Conditions: Prostate Cancer
Keywords: Diagnostic imaging High-Intensity Focused Ultrasound HIFU 18F-Fluciclovine high resolution diffusion-weighted imaging
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This prospective trial aims to determine if enhanced prostate imaging using two novel imaging technologies (high resolution DWI and 18F-fluciclovine PET-MRI) will detect prostate cancers not seen on standard multiparametric prostate MRI in patients considered candidates for focal HIFU.

Detailed description:
This is a prospective trial to evaluate the effectiveness of 18F-fluciclovine PET-hrMRI versus standard mpMRI at identifying prostate cancer targets for HIFU therapy.

Participants with clinically localized, unilateral high grade prostate cancer (Gleason score 7-10 prostate cancer localized to one lobe on prior biopsies) OR at high risk for having unrecognized high grade prostate cancer (overall Gleason score 6 with \> half of systematic biopsy cores positive and \> 50% of core involvement in at least one core), interested in HIFU would receive both a standard mpMRI and 18F-fluciclovine PET-hrMRI.

Participants would then undergo a mapping biopsy using a standard sextant template plus MRI/US-fusion targeted biopsy of any lesion suspicious lesion on mpMRI or PET-hrMRI.

Arms:
arm 1: 10mCi +/-20% 18F-fluciclovine injection

Interventions: intervention 1: 18F-Fluciclovine
Intervention descriptions: intervention 1: Imaging (comparing standard and experimental high resolution diffusion-weighted imaging \[DWI\] MRI with 18F-Fluciclovine)

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
IIT2016-19-DASKIVICH-18F: High-Resolution, 18F-fluciclovine PET-MRI for Mapping 
Prostate Cancer in Patients Considering Focal High-Intensity Focused Ultrasound (HIFU) 
Therapy 
 
Principal Investigator:           Timothy Daskivich, M.D. 
 
 
 
         Urology/Surgery 
                                 Cedars-Sinai Medical Center 
                                 8635 West Third Street, 1070W 
                                 Los Angeles, CA  90036 
                                 Email: timothy.daskivich@cshs.org 
                                 Tel: 310-423-4700 
                                 Fax: 310-423-1886 
 
Sub-Investigator(s): 
 
 
Name 
Department/Division 
Hyung Kim, M.D.  
Urology/Surgery 
Rola Saouf, M.D. 
Radiology 
Beatrice Knudsen, M.D., Ph.D. 
Pathology 
Alessandro D’Agnolo, M.D. 
Nuclear Medicine 
Louise Thomson, M.D. 
Nuclear Medicine 
Chris Nguyen, M.D. 
Biomedical Imaging Research Institute 
Dibiao Li, Ph.D. 
Biomedical Imaging Research Institute 
Stephen Freedland, M.D. 
Urology/Surgery 
Amit Gupta, M.D. 
Urology/Surgery 
 
 
 
 
 
Biostatisticians: 
 
Marcio Diniz, Ph.D 
 
 
 
 
Cedars Sinai Medical Center 
 
 
 
 
 
 
 
 
Study Intervention: 
 
High-resolution, 18F-Fluciclovine PET-MRI 
 
IND Number:  
136161 
 
IND Holder Name: 
Timothy Daskivich, MD 
 
ClinicalTrials.gov:  
Results Reporting Required  
 
  
NCT No:  
NCT03263780 
 
Funding Source:  
Cedars Sinai Precision Medicine Initiative 
 
Current Version: 
 
Version 2.4:  
17 June 2019 
 
Previous Version:  
 
Version 2.3: 
19 Mar 2019 
 
 


 
 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
Signature Page 
IIT2016-19-DASKIVICH-18F Protocol Version 2.4: 17 June 2019 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 


________________________________________________________________________ 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 1 
STUDY SCHEMA ........................................................................................................... 2 
STUDY SUMMARY......................................................................................................... 2 
1.0 
STUDY ABSTRACT ............................................................................................ 3 
2.0 
BACKGROUND AND RATIONALE ..................................................................... 4 
2.1 
Prostate Cancer:  Current Standard of Care in Treatment ................................ 4 
2.2 
HIFU:  Historical Background and FDA Approval .............................................. 4 
2.3 
HIFU:  International Experience with Prostate Cancer Treatment ..................... 4 
2.4 
MRI for Prostate Cancer Imaging ..................................................................... 5 
2.5 
High-Resolution Prostate MRI (hrMRI) ............................................................. 6 
2.6 
Fluciclovine and PET-MRI in Prostate Cancer .................................................. 6 
2.7 
MR/US-Fusion for Targeting of Prostate Cancers ............................................. 7 
2.8 
Combining MR/US-Fusion, hrMRI, and PET-MRI with HIFU for Focal Treatment of 
Prostate Cancer ........................................................................................................... 7 
3.0 
STUDY DESIGN: ................................................................................................. 7 
3.1 
Overview .......................................................................................................... 8 
3.2 
Study Population .............................................................................................. 8 
3.3 
Study endpoints ................................................................................................ 9 
3.4 
Study Procedures ............................................................................................. 9 
3.5 
Removal of Subjects from study ..................................................................... 13 
4.0 
Study Risks....................................................................................................... 13 
5.0 
ADVERSE EVENTS (AE) .................................................................................. 14 
5.1 
Definitions ...................................................................................................... 14 


________________________________________________________________________ 
ii 
5.2 
Reporting Requirements ................................................................................. 16 
6.0 
Statistical Analysis ........................................................................................... 17 
7.0 
STUDY MANAGEMENT .................................................................................... 18 
8.0 
REFERENCES ................................................................................................... 23 
9.0 
SUMMARY OF CHANGES ................................................................................ 25 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 1 of 26 
Version 2.4: 17 June 2019 
LIST OF ABBREVIATIONS 
AE 
Adverse Events 
ADC 
Apparent diffusion coefficient 
AUC 
Area under the curve 
AS 
Active Surveillance 
DCE 
Dynamic contrast enhanced 
DWI 
Diffusion-weighted imaging 
EPI 
Echo-planar imaging 
HIFU 
High-intensity focused ultrasound 
hrMRI 
High resolution MRI 
mpMRI 
Multiparametric MRI 
MR/US 
MRI-ultrasound 
MRI 
Magnetic resonance imaging 
PET 
Positron emission tomography 
PI-RAD 
Prostate Imaging-Reporting and Data System 
PSA 
Prostate specific antigen 
PSAM 
Prostate specific membrane antigen 
ROI 
Region of interest 
SAE 
Serious Adverse Events 
UTI 
Urinary Tract Infection 
 
 
 
 
 
 
 
 
 
 
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 2 of 26 
Version 2.4: 17 June 2019 
STUDY SCHEMA 
 
STUDY SUMMARY 
Title 
High-Resolution, 18F-fluciclovine PET-MRI for Mapping Prostate Cancer in 
Patients Considering Focal High-Intensity Focused Ultrasound (HIFU) Therapy 
Short Title 
High resolution PET-MRI before prostate cancer HIFU 
Protocol Number 
IIT2016-19-DASKIVICH-18F 
Phase 
Phase II 
Methodology 
Single arm, paired imaging 
Study Duration 
3 years 
Study Center(s) 
Cedars Sinai Medical Center 
Objectives 
To determine if enhanced prostate imaging using two novel imaging technologies 
(high resolution DWI and 18F-fluciclovine PET-MRI) will detect prostate cancers 
not seen on standard multiparametric prostate MRI in patients considered 
candidates for focal HIFU. 
Number of Subjects 
20 Study Subjects  
Diagnosis and Main Inclusion 
Criteria 
Diagnosis: Clinically localized, unilateral, high-grade prostate cancer OR at high 
risk for having unrecognized high grade Prostate Cancer 
Inclusion Criteria: 
• 
Biopsy consisting of ≥ 10 tissue cores sampled  
• 
PSA <20 ng/mL (within 3 months of consent) 
• 
cT1-cT2c 
• 
Either overall Gleason score > 7 with Gleason grade 4 or 5 component 
localized to one lobe (i.e. right or left) OR overall Gleason score 6 with > 
half of systematic biopsy cores positive and > 50% of core involvement 
in at least one core 
• 
Patient considering focal HIFU therapy 
Study Imaging 
18F-fluciclovine PET-MRI in combination with multiparametric prostate MRI 
using high resolution DWI  
Control Imaging 
Standard multiparametric prostate MRI 
Reference standard  
MRI-targeted prostate biopsies will serve as the reference standard and all 
lesions seen on any MRI protocol will be biopsied.   
Statistical analysis 
Our hypothesis is that 35% of biopsy-proven tumors will be detected on PET-
hrMRI and not on standard MRI.  If we assume that no biopsy proven tumors will 
only be detected on standard MRI, at alpha=0.05, n=20 provides a power of 
80%.   
Registration
Imaging (standard 
and experimental 
MRI)
Image-guided 
biopsy
Unilateral high 
grade disease:  
Focal HIFU
Repeat 
imaging/biopsy
Bilateral disease:  
Off study
Management per 
standard-of-care
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 3 of 26 
Version 2.4: 17 June 2019 
1.0 
STUDY ABSTRACT 
 
The arrival of High-Intensity Focused Ultrasound (HIFU) technology along with advances in 
prostate imaging may make focal gland ablation feasible.  While the mainstays of therapy for 
clinically localized prostate cancer, surgery and radiation therapy, induce significant morbidity 
such as urinary incontinence, erectile dysfunction, and bowel dysfunction due to bystander effects 
of whole-gland treatment, HIFU permits focal destruction of prostate cancers, which has the 
potential to minimize these morbidities and maximize quality of life.  Advances in prostate MRI 
allow the majority of high grade cancers to be detected.  Software platforms exist that enable real-
time fusion of prostate MRI images with ultrasound, which allows for targeting of prostate lesions 
found on MRI during transrectal biopsy.  The confluence of all of this technology—HIFU, 
multiparametric MRI (mpMRI), and MR/US-fusion targeting—creates the possibility of highly 
targeted focal ablation of prostate cancers. Nonrandomized clinical trials of hemigland and focal 
ablation with HIFU in Europe have shown promising trifecta rates—cancer control, potency, & 
continence—up to 1y post-treatment.   
 
While early results of HIFU therapy for clinically localized prostate cancer are promising, the 
effectiveness of HIFU therapy will ultimately be limited by the accuracy of prostate cancer 
imaging.  Because prostate cancer is often multifocal, identification of all clinically relevant 
prostate cancer lesions is critical to complete treatment of the disease, whether it is hemigland or 
true focal ablation.  Modern mpMRI is unable to detect 20% of high-grade cancer and 
approximately 50% of low-grade cancers.  To address this shortcoming, our team at Cedars-Sinai 
has developed high-resolution prostate MRI (hrMRI) technology that improves resolution 5-fold 
compared with standard multiparametric MRI. (1)  High-resolution imaging has been shown to 
detect 60% of tumors not seen on standard MRI.(2)  Pairing this technology with PET may allow 
highly specific targeting for focal therapy. Because the oncological effectiveness of focal therapy 
depends on robust targeting, PET-hrMRI could provide a significant advantage in cancer control 
outcomes for HIFU.   
 
We herein propose a prospective trial to evaluate the effectiveness of 18F-fluciclovine PET-hrMRI 
versus standard mpMRI at identifying prostate cancer targets for HIFU therapy.  Patients with 
clinically localized, unilateral high grade prostate cancer (Gleason score 7-10 prostate cancer 
localized to one lobe on prior biopsies) OR at high risk for having unrecognized high grade 
prostate cancer (overall Gleason score 6 with > half of systematic biopsy cores positive and > 
50% of core involvement in at least one core), interested in HIFU would receive both a standard 
mpMRI and 18F-fluciclovine PET-hrMRI.  They would then undergo a mapping biopsy using a 
standard sextant template plus MRI/US-fusion targeted biopsy of any suspicious lesion on mpMRI 
or PET-hrMRI. The primary endpoint would assess the number of biopsy-proven cancers that 
mpMRI would have missed compared with PET-hrMRI. Following our tumor mapping study, 
patients with high grade disease (i.e. Gleason grade 4 or 5) in one lobe undergo hemigland or 
focal HIFU of that lobe. At 6 months, patients would undergo repeat prostate biopsy to assess the 
negative biopsy rate in the treated region and absence of Gleason grade 4 or 5 in the untreated 
region as secondary endpoints.  


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 4 of 26 
Version 2.4: 17 June 2019 
2.0 
BACKGROUND AND RATIONALE 
2.1 
Prostate Cancer:  Current Standard of Care in Treatment 
 
Prostate cancer is the most common non-cutaneous cancer and the second-leading cause 
of cancer mortality in American men, accounting for 25% (192,280) of new cancer 
diagnoses and 9% (27,360) of male cancer deaths(3). Clinically localized prostate cancer 
accounts for the vast majority of new cancer diagnoses, with an estimated 91% of new 
cases diagnosed at local or regional stages(3).  Traditional treatment options for localized 
disease vary widely, from watchful waiting or active surveillance to aggressive treatment 
with surgery, radiation therapy, or brachytherapy.  Active surveillance is considered the 
standard-of-care for low grade (e.g. Gleason score 3+3=6) prostate cancers and even 
some intermediate risk cancers.  On active surveillance, patients with long life expectancy 
who develop a component of high Gleason grade cancer (i.e. Gleason grade 4 or 5) are 
recommended to have definitive local therapy such as prostatectomy or radiation.  While 
aggressive therapies such as surgery and radiation do offer the opportunity for cure, they 
are fraught with side effects that can significantly affect quality of life, including erectile 
dysfunction, urinary incontinence, and bowel dysfunction(4-7).  Even recent advances in 
robotic surgery and radiation techniques have not appeared to significantly reduce the 
long-term morbidities of definitive local therapy.  
 
2.2 
HIFU:  Historical Background and FDA Approval 
 
High-Intensity Focused Ultrasound (HIFU) is a noninvasive therapy that precisely delivers 
ablative ultrasonic energy to deep tissues through skin and mucosa, allowing for 
transrectal focal ablation of prostate cancers.  While the mainstays of therapy for clinically 
localized prostate cancer induce significant morbidity such as urinary incontinence, 
erectile dysfunction, and bowel dysfunction due to bystander effects of whole-gland 
treatment, HIFU permits focal destruction of prostate cancers by ablating either half of the 
prostate gland or only the tumor itself; these approaches have the potential to minimize 
morbidities associated with whole-gland treatment and thereby maximize quality of life.  
HIFU treatment (primarily hemigland and whole-gland) has been used extensively over 
the last fifteen years in Europe, Canada, and Mexico, and there are numerous articles 
describing its safety and effectiveness for this application in the Urology literature. 
 
While HIFU therapy has a long track record abroad, it has only recently been approved 
for prostate ablation in the US. In October 2015, the FDA gave de novo clearance to the 
Sonablate 450 HIFU platform (manufactured by SonaCare Medical) for the ablation of 
prostate tissue, making it the first to be approved for this indication in the US.  In November 
2015, the Ablatherm HIFU platform (manufactured by EDAP TM SA) was given 510(k) 
clearance for the same indication.  While the approvals for these devices do not 
specifically mention application to prostate cancer, academic and industry leaders are 
hailing this technology as a major advance for focal prostate therapy, hinting that this 
technology can avoid the morbidities of surgery for prostate cancer.  Local academic 
centers have already begun to use and market this technology. 
 
2.3 
HIFU:  International Experience with Prostate Cancer Treatment 
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 5 of 26 
Version 2.4: 17 June 2019 
HIFU therapy has been a mainstay of prostate cancer care in Europe, Canada, and Mexico 
for the last fifteen years, and cancer control and side effect outcomes have been very 
promising.  A review of the randomized clinical trials, meta-analyses, and systematic 
reviews reporting on efficacy and safety of HIFU as primary treatment was recently 
reported, though this review included a mixed population with regard to tumor mix and 
ablation zone (whole-gland and hemigland). 5-year disease free survival rates were 61–
95%.  Common complications associated with HIFU were urinary retention (<1–20%), UTI 
(2–48%), stress urinary incontinence of any degree (<1–34%), and erectile dysfunction 
(20–86%).  Rare complications included recto-urethral fistula (<2%), bladder neck 
stenosis, urethral stricture, perineal pain, urinary obstruction, epididymitis, and prostatitis. 
The largest institutional series of hemigland HIFU for low- (25%) and intermediate-risk 
(75%) prostate cancers suggested even better results, with return of erectile function for 
penetrative sex in 95% of men, 90% pad-free and leak-free continent, and 89% had no 
histological evidence of cancer at 6 months.  89% of men reached the trifecta status of 
pad-free, leak-free continence, erections sufficient for intercourse, and cancer control at 
12 months.(8) True focal therapy is in a nascent stage of development, but early results 
are similar to hemigland treatment.  In a prospective study of 42 men with low- and 
intermediate-risk cancer at University College London, 95% (95% CI 83–99%) were 
cancer free on biopsy at 12 months and 84% (95% CI 66–95%) reached trifecta status.(9)  
These results, though admittedly in highly selected populations, are clear improvements 
on cancer control and quality of life outcomes in modern surgical and radiation cohorts.  
 
2.4 
MRI for Prostate Cancer Imaging  
 
Multiparametric MRI (mpMRI) combining T2-weighted, diffusion-weighted, and dynamic 
contrast enhanced (DCE) images is quickly becoming part of the standard of care for 
detection and localization of prostate cancer.(10, 11)  Prostate MRI has been shown to 
have high sensitivity and specificity for high-grade prostate cancers, with approximately 
80% false negative rate for detection of Gleason 7 or higher tumors.  The Prostate 
Imaging-Reporting and Data System (PI-RADS) scoring system is a widely accepted 
rating system for estimating risk of cancer, using a 1–5 scale to provide clinicians with an 
estimate for likelihood of cancer; this scale uses T2-weighted imaging, diffusion weighted 
imaging, dynamic contrast-enhancement, and MRI spectroscopy to inform this 
assessment.  Some variations on this scale, such as the UCLA prostate MRI scoring 
system, give more weight to the diffusion-weighted imaging component, since it is the 
component providing the most predictive utility.    
 
Diffusion-weighted imaging (DWI) is sensitive to the diffusion of water molecules 
interacting with surrounding macromolecules.  DWI, which provides a quantitative 
biological parameter called apparent diffusion coefficient (ADC) value, is a robust MRI 
parameter for differentiating benign and malignant prostate tissue.(12, 13) In fact, the 
latest version of the Prostate Imaging-Reporting and Data System (PI-RADS) scoring 
system relies almost exclusively on DWI to identify tumors in the peripheral zone, which 
is where the vast majority of prostate cancers form. Findings on T2 images are not used 
to identify cancer, and DCE images are only used to differentiate between some PI-RADS 
3 and 4 lesions. In a pilot study of prostate cancer AS, DW-MRI was useful for detecting 
progression of Gleason score based on changes in ADC value.(14)  Tumor size is an 
important clinical criterion for defining low risk prostate cancer, and tumor size based on 
DWI has been shown to crudely predict low risk prostate cancer.(15) However, 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 6 of 26 
Version 2.4: 17 June 2019 
conventional DWI using single-shot echo-planar imaging is unable to detect small 
tumors(16) or detect small changes in tumor size on serial imaging.  
 
2.5 
High-Resolution Prostate MRI (hrMRI)  
 
Over the last several years, our group at Cedars-Sinai has developed technology to 
improve resolution of standard mpMRI, allowing for improved detection of smaller tumors. 
(1, 2)  By using a three-dimensional (3D) high-resolution diffusion-weighted imaging 
sequence (HR-DWI), image quality is improved and confers a 5-fold improvement in 
resolution when compared to standard two-dimensional (2D) DWI (S-DWI). This novel 3D 
DWI technique has been developed by our team and can be applied on existing 1.5T or 
3T MRI systems.  S-DWI suffers from two important limitations. a) It uses single-shot echo-
planar imaging (EPI) for data acquisition, which produces magnetic susceptibility induced 
streaking artifacts and geometric distortions so that round objects may appear oval.  b) 
The relatively low signal-to-noise ratio and 2D image acquisition with S-DWI limit spatial 
resolution, which is defined by the minimum distance between two objects required to 
resolve them uniquely. Our hrMRI incorporating HR-DWI overcomes these limitations by 
using magnetization prepared, multi-shot, turbo-spin-echo acquisition, which improves 
signal-to-noise ratio (SNR), spatial resolution, and image quality, and eliminates geometric 
distortions and streaking artifacts associated with EPI.   
In a prospective study assessing the performance of hrMRI in 17 prostate cancer patients 
on active surveillance, the technique was shown to detect tumors not seen on standard 
mpMRI.  Standard mpMRI predicted biopsy results (AUC 0.72, Fisher's exact p<0.001), 
but high-resolution DWI sequences allowed MP-MRI to be more highly predictive of biopsy 
results (AUC 0.88, Fisher's exact p<0.001).  hrMRI had a sensitivity of 95.7% and identified 
tumor in 22 of 23 zones proven to have cancer on biopsy. In contrast, standard mpMRI 
had a sensitivity of 60.9% and only identified 14 of 23 biopsy-positive zones (p=0.004). In 
all, hrMRI was shown to detect 60% of tumors not seen on standard MRI.  
 
2.6 
Fluciclovine and PET-MRI in Prostate Cancer  
 
Positron emission tomography (PET) imaging has also been increasingly used for 
detection of occult distant metastases in patients with advanced prostate cancer using 
prostate-cancer-specific radiotracers (PSMA) or those that accumulate preferentially 
within prostate cancer tissue (11C choline, 11C acetate, and 18F fluciclovine).  While PET 
technology is usually paired with CT imaging for 3D localization due to wide availability of 
CT technology, there have been efforts to pair PET technology with MRI to improve 
identification of lesions both within and outside of the prostate gland, given the advantages 
in spatial resolution of MRI over CT imaging.  While mpMRI is a very sensitive imaging 
modality for identifying localized prostate cancers, its specificity is limited; co-localization 
of tumors identified on MRI with PET imaging may be able to improve specificity to account 
for this limitation.  
 
18F-fluciclovine is a radiolabeled leucine (amino acid) analog that accumulates within 
prostate cancer, and early work has suggested that co-localization of this PET radiotracer 
with 3-D mpMRI imaging may enhance accuracy of localization of intraprostatic cancer 
lesions compared with mpMRI or PET/CT alone.  In a study of 21 patients who underwent 
18F-fluciclovine PET/CT and mpMRI prior to radical prostatectomy, combined 18F-


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 7 of 26 
Version 2.4: 17 June 2019 
fluciclovine PET/CT and mpMRI imaging yielded a positive predictive value of 82% for 
tumor localization, which was significantly higher than that with either modality alone. This 
would suggest that pairing 18F-fluciclovine PET imaging with MRI directly may improve 
localization of cancers within the prostate for HIFU treatment planning.  We hypothesize 
that further leveraging the sensitivity and spatial resolution of hrMRI with the specificity of 
PET imaging may further enhance performance in accurately identifying cancers within 
the prostate.   
  
2.7 
MR/US-Fusion for Targeting of Prostate Cancers  
 
The advent of improved prostate imaging using multiparametric MRI and PET have 
dovetailed with advances in fusion software platforms that offer the ability to overlay static 
MRI images with real-time ultrasound images at the time of biopsy.  This technology, called 
MR-US fusion, allows clinicians to target potential regions of interest in the prostate seen 
on mpMRI during an transrectal ultrasound-guided biopsy.  Targeted MR-US fusion 
biopsies have been shown to significantly improve sensitivity and overall accuracy of 
biopsy over standard sextant biopsy by 24% and 14%, respectively.  Most academic 
centers now offer MR-US fusion biopsies for patients with persistent rising PSA after 
negative standard biopsy and for surveillance biopsies while on active surveillance.  MR-
US fusion techniques are also being applied to focal ablation of prostate cancers with 
HIFU; both the Sonablate and Ablatheram HIFU plaforms have announced partnerships 
with MR-US fusion companies to provide targeting during tumor ablation with HIFU.  
However, despite these improvements, the accuracy of targeted biopsy and targeted focal 
therapy is necessarily limited by accuracy of the MRI imaging for detection and localization 
of lesions.   
 
2.8 
Combining MR/US-Fusion, hrMRI, and PET-MRI with HIFU for Focal 
Treatment of Prostate Cancer  
 
Because the oncological effectiveness of HIFU depends on robust mapping and targeting 
of lesions within the prostate, improved detection of lesions using hrMRI and/or PET-MRI 
could provide a significant advantage in HIFU cancer control outcomes.  Patients who are 
eligible for hemigland and focal HIFU absolutely depend on imaging for treatment 
planning; for example, in a patient with an index lesion of the right side of the prostate 
only, if imaging fails to detect a small focus of prostate cancer present on the left, 
hemigland HIFU (only treating the right side of the prostate) will not be effective at 
eradicating the entire bulk of his disease.  It is even more important to accurately identify 
all prostate cancers when mapping for true focal therapy, since only identified lesions are 
ablated.  We have previously shown that hrMRI detects up to 60% of tumors within the 
prostate not seen on mpMRI, and PET-MRI techniques may be able to improve the 
accuracy of this detection.  Even if lesions that are ignored by mpMRI but detected on 
PET-hrMRI are indolent, long-term growth of these lesions may certainly affect cancer 
control outcomes over time and require costly and morbid retreatment. We believe that 
improved imaging at the outset of focal therapy would provide more comprehensive 
eradication of cancer burden from the start, resulting in improved long-term outcomes.  
  
3.0 
STUDY DESIGN: 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 8 of 26 
Version 2.4: 17 June 2019 
 
3.1 
Overview 
 
This prospective trial will evaluate the effectiveness of 18F-fluciclovine PET-hrMRI versus 
standard mpMRI at identifying prostate cancer targets for HIFU therapy. Patients with 
clinically localized, Gleason score 7-10 prostate cancer localized to one lobe on prior 
biopsies or overall Gleason score 6 with > half of systematic biopsy cores positive and > 
50% of core involvement in at least one core, interested in HIFU would receive both a 
standard mpMRI and 18F-fluciclovine PET-hrMRI.  They would then undergo a mapping 
biopsy using a standard sextant template plus MR/US-fusion targeted biopsy of any 
lesions with PI-RADS scores ≥3 on hrMRI or 18F-fluciclovine PET positivity. The primary 
endpoint would assess the number of biopsy-proven cancers that mpMRI would have 
missed compared with hrMRI and/or 18F-fluciclovine PET. Following our tumor mapping 
study, patients with high grade disease (i.e. Gleason grade 4 or 5) in one lobe undergo 
hemigland or focal HIFU of that lobe. At 6 months, patients would undergo repeat mpMRI 
and prostate biopsy (MR/US-fusion biopsy plus standard sextant biopsy) to assess the 
negative biopsy rate in the treated region and absence of Gleason grade 4 or 5 in the 
untreated region as secondary endpoints  
3.2 
Study Population 
 
The study population for recruitment will be patients within the academic urology practice 
at Cedars-Sinai Medical Center. After initial visit, any patient with clinically localized 
prostate adenocarcinoma with Gleason score 7-10 prostate cancer localized to one lobe 
on prior biopsy desiring therapy with HIFU may be considered a potential study participant.  
Subjects with newly diagnosed disease or on active surveillance may be considered.  
 
3.2.1 
Inclusion Criteria 
1. Biopsy consisting of ≥ 10 tissue cores sampled  
2. PSA <20 ng/mL (within 3 months of consent) 
3. cT1-cT2c 
4. Either overall Gleason score > 7 with Gleason grade 4 or 5 component localized to 
one lobe (i.e. right or left) OR overall Gleason score 6 with > half of systematic 
biopsy cores positive and > 50% of core involvement in at least one core 
5. Patient considering focal HIFU therapy 
 
3.2.2 
Exclusion criteria: 
1. Previous local therapy for prostate cancer 
2. Inability to receive PET tracer 
3. Inability to receive MRI 
4. Suggestion of extracapsular extension or seminal vesicle invasion on imaging, if 
imaging was completed per SOC prior to or during screening 
5. Estimated creatinine clearance <45 mL/min (Cockcroft-Gault equation) 
6. Any other condition which, in the investigator’s option, may make the patient a poor 
candidate for participation in a clinical trial.  
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 9 of 26 
Version 2.4: 17 June 2019 
3.3 
Study endpoints 
 
Primary Endpoint: To determine the number of biopsy-proven cancers that standard imaging 
would have missed compared with PET-hrMRI on mapping MRI 
 
Secondary Endpoint: Negative biopsy rate on standard 12-core biopsy 6 months following HIFU 
therapy.   
 
Exploratory Endpoint: RNAseq transcriptome analysis of lesions that are positive on mapping 
biopsy.   
 
3.4 
Study Procedures 
3.4.1 
Screening/Baseline Procedures 
Subjects will be identified by study investigators within the academic urology practice at 
Cedars-Sinai Medical Center during routine clinical practice. All study assessments for 
eligibility are performed as part of standard of care. Once a patient has been diagnosed, 
expressed interest in HIFU, and recommended study participation, they will be 
presented with the Informed Consent Form, including a description of the study purpose, 
risks, benefits and possible alternatives. The prospective participant will be given 
sufficient time to consider participation in the research.  Patients will be asked to sign the 
study consent form after receiving a complete explanation of the study. 
 
This study will enroll patients with clinically localized, Gleason score 7-10 prostate cancer 
localized to one lobe on prior biopsies or overall Gleason score 6 with > half of systematic 
biopsy cores positive and > 50% of core involvement in at least one core, interested in 
HIFU as primary treatment. Patients with low Gleason grade cancer (e.g. Gleason grade 
3) on the contralateral lobe are allowed since the standard-of-care for such low grade 
disease is observation.  Patients with very low risk disease and low-volume, low-risk 
disease are excluded since their preferred management is active surveillance. Patients 
will present with newly diagnosed disease or after a period of active surveillance.  If there 
is suggestion of extracapsular disease or seminal vesicle involvement on MRI, these 
patients will be excluded.  Metastatic workup with cross sectional imaging and/or bone 
scan will not be mandatory, since they are not indicated for low- and intermediate-risk 
prostate cancers according to AUA and NCCN guidelines.   
 
Screening procedures include:  
3.4.1.1 
Informed Consent 
Informed consent must be obtained prior to any protocol assessment or procedure which 
is not performed as part of local routine care.  Subjects must also grant permission to 
use protected health information per the Health Insurance Portability and Accountability 
Act (HIPAA).  Signed and dated ICF and HIPAA for enrolled participants who are not 
subsequently screened or undergo study intervention will be maintained at the study 
site.   
3.4.1.2 
Medical history 
Medical history (comorbidities) includes clinically significant diseases that are currently 
active or that were active, including past surgical history, medications, social history, 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 10 of 26 
Version 2.4: 17 June 2019 
family history including history of prostate cancer, dates of previous prostate biopsies, 
prostate biopsy pathology results, PSA results, dates and results of previous prostate 
imaging 
3.4.1.3 
Reporting on Concomitant medication 
 
Any current concomitant medications and treatments will be recorded 
3.4.1.4 
Demographics 
 
Age, ethnicity/race 
3.4.1.5 
Review subject eligibility criteria 
 
All necessary procedures and evaluations must be performed to document that the 
 
subject meets all of the inclusion and none of the exclusion criteria. 
3.4.1.6 
Physical exam including vital signs, height, and weight 
Physician directed physical exam. This may be collected within 90 days of screening.  
3.4.1.7 
Adverse event assessment 
Adverse events will be assessed at imaging, post imaging (biopsy), HIFU, and HIFU 
follow up. See section 5.1 and 5.2 for Adverse Event and reporting. Only grade 3 and 
above imaging-related AEs will be captured and all SAEs following the receipt of 
fluciclovine F18.  
3.4.2 
Study Calendar 
 
Procedure 
Screening 
Imaging 
Post-
imaging2 
Standard of 
Care (SOC) 
Treatment 
Post SOC 
Treatment  
6 months 
(+/- 1.5 
months) 
following 
HIFU 
Informed 
Consent/Registration 
X 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
Prior and Current 
Medication Review 
X 
 
 
 
 
Vital Signs5 
X 
 
 
 
 
Physical Exam5 
X 
 
 
 
 
Symptoms 
Assessment  
X 
 
 
 
 
Standard MRI 
 
X  
(at least one day prior to 
targeted  prostate biopsy) 
 
 
X  
(at least 
one day 
prior to 
targeted  
prostate 
biopsy) 
 
 
 
X 
 
X 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 11 of 26 
Version 2.4: 17 June 2019 
Tissue collection4  
 
18-fluciclovine PET-
hrMRI 
 
X  
(at least one day prior to 
targeted  prostate biopsy) 
 
 
 
Adverse Event 
Review6 
 
X 
X 
X 
X 
Hemigland or Focal 
HIFU1 
 
 
 
X  
(performed 
within 4 months  
after mapping 
and/or targeted 
prostate 
biopsy) 
 
Standard Sextant 
Mapping Biopsy 
 
 
X 
 
X 
MR/US-fusion targeted 
biopsy 
 
 
X3 
 
X 
 
1. Focal HIFU performed on study for patients with confirmed unilateral high grade 
prostate cancer. 
2. End of study for bilateral Gleason >7 disease  
3. Of any lesions with PI-RADS scores >3 on hr MRI or 18F-fluciclovine PET positivity 
4. Tissue collection includes left over tissue from standard of care collection only. 
5. Do not need to be repeated if obtained within 90 days of screening.  
6. Only grade 3 and above imaging-related AEs will be captured and all SAEs 
following the receipt of fluciclovine F18.  
 
 
Pre-HIFU Imaging Protocol for Tumor Mapping 
Eligible participants will then undergo mapping MRI in advance of HIFU therapy using both 
standard mpMRI and PET-hrMRI.  All imaging will be completed in one sitting. hrMRI 
increases the length of the MRI by approximately 5 minutes.  PET-MRI sequences 
increased the length of mpMRI by 30 minutes. Scanning will be done on the Siemens 
Biograph mMR scanner at the Research Imaging Core facility in the Davis Building.  
 
Subjects undergoing a PET-hrMRI will be screened using the standard clinical protocol to 
determine whether it is safe to administer contrast to the subject.  
 
PET scans involve injection of a radioisotope. Subjects undergoing a contrast-enhanced 
MR-PET will be screened using the standard clinical protocol to determine whether it is 
safe to administer contrast to the subject.   An IV line will be inserted, and the participant 
will receive 10 mCi ±20% 18F-fluciclovine injection diluted up to 10mL injected via the 
IV, as an IV bolus injection followed by 10mL flush with normal saline solution. The 
participant will then be positioned supine in the scanner and will be scanned in the area 
of the prostate. The research PET scan will be a dynamic list mode scan. Meaning the 
PET would start first, then 18F fluciclovine would be injected immediately after the scan 
is started.  For the PET acquisition, participants will be imaged for approximately 30 
minutes. 
 
All MRI images will be read according to PI-RADS (version 2) by a dedicated GU 
radiologists who has experience reading over 500 prostate MRIs.  All PET scans will be 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 12 of 26 
Version 2.4: 17 June 2019 
read by nuclear medicine co-investigators on the study (DA, LT).  All lesions with PI-RADS 
greater than or equal to 3 and all PET positive areas will be considered suspicious for 
cancer.  A region of interest (ROI) application will be used. The circumference of a 
suspicious lesion will be drawn on each individual MRI slice. The lesion volume and 
average ADC will be calculated from the ROI’s. The tumor volumes and ADCs will be 
provided by the radiologist. To prevent the hrMRI from influencing the review of the 
mpMRI, all mpMRI’s will be reviewed first. The radiologist will always be blinded to 
previous pathology.  
 
Mapping Biopsy Protocols  
After the pre-HIFU imaging protocol for tumor mapping, all patients will undergo a 
transrectal ultrasound-guided targeted mapping biopsy. The biopsy will include a standard 
sextant template plus MR/US-fusion targeted biopsy of any lesions with PI-RADS scores 
≥3 on hrMRI or 18F-fluciclovine PET positivity.  These areas will be targeted using the 
UroNav targeting software platform.  As an exploratory analysis, remnant formalin-fixed 
paraffin embedded tumor tissue will be requested for RNAseq transcriptome analysis of 
lesions that are positive on mapping biopsy.   
 
Eligibility for HIFU 
If subjects are found to have unilateral high grade disease (i.e. Gleason grade 4 or 5), they 
will be considered as a candidate for hemigland or focal HIFU therapy. Clinician judgment 
may be exercised in determining eligibility for HIFU, since established criteria based on 
volume and extent of disease do not exist.  If patients have high grade disease in both 
lobes, they will not be eligible for HIFU therapy on this trial.  Their data will be used to 
assess the primary endpoint but they will not be considered for secondary endpoints.  
 
HIFU Therapy and Follow Up Schedule 
Patients who are eligible for HIFU will receive hemigland or focal HIFU per standard-of-
care.  All subjects will receive repeat mpMRI and MR/US-guided biopsy of all positive sites 
+ systematic 12-core prostate biopsy at 6 months (or as clinically indicated). As an 
exploratory analysis, remnant formalin-fixed paraffin embedded tumor tissue will be 
requested for RNAseq transcriptome analysis of lesions that are positive on biopsy.   
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 13 of 26 
Version 2.4: 17 June 2019 
3.5 
Removal of Subjects from study 
Patients can be taken off the study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation will be documented and may include: 
3.5.1 
Patient voluntarily withdraws (follow-up permitted);  
3.5.2 
Patient withdraws consent (discontinue all study procedures and follow-
up) 
3.5.3 
Patient is unable to comply with protocol requirements; 
3.5.4 
Treating physician determines continuation on the study would not be in 
the patient’s best interest; 
3.5.5 
Lost to follow-up. If a research subject cannot be located in order to 
obtaining data to inform the primary or secondary endpoint, the subject may be 
considered “lost to follow-up.” All attempts to contact the subject during the two 
years must be documented.  
 
4.0 
Study Risks 
 
All agents administered to patients and all invasive procedures used in this study are 
approved by the U.S. Food and Drug Administration.  This study investigates a novel 
software-based MRI imaging protocol that improves image resolution, and it investigates 
the off-label use of F18 fluciclovine for prostate PET-MRI.   
 
F18 fluciclovine is currently approved for PET-CT for men with suspected prostate cancer 
metastasis.  MR/ultrasound fusion biopsies and HIFU for prostate ablation are also 
approved procedures that are being routine performed as standard-of-care.  All invasive 
procedures will therefore be performed following standard informed consent. 
 
Magnetic Resonance Imaging (MRI) 
MRI imaging is among the least invasive of all imaging modalities. The U.S. Food and 
Drug Administration has labeled MR systems of up to 4.0 Tesla as having “non-significant 
risk” and currently there is no evidence that MR imaging causes any long-term or 
irreversible effects in human beings. However, there are certain risks, which are detailed 
below. 
 
MRI imaging utilizes magnetic fields and radiofrequency fields, both of which can be 
harmful in certain situations. Magnetic fields can cause ferromagnetic implants or 
ferromagnetic foreign bodies, such as intracranial aneurysm clips, shrapnel, and 
intraocular metal chips to become dislodged and tear the surrounding soft tissue. 
Therefore, MRI imaging is contraindicated in persons with ferromagnetic implants or 
ferromagnetic foreign bodies. It is also contraindicated in persons with electrically, 
magnetically or mechanically activated implants because the magnetic field can cause 
these to function erratically.  In addition, persons wearing metallic objects may be at 
danger for them becoming dangerous projectiles, due to them inadvertently becoming 
introduced into the magnetic field. All subjects will be prescreened carefully and all 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 14 of 26 
Version 2.4: 17 June 2019 
scanners are used in accordance with guidelines set by the Bureau of Radiological Health. 
 
Fluciclovine F18 (Axumin) 
The recommended dose is 370 MBq (10 mCi) administered as an intravenous bolus 
injection.  The (radiation absorbed) effective dose resulting from this dose of Axumin is 8 
mSv.  The clinical trial database for Axumin includes data from 877 subjects including 797 
males diagnosed with prostate cancer. Most patients received a single administration of 
Axumin, a small number of subjects (n = 50) received up to five administrations of the 
drug. The mean administered activity was 370 MBq (range, 163 to 485 MBq).  Adverse 
reactions were reported in ≤1% of subjects during clinical studies with Axumin. The most 
common adverse reactions were injection site pain, injection site erythema and dysgeusia. 
 
Hypersensitivity to Medications - Occasionally, people have allergic reactions when 
taking any medication. Subjects may receive medications such as contrast. 
Hypersensitivity reactions may include symptoms such as shortness of breath, wheezing, 
flushing, nasal congestion and skin rash. In most cases, initial symptoms occur within 
minutes of drug administration and quickly reverse themselves or resolve with prompt 
medical treatment.  
 
In general, allergic reactions to medicines are more likely to occur in people who have 
allergies to other drugs, foods, or things in the environment.  Subjects will be asked about 
any pre-existing allergies before administering any medications during the study.  
 
Incidental Findings  
Only noted clinically significant incidental findings will be communicated to the subject, per 
CSMC IRB and Legal Department approved policy, as a result of agreeing to undergo a 
research MRI scan. No reports or images will be provided to subjects and their medical 
records.  However, MRI mapping results will be provided to the treating physicians who 
will use this information for MR/ultrasound guided prostate biopsy. 
 
 
5.0 
ADVERSE EVENTS (AE) 
 
5.1 
Definitions 
5.1.1 
Adverse Event: An adverse event is any untoward medical occurrence in 
a patient receiving study intervention and which does not necessarily have a 
causal relationship with this intervention. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 15 of 26 
Version 2.4: 17 June 2019 
disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.  
5.1.2 
Serious Adverse Events (SAE): A “serious” adverse event is defined in 
regulatory terminology as any untoward medical occurrence that: 
• 
Results in death. If death results from (progression of) the disease, 
the disease should be reported as event (SAE) itself. 
• 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused 
death if it were more severe). 
 
• 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
 
• 
Results in persistent or significant disability or incapacity 
 
• 
Is a congenital anomaly/birth defect 
 
• 
Is an important medical event 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“.  
 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly. 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 16 of 26 
Version 2.4: 17 June 2019 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in: 
• 
the current known adverse events listed in section 1.4 
• 
the drug package insert 
• 
the current Investigator’s Brochure 
 
5.1.3 
Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets 
all of the following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
• 
Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known to an individual or group of individuals (including 
research subjects, research staff, or others not directly involved in the 
research). 
5.2 
Reporting Requirements  
5.2.1 
Reporting to the Institutional Review Board (IRB) 
The IRB must be notified within 10 business days of “any unanticipated problems 
involving risk to subjects or others.” 
 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol 
that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 17 of 26 
Version 2.4: 17 June 2019 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot 
be resolved by the Principal Investigator. 
 
5.2.2 
Reporting to the FDA 
The investigator or his designee must submit SAEs on FDA Form 3500A 
(MedWatch) according to the following reporting criteria: 
• 
Reporting any unexpected fatal or life-threatening suspected adverse 
reactions no later than 7 calendar days after initial receipt of the information. 
• 
Reporting any (1) serious, unexpected suspected adverse reactions, (2) 
findings from other clinical, animal, or in-vitro studies that suggest significant 
human risk, and (3) a clinically important increase in the rate of a serious 
suspected adverse reaction no later than 15 calendar days after determining 
that the information qualifies for reporting. 
 
5.2.3 
Reporting to Blue Earth Diagnostics 
 
In addition to reporting of SAEs to the responsible IRB/IEC and Health Authority, 
Principal Investigator or designee will document all SAEs that occur following 
receipt of fluciclovine Fl8 (whether or not related to study drug) to BED. Such 
SAEs must be reported within 24 hours of Principal Investigator or designee 
becoming aware of the event. All SAE information must be recorded and faxed or 
scanned and emailed to: 
 
Blue Earth Diagnostics SAE E mail:  Drugsafety@pharsafer.com 
Tel:  
 
 
 
 
1-855-AXUMINl (1-855-298-6461) 
Fax: 
 
 
 
 
+44 (0) 1483 212178 
 
Additional and further requested information (follow-up or corrections to the 
original case) will be detailed and faxed/emailed to the same address and must 
include the following minimum information: The name and contact information of 
the reporter, the name of the study drug(s), a description of the reported SAE, 
with the patient identified by one or more of the following (patient initials, patient 
number age, sex), an investigator assessment of study drug causality, and any 
additional data which would aid the review and causality assessment of the case 
including but not limited to the date of onset, severity, the time from 
administration of study drug(s) to start of the event, the duration and outcome of 
the event, any possible etiology for the event, and the final diagnosis or 
syndrome, if known. 
6.0 
Statistical Analysis  


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 18 of 26 
Version 2.4: 17 June 2019 
 
Primary Endpoint: To compare the number of biopsy-proven cancers that standard 
imaging would have missed compared with PET-hrMRI on mapping MRI (i.e. comparison 
of sensitivity of PET-hrMRI with mpMRI with biopsy-proven cancer as the gold standard).  
 
Our preliminary data suggests that up to 60% of tumors invisible to standard mpMRI are 
detected on hrMRI.  It is unclear how many additional lesions will be identified on 
fluciclovine PET-MRI.  Since all areas of concern will be biopsied and only biopsy-proven 
tumors will be treated with HIFU, the morbidity of the surgical intervention is minimized 
and its potential to achieve cure is maximized.   
 
Power Assessment: The power for the McNemar`s type test proposed by Durkalski et al. 
(2003) is evaluated based on four correlations: r1: between lesions evaluated by PET-
hrMRI for the same patient, r2: between lesions evaluated by mpMRI for the same patient, 
r3: between evaluations PET-hrMRI and mpMRI for the same lesion and r4: between 
evaluations PET-hrMRI and mpMRI for the different lesions at the same patient. In this 
way, we define four scenarios of correlation among lesions: (a) no correlation (r1 = r2 = r4 
= 0, r3 = 0.15), (b) low correlation (r1 = r2 = 0.1, r3 = 0.15, r4 = 0.015), (c) medium 
correlation (r1 = r2 = 0.4, r3 = 0.15, r4 = 0.06) and (d) high correlation (r1 = r2 = 0.8, r3 = 
0.15, r4 = 0.12). In addition, the number of lesions for each patient is defined as equal to 
1 - 2 on average from preliminary data.  
 
The minimum sample size to reach 80% of power is 22 patients when each patient has 
exactly 1 lesion (total of 22 lesions); 19 patients when the average number of lesions is 
1.35 (total of 26 lesions); and 17 patients when the average number of lesions is 2 (total 
of 34 lesions).  Given that our estimated number of biopsy-proven lesions per patient will 
be 1–2 based on historical data, we will proceed with a sample size of 20 patients.  
 
Statistical Analysis: Sensitivities will be compared using McNemar`s type test proposed 
by Durkalski et al. (2003) for cluster matched binary data. In addition, the 95% confidence 
interval for difference between sensitivities will be calculated as proposed by Yang et al. 
(2012). 
 
Secondary Endpoints: Negative biopsy rate within treatment zones on standard 12-core 
biopsy 6 months following HIFU therapy; rate of high grade cancer in the untreated lobe.   
 
Exploratory Endpoint:  Formalin-fixed paraffin embedded biopsy tissue will be requested 
from a subset of patients for RNAseq transcriptome analysis.  The number of cases 
analyzed will depend on availability of future funding.  The subset of cases requested will 
depend on the exploratory object of the pilot study and may include discovery of signatures 
to predict presence of high grade cancer, unilateral disease or treatment success.   
 
 
7.0 
STUDY MANAGEMENT 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in 
the Informed Consent Form. 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 19 of 26 
Version 2.4: 17 June 2019 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the consent 
form and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
Registration Procedures 
 
All subjects that sign informed consent will be assigned a subject number sequentially by 
their date of consent.  Those subjects that do not pass the screening phase will be listed 
as screen failures on the master list of consented subjects.  Eligible subjects, as 
determined by screening procedures and verified by a treating investigator, will be 
registered on study at Cedars Sinai Medical Center by the Study Coordinator.   
 
Issues that would cause intervention delays after registration should be discussed with 
the Principal Investigator (PI). If a patient does not receive protocol intervention following 
registration, the patient’s registration on the study may be canceled.  The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
Assignment of Subject ID: The study team will track all subjects who sign consent on a 
subject screening/enrollment log using a unique screening ID (S001, S002, etc.). 
Subjects found to be ineligible will be recorded as screen failures. Subjects found to be 
eligible will be registered using only the three-digit numeric ID assigned at screening that 
follows the standard SOCCI format (001, 002, etc.). 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the 
SOCCICancer Clinical Trials Office (CCTO) . The following documents will be 
completed and provided for review: 
 
• 
Registration form (or equivalent) 
• 
Copy of applicable source documents 
• 
Eligibility checklist (signed by investigator) 
• 
Signed patient consent form and Subject’s Bill of Rights 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 20 of 26 
Version 2.4: 17 June 2019 
• 
HIPAA authorization form 
 
B) 
Registration 
 
After eligibility is verified, registration is completed as follows: 
 
• 
Assign a patient study number 
• 
Enter the patient in OnCore 
 
Oversight by the principal investigator is required throughout the entire 
registration process 
 
7.1 
Data Management and Quality Control and Reporting 
The data will be entered into a HIPAA-compliant database. The Study Staff will be 
responsible for data processing, in accordance with procedural documentation. 
Database lock will occur once quality assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
7.2 
Data and Safety Monitoring 
This trial is considered a minimal risk study, in which the probability and magnitude of 
harm or discomfort anticipated in the research are not greater than those ordinarily 
encountered in daily life or during the performance of routine examinations or tests 
required for the subject’s disease.   
 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research 
Group (DRG) meetings (or equivalent). In addition, the SOCCI Cancer Clinical Trials 
Office (CCTO) Quality Management Core (QMC) will conduct a focused internal 
monitoring visits and audits for data quality and protocol compliance.  
QMC reports will then be forwarded to the SOCCI Data and Safety Monitoring (DSMC). 
 
QMC will also conduct the following: 
1. Central eligibility verification for all subjects enrolled as described in protocol 
section 3.2. 
2. Central review of all eligibility waiver requests by a SOCCI Medical Reviewer 
to assess appropriateness and risk to ensure quality data and ensure subject 
safety protections for investigator-initiated research 
 
Refer to the DSMC Charter for more details. For any protocol, QMC has the authority 
to request more frequent reviews or closer safety monitoring if it is deemed appropriate 
for any reason. 
 
7.2.1 
Safety Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will 
maintain continuous safety monitoring for the duration of the study by reviewing 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 21 of 26 
Version 2.4: 17 June 2019 
subject/study data. Adverse events and unanticipated problems are not expected, but if 
they occur they will be documented and reported according to CSMC IRB policies and 
procedures. If the PI becomes aware of any new safety information that may place 
subjects at increased risk than what was previously known the IRB will be promptly 
notified and if warranted, enrollment may be held until the PI determines whether a 
modification to the study is necessary and/or the informed consent documents are 
updated accordingly. 
 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee 
will provide another layer of data and safety oversight. Committee membership includes 
experts in the field of oncology, nursing, pharmacy, and biostatistics in reviewing the 
over data, safety, quality, and study integrity of SOCCI interventional IITs. DSMC 
membership and responsibilities are governed by the committee charter. The DSMC 
findings and recommendations will be reported in writing to the Principal Investigator. 
A summary letter will be forwarded by the Principal Investigator or his/her designee to 
the Cedars-Sinai Medical Center IRB. Refer to the DSMC Charter for details of the 
DSMC review.   
7.3 
Replacement of subjects 
Any subject who signs consent but does not undergo study intervention (i.e. high-res 
imaging) will be replaced.   
7.4 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study 
investigator must retain all study documentation pertaining to the conduct of a clinical 
trial. Study documents should be kept on file per local guidelines. 
7.5 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, or a protocol exception 
request approved by the SOCCI Medical Director and CSMC IRB, the study shall be 
conducted exactly as described in the approved protocol. 
7.5.1 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, the IRB must be notified as soon as possible, but 
no more than 10 days from the investigator’s awareness of the event. 
7.5.2 
Protocol Exceptions and Eligibility Waivers  
An exception is an anticipated or planned deviation from the IRB-approved research 
protocol, as described in the IRB Policy, Reporting Possible Unanticipated Problems 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 22 of 26 
Version 2.4: 17 June 2019 
Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement.  
A protocol exception most often involves a single subject and is not a permanent 
revision to the research protocol. Protocol exceptions that extend beyond a single 
subject should result in a protocol amendment to avoid serial violations.  
 
Planned exceptions to the protocol that are more than logistical and/or have the 
potential to affect the subject’s safety and/or study integrity may not be implemented 
without prior approval from the SOCCI Cancer Center Trials Office (CCTO) Medical 
Director and IRB. The PI or her/his designee is responsible for submitting a protocol 
exception and its supporting documents to the SOCCI CCTO Medical Director for 
review. 
 
Study team should refer to the IRB Reporting Possible Unanticipated Problems 
Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement guidelines to determine which 
deviations and exception requests require prior approval from the SOCCI CCTO 
Medical Director. Once approved, the deviation or exception request must be submitted 
to the IRB for review and approval prior to implementation. 
 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. 
In the rare event that it is appropriate for subject inclusion, the rationale/justification and 
subject case history should be forwarded to the SOCCI CCTO Medical Director for 
assessment prior to submission to the IRB for approval.  
 
The CCTO Medical Director will review the case and contact the investigator if additional 
information is needed or further discussion is warranted. The CCTO Medical Director will 
provide a written assessment/recommended course of action. The CCTO Medical 
Director’s assessment must be uploaded into CS-IRB with the waiver request for IRB 
review and consideration. The CCTO Medical Director may recommend future protocol 
changes.  
 
Eligibility Waiver Submission Process  
The PI and/or treating physician should provide written request for waiver which includes 
case history and justification for prospective deviation from the study design to the 
SOCCI CCTO Medical Director. “IIT Monitoring – Eligibility Waivers and 
Exception Requests (EW/ER) Form” must be completed, along with any applicable 
supporting documents, must be emailed to QMC (GroupSOCCICROQMC@cshs.org) 
to request an eligibility exception request from the CCTO Medical Director. This is 
only a requirement for studies with DSM classification of moderate or high. An 
assessment from the CCTO Medical Director or designee must be done prior to 
submission to the IRB for review. 
 
7.5.3 
Other Protocol Deviations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an 
individual subject) do not require prior IRB approval unless the deviation has the 
potential to affect the subject’s safety. Such planned deviations that do meet this 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 23 of 26 
Version 2.4: 17 June 2019 
definition and do not affect the subject’s safety should be noted in the subject’s research 
record or deviation log as described in the SOCCI Clinical Research Office’s Working 
Instruction 11: Deviation and Noncompliance Reporting. 
 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB within 10 days from when the investigator 
becomes aware that such a deviation has occurred, as outlined in the SOCCI Clinical 
Research Office’s Working Instruction 11: Deviation and Noncompliance Reporting. In 
this case, a Protocol Deviation report must be submitted in Webridge, per IRB policy, 
Reporting Possible Unanticipated Problems Involving Risks to Subject or Others 
(UPIRSO) Policy: Institutional Review Board/Research Compliance and Quality 
Improvement. All submissions should include a description of the plan to avoid similar 
deviations or exceptions in the future.   
 
7.5.4 
Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
7.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients. The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will 
be collected and entered onto the Case Report Forms and/or into a HIPAA-compliant 
study database. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all case report forms will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy of the 
data. 
 
 
 
8.0 
REFERENCES 
 
 
1. Nguyen C, Sharif-Afshar AR, Fan Z, Xie Y, Wilson S, Bi X, et al. 3D high-resolution 
diffusion-weighted MRI at 3T: Preliminary application in prostate cancer patients 
undergoing active surveillance protocol for low-risk prostate cancer. Magnetic resonance 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 24 of 26 
Version 2.4: 17 June 2019 
in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society 
of Magnetic Resonance in Medicine. 2016;75(2):616-26. 
2. Sharif-Afshar AR, Nguyen C, Feng TS, Payor L, Fan Z, Saouaf R, et al. Prospective Pilot 
Trial to Evaluate a High Resolution Diffusion-Weighted MRI in Prostate Cancer Patients. 
EBioMedicine. 2016;7:80-4. 
3. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 
2010;60(5):277-300. 
4. Gore JL, Kwan L, Lee SP, Reiter RE, Litwin MS. Survivorship beyond convalescence: 48-
month quality-of-life outcomes after treatment for localized prostate cancer. J Natl Cancer 
Inst. 2009;101(12):888-92. 
5. Potosky AL, Harlan LC, Stanford JL, Gilliland FD, Hamilton AS, Albertsen PC, et al. 
Prostate cancer practice patterns and quality of life: the Prostate Cancer Outcomes Study. 
J Natl Cancer Inst. 1999;91(20):1719-24. 
6. Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, et al. Quality of 
life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 
2008;358(12):1250-61. 
7. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the 
expanded prostate cancer index composite (EPIC) for comprehensive assessment of 
health-related quality of life in men with prostate cancer. Urology. 2000;56(6):899-905. 
8. Ahmed HU, Freeman A, Kirkham A, Sahu M, Scott R, Allen C, et al. Focal therapy for 
localized prostate cancer: a phase I/II trial. The Journal of urology. 2011;185(4):1246-54. 
9. Ahmed HU, Hindley RG, Dickinson L, Freeman A, Kirkham AP, Sahu M, et al. Focal 
therapy for localised unifocal and multifocal prostate cancer: a prospective development 
study. Lancet Oncol. 2012;13(6):622-32. 
10. Lawrence EM, Gnanapragasam VJ, Priest AN, Sala E. The emerging role of diffusion-
weighted MRI in prostate cancer management. Nature reviews Urology. 2012;9(2):94-
101. 
11. Outwater EK, Montilla-Soler JL. Imaging of prostate carcinoma. Cancer control : journal 
of the Moffitt Cancer Center. 2013;20(3):161-76. 
12. Boesen L, Chabanova E, Logager V, Balslev I, Thomsen HS. Apparent diffusion 
coefficient ratio correlates significantly with prostate cancer gleason score at final 
pathology. Journal of magnetic resonance imaging : JMRI. 2014. 
13. Jie C, Rongbo L, Ping T. The value of diffusion-weighted imaging in the detection of 
prostate cancer: a meta-analysis. European radiology. 2014;24(8):1929-41. 
14. Morgan VA, Riches SF, Thomas K, Vanas N, Parker C, Giles S, et al. Diffusion-weighted 
magnetic resonance imaging for monitoring prostate cancer progression in patients 
managed by active surveillance. The British journal of radiology. 2011;84(997):31-7. 
15. Lee DH, Koo KC, Lee SH, Rha KH, Choi YD, Hong SJ, et al. Tumor lesion diameter on 
diffusion weighted magnetic resonance imaging could help predict insignificant prostate 
cancer in patients eligible for active surveillance: preliminary analysis. The Journal of 
urology. 2013;190(4):1213-7. 
16. van As NJ, de Souza NM, Riches SF, Morgan VA, Sohaib SA, Dearnaley DP, et al. A 
study of diffusion-weighted magnetic resonance imaging in men with untreated localised 
prostate cancer on active surveillance. European urology. 2009;56(6):981-7. 
 
 
 
 
 
 
 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 25 of 26 
Version 2.4: 17 June 2019 
 
9.0 
SUMMARY OF CHANGES 
 
Protocol Version 2, dated 02 JUL 2018, amends Protocol Version 1 IRB approval 
on 07 DEC 2017.  
 
Amendment 1: See changes below:  
 
Section 3.4 (Study Procedrues) 
• 
Clarification that physician directed physical exam may be collected within 90 days of 
screening.  
• 
Clarification to adverse event assessment: “Only grade 2 and above imaging-related AEs 
will be captured and all SAEs following the receipt of fluciclovine F18.”  
• 
Clarification that MRI images will be read by one GU radiologist, not two.  
 
Section 5.0 (Adverse Events) 
• 
Reporting procedures for “Serious Adverse Events” included.  
 
Section 5.2 (Reporting Requirements)  
• 
Addition of “Reporting to the FDA section” describing the procedures for reporting SAEs 
to the FDA.  
• 
Addition of “Reporting to Blue Earth Diagnostics” describing the procedures for 
reporting SAEs to Blue Earth Diagnostics.  
 
Protocol Version 2.1, dated 13 NOV 2018, amends Protocol Version 2 IRB approval 
on 23 JUL 2018. 
 
Amendment 2: See changes below: 
 
Section 3.2.2 (Exclusion Criteria) #4 
• 
Clarification of exclusion #4 “suggestion of extracapsular extension or seminal 
vesicle invasion on imaging, if imaging was completed per SOC prior to or during 
screening”. Exclusion #4 would only apply if the subject had imaging performed 
as part of SOC. Study calendar confirm that imaging is not required as part of 
screening and therefore this criterion does not apply to patients who do not 
receive SOC imaging prior to or during the screening period. 
 
Protocol Version 2.2, dated 06 FEB 2019, amends Protocol Version 2.1 IRB 
approval on 19 NOV 2018. 
 
Amendment 3: See changes below: 
 
Section 3.2.1 (Inclusion Criteria) #2 
• 
Clarification of inclusion #1 “PSA <20 ng/mL (within 3 months of consent)”. 
Timeframe for the PSA result clarified to be within 3 months of consent. 
 
Protocol Version 2.3, dated 19 MAR 2019, amends Protocol Version 2.2 IRB 
approval on 22 APR 2019. 


________________________________________________________________________ 
IIT2016-19-Daskivich-18F 
 
    Page 26 of 26 
Version 2.4: 17 June 2019 
 
Amendment 4: See changes below: 
 
Section 3.4.2 (Pre-HIFU Imaging Protocol for Tumor Mapping) 
• 
Clarification in regard to 18F fluciclovine injection and PET scan time. The 
research PET scan will be a dynamic list mode scan. Meaning the PET would 
start first, then 18F fluciclovine would be injected immediately after the scan is 
started.  
 
Protocol Version 2.4, dated 17 June 2019, amends Protocol Version 2.3 IRB 
approval on XX XXX XXXX 
 
Amendment 5: See changes below: 
 
Section 7.2 Data and Safety Monitoring 
• 
Clarification of QMC monitoring role. 
 
Section 7.2.1 Safety Monitoring 
• 
Clarification of site monitoring. 
 
Section 7.5.2 Protocol Exceptions and Eligibility Waivers 
• 
Clarification of protocol exception and eligibility waiver process.