will be maintained 
and each subject’s identity will be protected from unauthorized parties. A number will 
be assigned to each subject upon study entry and the number and the subject’s initials
will be used to identify the subject for the duration of the study. The investigator will
maintain all documents related to this study in strict confidence.
11.3 Informed Consent and Permission to Use Protected Health Information
It is the responsibility of the investigator to obtain written informed consent from 
each subject participating in this study after adequate explanation, in lay language, of 
the methods, objectives, anticipated benefits, and potential hazards of the study. The 
investigator must also explain that the subject is completely free to refuse to enter the 
study or to discontinue participation at any time (for any reason) and receive alternative 
 
        
 
 

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conventional therapy as indicated. Prior to study participation, each subject will sign an 
IRB approved informed consent form and receive a copy of same (and information 
leaflet, if appropriate). For subjects not qualified or able to give legal consent, consent 
must be obtained from a parent, legal guardian, or custodian.
The investigator or designee must explain to the subject before enrollment into 
the study that for evaluation of study results, the subject’s protected health information 
obtained during the study may be shared with the study sponsor, regulatory agencies, 
and the IRB. It is the investigator’s (or designee’s) responsibility to obtain permission to 
use protected health information per HIPAA from each subject, or if appropriate, the 
subjects’ parent or legal guardian.
11.4 Source Documentation and Investigator Files
The investigator will maintain adequate and accurate records to document the 
conduct of the study and to ensure that study data can be subsequently verified. These 
documents will be classified into two separate categories: (1) investigator study file and
(2) subject clinical source documents that corroborate data collected on the CRF’s. 
Subject clinical source documents would include hospital/clinic patient records; 
physician's and nurse's notes; original laboratory, radiology, pathology, and special 
assessment reports; QOL forms, signed informed consent forms. When the CRF or any 
form is used as the source document, this will be clearly stated in the investigator study 
file.
At a minimum, the following be documented in source documents:

Medical history/physical condition and diagnosis of the subject before 
involvement in the study sufficient to verify protocol entry criteria

Study number, assigned subject number, and verification that written informed 
consent was obtained (each recorded in dated and signed notes on the day of 
entry into the study)

Progress notes for each subject visit

Laboratory test results

Condition and response of subject upon completion of or early termination from 
the study

Quality of Life Surveys

DCE-MRI tumor size and location generated by the in-house developed software
11.5 Recording and Processing of Data
Data for this study will be entered into electronic CRFs in REDCap A CRF is 
required for every patient who received any study intervention. The investigator will
ensure that the CRF’s are accurate, complete, legible and timely. All corrections to
study data will be made by drawing a single line through the information to be corrected 
without obscuring it. All corrections will be initialed, dated and explained, if necessary. 
Do not use “white-out” or obscuring correction tape.
11.6 Non-Protocol Research
No investigative procedures other than those described in this protocol will be 
undertaken on the enrolled subjects without the agreement of the IRB.
11.7 Ethics
The investigator agrees to conduct the study in compliance with the protocol, 
current good clinical practices, and all applicable (local, FDA) regulatory guidelines and 
 
        
 
 

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standard of ethics.
11.8 Essential documents for the conduct of a clinical trial
Essential documents are those documents with individually and collectively 
permit evaluation of the conduct of a trial and the quality of the data produced.
The following documents will be on file:

CV’s and license of all investigators

IRB documentation/correspondance

Documentation of IRB certification
12.
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APPENDIX I: LIST OF STAND-ALONE DOCUMENTS
Number
Document 
reference number
Date
Title
1
MAX-PC
1Jun2003
The Modified 18-Item Memorial 
Anxiety Scale for Prostate Cancer
2
EPIC-SF12
Feb2002
The Expanded Prostate Cancer 
Index Composite + SF12 and 
AUASI
3
FFQ
Food Frequency Questionnaire 
(Optional-collected at baseline 
only)
 
        
 
 

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APPENDIX II: STUDY CALENDAR
Post-initial study biopsy (+1.5 months)
FU
Assessment
Screening 
(within 3 months of 
enrollment)
Baseline 
(within 3 months of 
enrollment unless 
otherwise specified)
6 mo
12mo
18mo
24 mo
30 mo
36
mo
Diagnostic biopsy (consisting 
of at least 8 cores)
X (within 18 months of 
enrollment & reviewed 
by UM Pathology)
History & Physical Exam
X
XB
XB
XB
XB
XB
XB
PSA
X
X (if not done within 6
mos [+1.5 mos] of 
initial study biopsy)
XC
XC
XC
XC
XC
XC
XA
MP-MRI of prostate/pelvis
X (+/- 3months of 
enrollment)
X
X
X
MRI-guided prostate biopsy
X
X
X
X
EPIC-SF12 & MAX-PC
X
X
X
X
FFQ
X (optional)
Plasma and serum collection 
for research (five tubes of 
blood, if patient has consented)
X
X
X
X
Urine collection for research 
(Approximately 50 mL, post 
prostate massage, if patient
has consented and if research 
funds are available)
X
X
X
X
A: Men undergoing protocol defined progression

Men undergoing surgery: will be followed every 3-6 months (+/- 2 months) for the first year, every 6-12 months (+/- 3 months) in the second 
year, and annually (+/- 6 months) thereafter up to 5 years post surgery. Any adjustments to this schedule will be permitted under the 
discretion of the clinician.

Men undergoing radiation therapy: follow up serum PSA testing should occur every 6 months (+/- 3 months) for the first 3 years and then 
annually thereafter (+/- 6 months) for up to 5 years post treatment. If the patient enters a radiation oncology clinical trial then the timing of 
PSA and other labs will be tmed in accordance with the radiation treatment protocol.

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B History and Physical Exams will be done at the discretion of the treating physician
C Serum PSA will be done preferably every 6 months or at least once a year up to 36 months from the initial biopsy.