High-Resolution, 18F-PSMA PET-MRI for Mapping Prostate Cancer in Patients Considering Focal High-Intensity Focused Ultrasound (HIFU) Therapy or Radical Prostatectomy
Phase: PHASE2
Conditions: Prostatic Neoplasms, Genital Neoplasms, Male, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Genital Diseases, Male, Prostatic Disease
Sponsor: Alessandro D'Agnolo

 
 
 
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. 
 
 
 
IIT2020-14-DAGNOLO-HIFU 
High-Resolution, 18F-PSMA PET-MRI for Mapping Prostate Cancer in Patients 
Considering Focal High-Intensity Focused Ultrasound (HIFU) Therapy or Radical 
Prostatectomy 
 
Principal Investigators:            
Alessandro D’Agnolo, M.D. 
Imaging/Nuclear Medicine 
Cedars-Sinai Medical Center 
8700 Beverly Blvd, PACT 400 
Los Angeles, CA  90048 
Email: Alessandro.dagnolo@cshs.org 
Tel: 310-423-4682 
Fax: 310-423-1886 
 
Timothy Daskivich, M.D. 
Urology/Surgery 
8635 West Third St, 1070 
Los Angeles, CA. 90048 
Timothy.Daskivich@cshs.org 
Tel: 310-423-4700 
 
Sub-Investigator(s): 
 
 
Name 
Department/Division 
Hyung Kim, M.D.  
Urology/Surgery 
Timothy Daskivich, M.D. 
Urology/Surgery 
Rola Saouaf, M.D. 
Radiology 
Yaniv Raphael, M.D.  
Radiology 
Louise Thomson, MB, ChB 
Nuclear Medicine 
Debiao Li, Ph.D. 
Biomedical Imaging Research Institute 
Stephen Freedland, M.D. 
Urology/Surgery 
Susan Win, M.D. 
Radiology 
Michael Ahdoot, M.D.  
Urology 
 
 
 
 
 
Biostatisticians: 
 
Marcio Diniz, Ph.D 
 
 
 
 
Cedars Sinai Medical Center 
 
 
 
 
 
 
 
 
Study Intervention: 
 
High-resolution, 18F-PSMA PET-MRI 
 
IND Number:  
150-777 
 
IND Holder Name: 
Alessandro D’Agnolo, MD 
 
ClinicalTrials.gov:  
Results Reporting Required  
 
  
NCT No:  
NCT04461509 

 
 
 
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. 
 
 
Funding Source:  
Internal/Departmental Funding  
 
Current Version: 
 
Version 8.0: 08 November 2023 
Previous Version: 
 
Version 7.0: 16 August 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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 
IIT2020-14-DAGNOLO-HIFU Protocol Version 8.0: 08 November 2023 
 
 
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 ..............................................................................................4 
2.0 
BACKGROUND AND RATIONALE ..................................................................5 
2.1 
Prostate Cancer:  Current Standard of Care in Treatment .............................................. 5 
2.2 
HIFU:  Historical Background and FDA Approval ............................................................ 5 
2.3 
HIFU:  International Experience with Prostate Cancer Treatment .................................. 5 
2.4 
MRI for Prostate Cancer Imaging .................................................................................... 6 
2.5 
High-Resolution Prostate MRI (hrMRI) ............................................................................ 7 
2.6 
PSMA and PET-MRI in Prostate Cancer ......................................................................... 7 
2.7 
MR/US-Fusion for Targeting of Prostate Cancers ........................................................... 8 
2.8 
Combining MR/US-Fusion, hrMRI, and PET-MRI with HIFU for Focal Treatment of Prostate 
Cancer 8 
2.9 
PET-hrMRI prior to prostatectomy ................................................................................... 8 
3.0 
STUDY DESIGN: ...................................................................................................9 
3.1 
Overview .......................................................................................................................... 9 
3.2 
Study Population .............................................................................................................. 9 
3.3 
Study endpoints ............................................................................................................. 10 
3.4 
Study Procedures .......................................................................................................... 10 
3.5 
Removal of Subjects from study .................................................................................... 18 
4.0 
Study Risks ............................................................................................................19 
5.0 
ADVERSE EVENTS (AE) ...................................................................................20 
5.1 
Definitions ...................................................................................................................... 20 
5.2 
Reporting Requirements ................................................................................................ 22 
6.0 
STATISTICAL ANALYSIS ................................................................................25 
6.1 
HIFU Phase II Study ...................................................................................................... 25 
6.2 
Radical Prostatectomy Phase II Study .......................................................................... 26 
 

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ii 
6.3 
Exploratory Objectives ................................................................................................... 27 
7.0 
STUDY MANAGEMENT ...................................................................................27 
7.1 
Data Management and Quality Control and Reporting ................................................. 30 
7.2 
Data and Safety Monitoring ........................................................................................... 30 
7.3 
Replacement of subjects ............................................................................................... 31 
7.4 
Record Retention ........................................................................................................... 32 
7.5 
Adherence to Protocol ................................................................................................... 32 
7.6 
Obligations of Investigators ........................................................................................... 34 
8.0 
REFERENCES .....................................................................................................35 
9.0 
Summary of Changes ...........................................................................................37 

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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 
PSMA 
Prostate specific membrane antigen 
ROI 
Region of interest 
SAE 
Serious Adverse Events 
UTI 
Urinary Tract Infection 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SCHEMA  
 
High-Resolution, 18F-PSMA PET-MRI for Mapping Prostate Cancer in Patients Considering Focal High-
Intensity Focused Ultrasound (HIFU) Therapy
 
Radical Prostatectomy 
 
 
 
STUDY SUMMARY 
Title 
High-Resolution, 18F-PSMA PET-MRI for Mapping Prostate Cancer in Patients 
Considering Focal High-Intensity Focused Ultrasound (HIFU) Therapy or Radical 
Prostatectomy 
Short Title 
High resolution PET-MRI before prostate cancer HIFU or radical prostatectomy 
Protocol Number 
Pro00000832 
Phase 
Two parts: Phase II and Pilot 
Methodology 
Single arm, paired imaging (Phase II) 
Study Duration 
3 years 
Study Center(s) 
Cedars Sinai Medical Center 
Objectives 
Phase II Study (HIFU):  
Primary Endpoint: Number of additional biopsy-proven cancers that novel imaging 
modalities of hrMRI and/or F18-PSMA PET would detect when compared to 
reference standard imaging of mpMRI in patients undergoing HIFU procedure. 
Secondary Endpoint: Negative biopsy rate of standard 12-core biopsy 6 months 
following HIFU therapy. 
 
Phase II Study (Radical Prostatectomy(RP)):  
Primary Endpoint: To determine the sensitivity in detection of prostatic carcinoma 
of novel imaging modalities of hrMRI and /or F18-PSMA PET compared to 
reference standard mpMRI in patients scheduled to undergo radical 
prostatectomy.  
Secondary Endpoint: Specificity of hrMRI, F18--PSMA PET and mpMRI for 
detecting all tumors and metastasis at 6 months follow up.  
Number of Subjects 
30 Study Subjects (Phase II HIFU), 31 Study Subjects (Phase II RP) 
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
 

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Diagnosis and Main Inclusion 
Criteria 
Diagnosis for Pilot trial: Any patient scheduled to undergo radical prostatectomy 
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 
• 
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 
• 
Patients considering focal HIFU therapy 
• 
Patients considering radical prostatectomy 
Study Imaging 
F18-PSMA 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.  In the pilot trial, the 
prostatectomy pathology will serve as the reference standard. 
Statistical analysis 
Our hypothesis is that 20% 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=40 provides a power of at 
least 90% when we account for 5 cases that will not be evaluable.  The RP 
phase II study is a parallel study arm using PSMA-PET imaging for intraprostatic 
cancer detection, but using radical prostatectomy pathology as the gold 
standard. The radical prostatectomy pilot arm will allow us to compensate for 
limitations and describe this data in parallel with the HIFU analysis.  

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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 F18-PSMA 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 F18-PSMA 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.  
 
Tumors invisible on MRI tend to be small, low-grade tumors that do not require treatment. 
However, it may be important to identify these tumors for future surveillance. An important 
limitation of this phase II study is that it will not be able to define the sensitive of imaging for these 
low-grade tumors. Therefore, a pilot study is included in which patients scheduled to undergo 
radical prostatectomy will have a preoperative PET-hrMRI.  The prostatectomy pathology will be 
the reference standard.  Since the true location of all tumors will be known, both the sensitivity 
and specificity of PSMA-PET MRI can be determined 

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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 
 
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 

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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, 
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.  

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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 
PSMA and PET-MRI in Prostate Cancer  
 
Positron emission tomography (PET) imaging has been increasingly used for detection of 
occult distant metastases in patients with advanced prostate cancer using prostate-
cancer-specific radiotracers (PSMA) or radiotracers that accumulate preferentially within 
prostate cancer tissue (11C choline, 11C acetate, and 18F fluciclovine).  Prostate-specific 
membrane antigen (PSMA) is a type II membrane protein originally characterized by the 
murine monoclonal antibody (mAb) 7E11-C5. 3 and is expressed in all forms of prostate 
tissue, including carcinoma. F18-PSMA is a radiolabeled antibody that binds to PSMA 
antigen expressed on the surface of the prostatic cancer cells.   
 
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.  
 
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-fluciclovine PET/CT 
and mpMRI imaging yielded a positive predictive value of 82% for tumor localization, which 

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was significantly higher than that with either modality alone.  
This would suggest that pairing also F18-PSMA 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 platforms 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.  
2.9 
PET-hrMRI prior to prostatectomy 
 
An important limitation of studying a new imaging modality in patients undergoing HIFU is 
that tumors are identified by biopsy, which is susceptible to sampling error.  In other words, 
tumors invisible on MRI and missed on systematic prostate biopsy are not considered in 

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defining the limitation of our novel imaging. These tumors are expected to be small, low 
grade tumors that do not require treatment.  However, future research will need to consider 
appropriate surveillance strategies for these MRI-invisible tumors. To define sensitive of 
PET-hrMRI, we would need to know where all the tumors are.  Therefore, a pilot study is 
included in which patients scheduled to undergo radical prostatectomy will have a 
preoperative PET-hrMRI.  The prostatectomy pathology will be the reference standard.  
Since the true location of all tumors will be known, both the sensitivity and specificity of 
PSMA-PET MRI can be determined.   
3.0 
STUDY DESIGN: 
3.1 
Overview 
 
This prospective trial will evaluate the effectiveness of F18-PSMA 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 F18-PSMA 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-PSMA PET positivity. The primary endpoint of the 
Phase II study would assess the number of biopsy-proven cancers that mpMRI would 
have missed compared with hrMRI and/or F18-PSMA 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 which will be the secondary endpoint of the Phase II study. 
 
As the gold standard for evaluation of sensitivity and specificity of any imaging test is the 
pathologic analysis of the whole prostatic gland obtained at prostatectomy (as the biopsy 
is subject to error sampling), a concurrent pilot study will enroll patients scheduled to 
undergo prostatectomy with the primary endpoint to define sensitivity of PET-hrMRI versus 
mpMRI compared against the prostatectomy pathology and with the secondary endpoint 
define specificity of hrMRI, F18-PSMA PET and mpMRI for detecting all tumors and 
metastasis at 6 months follow up. 
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 (for HIFU arm only) 
3. cT1-cT2c 

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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 (for HIFU 
arm only) 
5. Patient considering focal HIFU therapy or robotic radical prostatectomy 
 
3.2.2 
Exclusion criteria: 
1. Previous local therapy for prostate cancer 
2. Inability to receive PET tracer 
3. Inability to receive MRI 
4. Estimated glomerular filtration rate (GFR) <15 mL/min/1.73 m2 
5. Any other condition which, in the investigator’s option, may make the patient a poor 
candidate for participation in a clinical trial.  
 
3.3 
Study endpoints 
 
Primary Endpoint (HIFU): Number of additional biopsy-proven cancers that novel imaging 
modalities of hrMRI and/or F18-PSMA PET would detect when compared to reference standard 
imaging of mpMRI in patients undergoing HIFU procedure. 
 
Secondary Endpoint (HIFU): Negative biopsy rate on standard 12-core biopsy 6 months 
following HIFU therapy.   
 
Primary Endpoint (Prostatectomy):  To determine the sensitivity in detection of prostatic 
carcinoma of novel imaging modalities of hrMRI and/or F18-PSMA PET compared to reference 
standard mpMRI in patients scheduled to undergo radical prostatectomy. 
 
Secondary Endpoint (Prostatectomy):  Specificity of hrMRI, F18-PSMA PET and mpMRI for 
detecting all tumors and metastasis at 6 months follow up. 
 
Exploratory Endpoint: RNAseq transcriptome analysis of lesions that are positive on mapping 
biopsy.  Sensitivity and specificity of PET-hrMRI for detecting all tumors detected on 
prostatectomy pathology. 
 
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. 
 
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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.   
 
The pilot study will allow enrollment of patients scheduled to undergo radical 
prostatectomy performed either at Cedars-Sinai Medical Center (CSMC) or an outside 
hospital (OSH). If the radical prostatectomy is performed at an OSH, authorization from 
subjects will first be obtained. Then the final pathology report of the radical prostatectomy 
from OSH will be obtained, reviewed and considered at CSMC for final data analysis. 
Additionally, the outside pathology slides may need to be reviewed here at CSMC for final 
data analysis as well, however this decision will be made later. They will get a preoperative 
PET-hrMRI. All surgical interventions and postoperative care are per standard-of-care. 
Scan results may identify patients who do not qualify for surgery. 
 
The investigator may decide to change arms for a subject (i.e. HIFU to RP or RP to HIFU) 
based on MRI finding or replace the subject after imaging review.    
 
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, 
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 

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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 180 days of screening.  
Vital Signs will include heart rate (pulse), respiratory rate, blood pressure, and body 
temperature. 
3.4.1.7 
Adverse event assessment 
Adverse events will be assessed at imaging, post imaging (biopsy), HIFU/Prostatectomy, 
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 18F-DCFPyL agent. 
3.4.2 
Study Calendar for Focal High-Intensity Focused Ultrasound (HIFU) 
Therapy  
 
 
 
Procedure 
Screening 
Imaging 
Post-
imaging2 
Standard of 
Care (SOC) 
Treatment 
Post SOC 
Treatment  
6 months 
(+/- 1.5 
months) 
following 
HIFU 
Informed 
Consent/Registration 
X 
 
 
 
 
Review Eligibility 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Prior and Current 
Medication Review 
X 
 
 
 
 
Vital Signs5 
 
X 
X 
 
 
Physical Exam 
(including symptoms 
assessment, height, 
weight) 5 
X 
 
 
 
 
Standard MRI with 
Gadolinium 
 
X  
(at least one day prior to 
targeted  prostate biopsy) 
 
 
X  
(at least 
one day 
prior to 
targeted  
prostate 
biopsy) 
 
Optional: Tissue 
collection4  
 
 
X 
 
X 
Optional: Blood 
collection6 
X7 
X 7 
X7 
X7,8 
X8 

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18-PSMA PET-hrMRI 
 
X  
(at least one day prior to 
targeted  prostate biopsy) 
 
 
 
Adverse Event Review 
 
X 
X 
X 
X 
Hemigland or Focal 
High Intensity Focused 
Ultrasound (HIFU)1 
 
 
 
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-PSMA PET positivity 
4. Tissue collection includes left over tissue from standard of care collection only. 
5. Need to be obtained within 180 days of screening. Vital signs will be assessed 
before and after administration of 18F-DCFPyL. 
6. Blood collection will be approximately 17 mL  (approximately 1 tablespoon) of 
whole blood. As of August 2023, optional blood draw has been removed from ICF 
(MODCR00000250).  
7. Pre-treatment blood will be drawn once before HIFU or on the day of surgery with 
standard of care blood draw. 
8. Post-treatment blood will be drawn once after HIFU with standard of care blood 
draw. 
 
Study Calendar for Radical Prostatectomy 
Procedure 
Screening 
Imaging 
Standard of 
Care (SOC) 
Treatment 
Post SOC 
Treatment      
6 months (+/- 
1.5 months) 
following 
Prostatectomy 
Informed 
Consent/Registration 
X 
 
 
 
Review Eligibility 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History 
X 
 
 
 
Prior and Current 
Medication Review 
X 
 
 
 
Vital Signs2 
 
X 
 
 
Physical Exam 
(including symptoms 
assessment, height, 
weight)2 
X 
 
 
 

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Standard MRI with 
Gadolinium 
 
X  
(preoperative PET-hrMRI 
prior to prostatectomy) 
 
 
 
Optional: Tissue 
collection1  
 
 
X 
 
Optional: Blood 
collection3 
X4 
X 4 
X5  
 
 
18-PSMA PET-
hrMRI 
 
X  
(at least one day prior to 
prostatectomy) 
 
 
PSA Lab Result 
 
 
 
X 
Adverse Event 
Review 
 
X 
X 
X 
Prostatectomy 
 
 
X 
 
1. Tissue collection includes left over tissue from standard of care collection only. 
2. Need to be obtained within 180 days of screening. Vital signs will be assessed 
before and after administration of 18F-DCFPyL. 
3. Blood collection will be approximately 17 mL (approximately 1 tablespoon) of 
whole blood. As of August 2023, optional blood draw has been removed from ICF 
(MODCR00000250). 
4. Pre-treatment blood will be drawn once before prostatectomy or on the day of 
surgery with standard of care blood draw. 
5. Post-treatment blood will be drawn once after prostatectomy with standard of care 
blood draw. 
3.4.3 
Study Intervention 
3.4.3.1 
Study Intervention(s) Administration 
 
Study Interventions Description  
18F-DCFPyL Injection is a radioactive diagnostic PET imaging agent indicated for (1) use 
in staging of men with high risk prostate cancer and (2) the detection of recurrent or 
metastatic prostate cancer. 
 
Dosing and Administration 
The recommended dose of 18F-DCFPyL Injection is 9 mCi (333 MBq), administered 
intravenously as a bolus injection followed by a flush of normal saline. The drug product 
contains radioactive material and will only be handled by personnel trained and certified  
in the use of radioactive isotopes with proper shielding and monitoring. 
3.4.3.2 
Preparation/ Handling/ Storage/ Accountability 
Acquisition and Accountability 
Progenics Pharmaceuticals will be providing the injection to the investigator. 
 
Formulation, Appearance, Packaging, and Labeling  
18F-DCFPyL Injection is a Fluorine-18 labeled small molecule that targets the extracellular 
domain of PSMA. 18F-DCFPyL is a radioactive diagnostic agent used with PET imaging. 
Chemically, 
18F-DCFPyL 
is 
2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-
amino]-pentyl}ureido)-pentanedioic acid. The structural formula is: 

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18F-DCFPyL Injection is a sterile, clear particle-free solution for intravenous use. It is 
supplied at a specific activity of at least 1000 mCi/μmol at the Time of Administration, 
corresponding to a total administered chemical mass of DCFPyL of ≤ 4 μg, and a 
radioactivity concentration of 1 to 80 mCi/mL at the Time of Calibration (TOC), or, end of 
synthesis (EOS). The pH is between 4.5 and 7.5. The product is to be stored at room 
temperature; beyond-use date is 10 hours from EOS. 
 
Based on information provided by the cross-referenced IND 129,952, there are a total of 
three labels for the drug product, 18F-DCFPyL:  a label on the finished drug product vial, 
a prescription label for the lead pig, and a label for the unit-dose syringe.  The finished 
drug product within the vial is dispensed into unit-dose(s) at the radiopharmacy and 
shipped in the lead pig to the clinical site. 
 
•The batch label of the finished drug product vial:  An example label of the 18F-DCFPyL 
finished drug product vial from Sofie (formerly Zevacor)-Gilroy facility is provided.  It 
complies with 21 CFR 312.6.    
  
 
 
•The prescription label on the lead pig: This label is for the lead pig shipped from the 
radiopharmacy to the clinical site.  The labeling provides detailed information of the drug 
product for the clinical sites.  It is in compliance with 21 CFR 312.6 requirements. 
 
Example prescription label on the lead pig as dispensed by the Gilroy-radiopharmacy; 
similar label will be prepared for Cedars-Sinai Medical Center:  

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•The unit-dose syringe label:  This label is for the unit-dose syringe as dispensed by the 
radiopharmacy. The labeling provides the minimum necessary and useful information (due 
to the space limitation and high levels of radioactivity) of the drug product for the clinical 
sites during drug administration.  It is in compliance with the 21 CFR 312.6 requirements. 
 
Example label on the unit-dose syringe as dispensed by the Gilroy-radiopharmacy; similar 
label will be prepared for Cedars-Sinai Medical Center: 
  
  

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Product Storage and Stability 
Based on routine pharmacy practice and State Board of Pharmacy regulation, the storage 
condition is not specified on the labeling if the drug is to be stored at room temperature, 
which is the case for 18F-DCFPyL. Beyond-use date is 10 hours from EOS.  
 
 
Preparation 
The study drug will be prepared and shipped by the radiopharmacy. They will label the 
injections with detailed information of the drug product for the clinical sites.  It is in 
compliance with 21 CFR 312.6 requirements. 
3.4.3.3 
Measures to Minimize Bias: Randomization and Blinding 
The study will not have randomized or blinding components. All participants will be 
provided with the intervention drug if they meet the inclusion criteria listed in section 3.2.1.  
3.4.3.4 
Study Intervention Compliance 
Physicians will recruit patients that meet the inclusion criteria for the study. Throughout 
the process, patients will be monitored by the physician and the study team assisting with 
the trial. They will keep track of the administration of 18F-PSMA by entering it on RedCap, 
a software used to capture data for research studies. The study staff will follow up with the 
patient if needed. 
3.4.3.5 
Concomitant Therapy and Rescue Medicine 
Not applicable to this study  
 
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 9 mCi ±20% F18-PSMA 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 time from end of injection of F18-PSMA injection to the start of imaging should be 60 
minutes.  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 
radiologist who has experience reading over 500 prostate MRIs.  All PET scans will be 
read by nuclear medicine 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 

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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 F18-PSMA PET positivity.  These areas will be targeted using the UroNav 
targeting software platform. We use the UroNav platform for performing MR-PET-US 
fusion biopsies.  It is an FDA approved, commercially available platform. Uronav received 
510(k) clearance from the FDA and it is a commercially available platform, link to 
document: 
https://www.accessdata.fda.gov/cdrh_docs/pdf15/K153073.pdf. 
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.   
 
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: 

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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 
 
This study investigates a novel software-based MRI imaging protocol that improves image 
resolution, and it investigates the use of F18-PSMA for prostate PET-MRI.   
 
F18-PSMA is currently not approved by FDA.  MR/ultrasound fusion biopsies and HIFU 
for prostate ablation are 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 
scanners are used in accordance with guidelines set by the Bureau of Radiological Health. 
 
F18-PSMA 
The recommended dose is 333 MBq (9 mCi) administered as an intravenous bolus 
injection.  The (radiation absorbed) effective dose resulting from this dose of F18-PSMA 
is 8 mSv.  The clinical trial database for F18-PSMA includes data from 208 subjects. The 
mean administered activity was 333 MBq.  Adverse reactions were reported in ≤1% of 
subjects during clinical studies with F18-PSMA. The most common adverse reactions 
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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 
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 

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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“.  
Evaluable for toxicity  
Any patient who receives at least one dose of investigational product is evaluable 
for toxicity and will be included in the safety analysis. 
 
Severity of Adverse Events  
• 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of 
the event. 
• 
Fatal (grade 5): the event caused death. 
Reporting Requirements for Adverse Events  
 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE – CURRENT VERSION 5.0).  
 
Step 2: Grade the adverse event using the CTCAE – CURRENT VERSION 5.0. 
 
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. 
 

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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 the Agent Information Section 
of this protocol; 
• 
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 Principal Investigator  
The Principal Investigator must be notified by study staff or co-investigators within 24 
hours of learning of any serious adverse events, regardless of attribution, occurring 
during the study or within 30 days (refer to Section 7.1) of the last administration of the 
study drug. 
 
Phone Number for Expedited Reporting: 
Alessandro D’Agnolo, MD   
310-423-4682 
Alternate Phone Number for Expedited Reporting: 
ALTERNATE NAME AND PHONE 
Timothy Daskivich, MD  
310-423-4700 
 
5.2.1.1 
Participating Site Reporting Responsibilities 

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Any serious adverse event or unanticipated problem at all participating sites, which 
occur in research subjects on protocols for which SOCCI is the DSMC of record requires 
reporting to the DSMC regardless of whether IRB reporting is required. All 
SAEs/UPIRSOs occurring during the protocol-specified monitoring period should be 
submitted to the SOCCI DSMC, copying the CCTO Coordinating Center Study Lead, as 
detailed in section 7.4.2.3. In addition, for participating centers other than SOCCI, local 
IRB guidance should be followed for local reporting of serious adverse events.  
 
 
If the event occurs on a multi-site clinical trial coordinated by the SOCCI, the Study Lead 
at the Coordinating Center will ensure that all participating sites are notified of the event 
and resulting action, according to FDA guidance for expedited reporting. Copies of all 
serious adverse event reports or unanticipated problems reports will be kept on file in the 
Cedars-Sinai CCTO. 
 
Reporting of SAEs/UPIRSOs must be accompanied by a cover letter which:  identifies 
the event, is signed by the local principal investigator or treating physician from the 
participating site, includes the applicable study number and title, and contains the 
following: 
• 
Site assessment of the event attribution to investigational product or 
study procedure 
• 
Site assessment of event expectedness (expected vs. unexpected) 
• 
Assessment of whether or not the research places subjects at a 
greater risk of harm than was previously known or recognized 
• 
Assessment of the event’s effect on the risk to benefit ratio  
• 
Statement as to whether the informed consent statement should 
reflect changes in the potential risks involved 
• 
Statement as to whether the event has been reported previously, and 
if so, whether the frequency is considered unusually high 
 
 
 
 
Send to: 
SOCCI Cancer Clinical Trials Office 
 
 
 
 
 
ATTN: SPIN/ Protocol # STUDY00000832 
 
 
 
 
 
Fax: (310) 423-1998 
 
 
 
 
 
E-mail: GroupSOCCICCTODSMCAdmin@cshs.org 
 
 
 
 
 
CC: GroupCCTOSPIN@cshs.org 
 
5.2.1.2 
Reporting to DSMC:  
 
Serious Adverse Events deemed to be related to the protocol and on-study deaths, 
including death of a research subject unless the death is expected (e.g. due to disease 
progression) to be reported to the DSMC within 24 hours of awareness. Hardcopies or 
electronic versions of the MedWatch Form 3500A (Mandatory Reporting) or SAE Form, 
along with any other supporting documentation available, should be submitted to the 
DSMC Coordinator. The DSMC Coordinator will forward the information to the DSMC 
Chair, and/or medical monitor. The DSMC Chair will review all SAEs/UPIRSOs upon 
receipt from the DSMC Coordinator and determination of whether the following actions 
are required: 1) takes action immediately, 2) convenes a special DSMC session 
(physical or electronic), or 3) defers the action until a regularly scheduled DSMC 
meeting. Reports are to be emailed to the DSMC team at 
GroupSOCCICCTODSMCAdmin@cshs.org.  
 

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5.2.1.3 
Reporting to Drug Manufacturer 
 
In accordance with Applicable Laws, Study Staff will advise the sponsor of any adverse 
reactions or side effects occurring during and after the conduct of the Study that become 
known to it. Institution agrees and shall cause Principal Investigator to comply with all 
applicable safety reporting regulations as set forth in the Code of Federal Regulations. 
Any correspondence to the FDA regarding adverse events or other safety issues 
associated with the Study Drug will be simultaneously copied via facsimile or e-mail to 
Progenics. Within 24 hours of becoming aware of a serious adverse event, Institution will 
communicate the occurrence of such event to Progenics and, if another drug or product 
is being used in the Study, to the manufacturer of the associated drug or product. Please 
note that the reporting period begins when a subject receives the Study Drug. Adverse 
event reports should reference the Progenics Clinical Grant Number, which will be 
supplied to the Principal Investigator by Progenics. The MedWatch 3500A form or such 
other form as may be required by the FDA from time to time should be utilized to report 
serious adverse events to the FDA. For Progenics products, report the adverse event 
information to the following: DocuSign Envelope ID: 3191B4AA-7E39-4BB7-9A69-
037F85430112 DocuSign Envelope ID: C3AF2C8C-BFA9-423E-95B8-26A66809B56A4 
Pharmacovigilance Agent Phone: 1-800-343-7851 or 1-978-667-9531 Fax: 1-978-436-
7296 Email: lantheussafety@lantheus.com 
5.2.2 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. 
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. 
5.2.3 
Reporting to the FDA 
The sponsor-investigator of the IND, or designee at the Coordinating Center, 
must submit all reported SAEs from all participating sites to the FDA on the FDA 
Form 3500A (MedWatch) according to the following reporting criteria: 
7-Day Reports: 
The investigator-sponsor of the IND must notify the FDA as soon as possible but 
no later than 7 calendar days after the investigator-sponsor’s initial receipt of the 

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information and all participating sites in a written IND safety report of any adverse 
reaction: 
▪ 
fatal or life-threatening adverse reaction that is both 
▪ 
suspected to be associated with use of the drug and 
▪ 
unexpected 
 
 
 
15-Day IND Reports:  
The investigator-sponsor of the IND must notify the FDA as soon as possible but 
no later than 7 calendar days after the investigator-sponsor’s initial receipt of the 
information and all participating sites in a written IND safety report of any adverse 
reaction: 
• 
suspected to be associated with use of the drug that is both  
• 
serious and  
• 
unexpected  
 
Copies of Expedited Safety Reports will be kept in the Trial Master File in 
the SOCCI CCTO. 
 
6.0 
STATISTICAL ANALYSIS  
 
6.1 
HIFU Phase II Study 
Our preliminary data suggests that up to 60% of tumors invisible to standard mpMRI are 
detected on hrMRI in an active surveillance population.  It is unclear how many additional 
lesions will be identified on PSMA 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 main hypothesis to be tested is whether the sensitivity of PSMA 
PET-hrMRI is greater than mpMRI alone in 20% considering the prostate divided in 6 
sections for each patient.  The power is evaluated using 1000 simulations based on the 
McNemar`s type test proposed by Yang et al. (17,2010). Data is generated based on four 
correlations: r1: between lesions evaluated by PSMA PET-hrMRI for the same patient, r2: 
between lesions evaluated by mpMRI for the same patient, r3: between evaluations PSMA 
PET-hrMRI and mpMRI for the same lesion and r4: between evaluations PSMA PET-
hrMRI and mpMRI for the different lesions at the same patient. Based on preliminary data, 
we estimated mpMRI sensitivity of 42%, (r1, r2, r3, r4) = (-0.249, -0.119, 0.714, -0.172) 
using Spearman correlation, average number of lesions of 2.5 per patient and prevalence 
of patients with at least one positive biopsy section equal to 82%. The results are 
presented in Table 1.  
 
 
Table 1. Power for McNemar test proposed by Yang et al. (2010) to detect a 
difference of 20% between sensitivities of the combination (PET-hrMRI or 
mpMRI) and mpMRI  
Total Sample 
Size 
# Patients with at least one positive biopsy 
section 
Power 

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20 
16 
70.2 
25 
21 
81.5 
30 
25 
88.9 
35 
29 
93.1 
40 
33 
95.5 
 
The minimum sample size to reach at least 85% of power is 30 patients with complete 
imaging data. Patients with incomplete imaging data will be replaced.  
 
Statistical Analysis: Sensitivities will be compared using McNemar`s type test proposed 
by Yang et al. (17,2010). for cluster matched binary data. In addition, the 95% confidence 
interval for difference between sensitivities will be calculated as proposed by Yang et al. 
(18,2012). 
 
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.   
 
6.2 
Radical Prostatectomy Phase II Study  
 
Our previously conducted pilot study investigating the impact of fluciclovine PET imaging 
on improving sensitivity of prostate cancer detection (identical to this study but using 
fluciclovine tracer instead of PSMA) was criticized due to lack of a gold standard based 
on radical prostatectomy (outcome was based on biopsy only).  Since the HIFU arm in this 
PSMA PET study has a biopsy-only gold standard, we elected to include a parallel study 
arm using PSMA-PET imaging for intraprostatic cancer detection but using radical 
prostatectomy pathology as the gold standard.  While there are historical references for 
sensitivity of PSMA-PET for intraprostatic cancer detection, they are not ideal to be used 
as a reference for our study since: they are few in number and may not provide 
generalizable estimates; the analysis to date has only been done on a per-patient (rather 
than a per-lesion) basis; and there is variation in reading of mpMRI by center/radiologist.  
The described parallel radical prostatectomy pilot arm will allow us to compensate for 
these limitations and describe this data in parallel with our HIFU analysis.  
 
Power Assessment: The main hypothesis to be tested is whether the sensitivity of PSMA 
PET-hrMRI is 20% greater than mpMRI alone on a per lesion basis. It is expected 6 lesions 
in average per patient. Therefore, the power considerations are the same as presented 
for the HIFU cohort as displayed on Table 1.  
 
Table 1. Power for McNemar test proposed by Yang et al. (2010) to detect a difference 
of 20% between sensitivities of the combination (PET-hrMRI or mpMRI) and mpMRI  

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Total Sample 
Size 
# Patients with at least one positive biopsy 
section 
Power 
20 
16 
70.2 
25 
21 
81.5 
30 
25 
88.9 
35 
29 
93.1 
40 
33 
95.5 
 
Statistical Analysis:  Sensitivities will be compared using McNemar`s type test proposed 
by Yang et al. (17,2010). for cluster matched binary data. In addition, the 95% confidence 
interval for difference between sensitivities will be calculated as proposed by Yang et al. 
(18,2012). 
 
Secondary Endpoints: Specificity of imaging for detecting all tumors on prostatectomy   
 
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.   
 
 
6.3 
Exploratory Objectives 
Residual tissue and blood may be stored for future correlative studies that will be 
performed when funding is available.  Examples of studies that may be performed 
include DNA or RNA sequencing from tumor or blood. As of August 2023, optional blood 
draw has been removed from ICF (MODCR00000250). 
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. 
 
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 protocol and consent form will be 
reviewed and approved by the IRB of each participating center prior to study initiation, 
unless participating sites are utilizing a reliance agreement with the Coordinating 
Center’s IRB of record. 
 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent 
information) will be submitted to the IRB.  The IRBs written approval of the study 
protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated and prior to the shipment of study supplies to participating 

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sites, if applicable.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review. 
 
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. 
 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be 
provided to the Study Lead at the Coordinating Center.  
• 
A copy of the official IRB approval letter for the protocol and informed 
consent 
• 
IRB membership list or Federal-wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if {institution} holds the IND. 
Otherwise, the affiliate Investigator’s signature on the protocol is sufficient 
to ensure compliance) 
• 
A financial conflict of interest statement from each investigator has been 
obtained. 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal 
values 
• 
Executed clinical research contract 
 
 
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 

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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 teams will track all subjects who sign consent using 
OnCore. Subjects found to be ineligible will be recorded as screen failures. Subjects 
found to be eligible will be registered using a six-digit numeric ID that follows the 
standard SOCCI format (832-001, 832-002, etc.).  Participating sites for multi-center 
studies will also need to track all subjects consented.  Upon registration, the participating 
site will enter patient study ID and limited patient information into OnCore, updating 
status to enrolled, as per CCTO guidance.  If a participating site does not or cannot gain 
access to OnCore, an exception will be granted with approval of the Executive Director 
of the CCTO. 
 
Note: For multi-center studies, assign a lead-in identifier for each site and define in the 
protocol. For example, the first site will be designated a lead-in number of 001, while the 
second site will be designated a lead-in number of 002. For a study which includes two 
sites, the first patient consented and enrolled at the first site will be subject 01-001.  As a 
general rule CSMC will always have the lead-in identifier 01. The third subject enrolled at 
the second site might be 02-003. It is the responsibility of each site to track subjects 
enrolled at their respective sites and assigned consecutive subject numbers. 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo an eligibility verification by the 
study-specific research staff. Minimal risk studies are exempt from SOCCI 
Quality Management Core (QMC) central eligibility checklist review and eligibility 
verification. QMC central eligibility checklist review and eligibility verification for 
all subjects enrolled is performed only if requested by the PI at any time during 
the life of the study. 
 
B) 
Registration 
 
After eligibility is verified, each site will assign the subject a study number and 
site staff will then register the patient in OnCore®.   
 
 
Registration is completed as follows: 
 
• 
Assignment of a patient study number 
• 
Assignment to the patient a dose/treatment arm as determined through 
communication with Biostatistics and the principal investigator, if 
applicable  
• 
Enter the patient in OnCore 
• 
Notify the investigational pharmacy and treating physicians that a subject 
has gone on study and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire 
registration process. 

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Data Management and Quality Control and Reporting 
REDCap is the Cedars-Sinai Cancer institutional choice for the electronic data capture of 
case report forms for SOCCI Investigator Initiated Trials. REDCap, a HIPAA-compliant 
database, will be used for electronic case report forms in accordance with institutional 
requirements, as appropriate for the project. 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. 
 
In order to facilitate remote source to case report form verification, the CCTO study team 
will require other institutions participating in this trial as sub-sites to enter data into the 
selected EDC system and upload selected de-identified source materials when 
instructed, or as applicable. 
 
Frequency of trial monitoring will be conducted based on risk level of the study and this 
review includes but is not limited to accuracy of case report forms, protocol compliance, 
timeliness and accuracy of CTMS entries and AE/SAE management and reporting. The 
investigator and study team at all participating sites will ensure that the monitor or other 
compliance or quality assurance reviewer is given access to all the above noted study-
related documents and study related facilities (i.e., EMR and pharmacy access), and has 
adequate space to conduct the monitoring visit. Such monitoring visits may include on-
site and/or remote monitoring. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
Data and Safety Monitoring 
 
PI should assess the protocol for risk and assign an appropriate level of monitoring in 
concurrence with the CCTO. The risk level is then reviewed for final determination by the 
Protocol Review and Monitoring Committee (PRMC). PRMC will notify the PI of the final 
risk determination and of any changes to the protocol as needed. Please refer to the 
SOCCI Data and Safety Monitoring Committee Charter for more information.  
 
Data Monitoring and Quality Assurance  
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 focused internal 
monitoring visits and audits for data quality and protocol adherence. QMC reports will be 
forwarded to the SOCCI Data and Safety Monitoring Committee (DSMC). Refer to the 
DSMC Charter for more details. For any protocol, QMC has the authority to request 
more frequent reviews or focused safety monitoring if it is deemed appropriate for any 
reason.  
7.1.1 
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 
subject/study data. Adverse events and unanticipated problems are not expected, but if 

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they occur, they will be documented and reported according to CS-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. It is the responsibility of the principal investigator to adhere to the 
Data Safety Monitoring Plan throughout the life of the study. 
 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee 
will provide another layer of data and safety oversight. DSMC membership and 
responsibilities are governed by the committee charter. The annual DSMC findings and 
recommendations will be reported in writing to the Principal Investigator as a summary 
letter which will be forwarded by the Principal Investigator or designee to the CS-IRB. 
The DSMC may increase or decrease the frequency of study review, at their discretion. 
Refer to the DSMC Charter for details of the DSMC review.  
 
Multicenter Monitoring Plan  
This trial will comply with the current requirements of the SOCCI Data and Safety 
Monitoring Committee.  The SOCCI CCTO will be the Coordinating Center for this 
multicenter phase trial.  
 
In accordance with the Data and Safety Monitoring Committee, investigators will conduct 
continuous review of data and patient safety.  In addition, conference calls facilitated by 
the Study Lead at the Coordinating Center with investigators and staff at all participating 
sites will be scheduled at least monthly (and more often as needed) to discuss study 
progress. If there are no patients on treatment or in follow-up, email communication may 
be used in lieu of a teleconference, or in the circumstance where a scheduling conflict 
does not permit phone attendance. Meeting summaries will be included and document 
review of data and patient safety; meeting minutes will be submitted and reviewed by the 
DSMC.   
 
All multicenter investigator-initiated trials conducted at the SOCCI are subject to data 
monitoring by the CCTO Quality Monitoring Committee (QMC).  QMC has the 
responsibility for study monitoring for protocol compliance, data accuracy, performance 
of audits and monitoring of accrual (details found in the SOCCI Data Safety Monitoring 
Plan).  All open trials are reviewed at a minimum once a year by the QMC (or more often 
depending on risk).  This annual review includes the following: evaluation of the current 
accrual relative to the planned total accrual; examination of all reported violations; review 
of past monitoring visits and correspondence with the PI; review of previous 
correspondence between the PI and the QMC/DSMC.  External sites will be notified of 
upcoming monitoring visits and will be expected to provide de-identified source 
documents for remote monitoring of patients, and/or access to the site EMR.  Queries 
will be issued in the EDC and a detailed monitoring report will be provided to the 
participating site.  The SOCCI CCTO will also forward any monitoring and/or auditing 
reports to the DSMC. 
7.2 
Replacement of subjects 
Any subject who signs consent but does not undergo study intervention (i.e. high-res 
imaging) will be replaced.   

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7.3 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, records of study drug receipt, 
dispensation, destruction 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 in accordance with all applicable federal guidelines 
and local guidelines. 
 
Investigators must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request. 
 
Following closure of the study, each participating site will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the 
investigator at each site at such time that the records may be destroyed.  
7.4 
Adherence to Protocol 
7.4.1 
It is the responsibility of the Investigator-sponsor to ensure that patient 
recruitment and enrollment, treatment, follow-up for toxicities and response, and 
documentation and reporting at SOCCI are all performed as specified in the protocol. 
For multi-site studies, the site Principal Investigator at each participating site will assume 
the responsibilities for the day-to-day monitoring of the trial, including but not limited to 
review of eligibility of new subjects, proper documentation informed consent, 
administration of treatment per protocol, thorough documentation and capturing of 
research notes in the subject’s charts, and timely completion of required case report 
forms.  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 IRB of record, the study shall be 
conducted exactly as described in the approved protocol.  
7.4.2 
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. 
7.4.3 
Protocol Exceptions and Eligibility Waivers 
A protocol exception is an anticipated or planned deviation from the IRB-approved 
research protocol, as described in the CSMC IRB Policy, Reporting Possible 
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) Policy: 
Institutional Review Board/Research Compliance and Quality Improvement.  For multi-
site studies, the policy of the IRB of record must be followed. 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.  

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Planned exceptions to the protocol that are more than logistical in nature and/or impact 
an eligibility criterion, affect timing of study drug administration, or the investigator 
assesses the event may impact subject safety and/or study integrity, may not be 
implemented without prior IRB approval. The PI or her/his designee is responsible for 
submitting a protocol exception request and its supporting documents to the CSMC IRB 
if it meets the CS-IRB UPIRSO policy guidelines of a reportable exception/waiver. Study 
team should also 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 IRB reporting. For multi-site studies, the policy of the IRB of 
record must be followed. Once IRB approved, the deviation or exception can be 
implemented. 
 
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 submitted to the IRB for approval. Such requests for 
minimal risk studies do not require prior review by the CCTO Medical Director. 
7.4.4 
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 or study integrity. Such planned deviations that do 
meet this definition and do not affect the subject’s safety or study integrity should be 
noted in the subject’s research record or deviation log as described in the SOCCI 
CCTO’s Standard Operating Procedure 12: Deviation and Noncompliance Reporting. 
For multi-site studies, follow local policy. 
 
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 CCTO’s 
Standard Operating Procedure 12: Deviation and Noncompliance Reporting (or local 
policy, for multi-site studies). In this case, a Protocol Deviation report must be submitted 
in CS-IRB (or the IRB of Record), per CSMC IRB policy, Reporting Possible 
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) Policy: 
Institutional Review Board/Research Compliance and Quality Improvement. For multi-
site studies, the policy of the IRB of record must be followed. All submissions should 
include a description of the plan to avoid similar deviations or exceptions in the future.   
7.4.5 
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. 

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7.5 
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 
 
Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
sponsor-investigator and participating institutions.  The publication or presentation of any 
study results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
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 

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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. 
17. Yang, Z., Sun, X., & Hardin, J. W. (2010). A note on the tests for clustered matched‐pair 
binary data. Biometrical journal, 52(5), 638-652. 
18. Yang, Z., Sun, X., & Hardin, J. W. (2012). Confidence intervals for the difference of 
marginal probabilities in clustered matched‐pair binary data. Pharmaceutical 
statistics, 11(5), 386-393. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.0 
Summary of Changes 
 
Protocol Version 1.0, dated 15 July 2020, amends Protocol Version 1.1, dated 22 
March 2021. 
 
Amendment 1: See changes below: 
 
Section Study Schema added for clarification of study procedures for HIFU and 
prostatectomy patients. Both HIFU and prostatectomy patients will undergo the same 
screening procedures, research scan and the rest is standard of care. The only 
difference is that the repeat mpMRI only applies to the HIFU patients. 
 
Section 3.4.2 Study calendar  
Revised to include separate calendar for prostatectomy patients. 
 
Section 5.0 Adverse Events 
Revised to include minimal risk study language. 
 
Section 5.2 Reporting Requirements 
Revised to include minimal risk study language. 
 
Section 7.0 Study Management 
Revised to minimal risk study language. 
 
Protocol Version 1.1, dated 22 March 2021, amends Protocol Version 2.0, dated 20 
May 2021. 
 
Amendment 2: See changes below: 
 
Section 3.2.2 Exclusion criteria 
Exclusion criteria #5, eGFR revised from less than 45 to less than 15 to follow current 
SOC Imaging guidelines. 
 
Section 3.4.1.6 Physical exam including vital signs, height, and weight 
Revised to define what are included for vital signs, which are heart rate, respiratory rate, 
blood pressure, and body temperature. 
 
Section 3.4.1.7 Adverse event assessment 
Revised to clarify only grade 3 and above imaging-related AEs will be captured and all 
SAEs following the receipt of 18F-DCFPyL agent. 
 
Section 3.4.2 Study Calendar 
Screening data expanded from 90 days to 180 days. 
 

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7.0 Study Management 
Subject ID number clarified from three to six digits (ex. 832-001) to match sources. 
 
For the Prostatectomy flowchart, study participation is complete after the SOC 
prostatectomy; there are no additional study related procedure after the SOC 
prostatectomy. Flowchart revised accordingly for clarification and to match MCA 
reviewed flowchart.   
 
Sub-investigator list on protocol’s first page updated to remove Grant Dagliyan and 
Beatrice Knudsen. 
 
Protocol Version 2.0, dated 20 May 2021, amends Protocol Version 3.0, dated 14 
September 2021. 
 
Amendment 3: See changes below: 
 
Section 3.2.2 Exclusion criteria 
Exclusion criteria #4 revised to state that the exclusion applies to the HIFU arm only. 
The following reflects the modification “Suggestion of extracapsular extension or seminal 
vesicle invasion on imaging, if imaging was completed per SOC prior to or during 
screening for HIFU arm only” 
 
Protocol Version 3.0, dated 14 September 2021, amends Protocol Version 4.0, 
dated 23 September, 2021. 
 
Amendment 4: See changes below: 
 
3.2.1 Inclusion Criteria 
Inclusion criteria #2 revised to state that the inclusion applies to the HIFU arm only. The 
following reflects the modification “PSA <20 ng/mL (for HIFU arm only)”. 
 
Inclusion criteria #4 revised to state that the inclusion applies to the HIFU arm only. The 
following reflects the modification “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 (for HIFU arm only)” 
 
Inclusion #5 revised to add robotic radical prostatectomy. The following reflects the 
modification “Patient considering focal HIFU therapy or robotic radical prostatectomy”. 
 
3.2.2 Exclusion Criteria 
Exclusion criteria #4 was removed.  
 
Protocol Version 4.0, dated 23 September 2021, amends Protocol Version 5.0, 
dated 07 February 2022. 
 
Amendment 5: See changes below: 
 
Sub-investigators(s) Table 
Removed Dr. Amit Gupta and added Dr. Susan Win and Dr. Michael Ahdoot.  
 

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Study Summary Table 
The number of subjects in the Study Summary table was revised from 40 Study Subjects 
(Phase II), 20 Study Subjects (Pilot) to 40 Study Subjects (Phase II), 40 Study Subjects 
(Phase II).  
 
Modified the objectives to reflect clarifications in primary and secondary endpoints for 
both cohorts. 
 
Modified statistical analysis to reflect clarifications in primary and second endpoints for 
both cohorts.  
 
3.1 Overview 
Per PRMC recommendations, provided clarifications to the primary and secondary 
endpoints for both cohorts. 
3.3. Study Endpoints 
Per PRMC recommendations, provided clarifications to the primary and secondary 
endpoints for both cohorts. 
 
3.4 Study Procedures 
The following text were added " Scan results may identify patients who do not qualify for 
surgery" and "The investigator may decide to change arms for a subject (i.e. HIFU to RP 
or RP to HIFU) based on MRI finding or replace the subject after imaging review".     
 
3.4.2 Study Calendar 
For tissue collection, in addition to left-over tissue, the study allows for collection of 2 
tubes of blood for research.  We added “..and 2 yellow top (8.5mL) tubes of whole 
blood”. 
 
6.1 HIFU Phase II Study 
Added HIFU Phase II Study as header at the beginning of the statistical analysis section. 
 
6.2 Radical Prostatectomy Phase II Study 
Added Radical Prostatectomy Phase II Study description per PRMC's recommendation 
for two separate primary and secondary endpoints for both cohorts.  
 
6.3 Exploratory Objectives 
This section was added to explain that tissue and blood will be used for future correlative 
studies. 
 
Protocol Version 5.0, dated 07 February 2022, amends Protocol Version 6.0, dated 
24 October 2022. 
 
Amendment 6: See changes below: 
 
3.4.1  
 
This section is changed to allow enrollment of patients scheduled to undergo radical 
prostatectomy performed either at Cedars-Sinai Medical Center (CSMC) or an outside 
hospital (OSH). If the radical prostatectomy is performed at an OSH, authorization from 
subjects will first be obtained. Then the final pathology report of the radical prostatectomy 
from OSH will be obtained, reviewed and considered at CSMC for final data analysis. 

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Additionally, the outside pathology slides may need to be reviewed here at CSMC for final 
data analysis as well, however this decision will be made later. The principal investigator 
has confirmed that completing the radical prostatectomy at an OSH does not compromise 
the study and does not impact subject safety or study integrity. 
 
6.1 
 
This section is changed to allow the number of patients enrolled in the HIFU arm to 
decrease from 40 to 30, and the number of patients enrolled in the Radical 
Prostatectomy arm to decrease to 31. The reduction in sample size allows for 85% 
power for both arms, which the investigators consider adequate for the scope of the 
study. 
 
Protocol Version 6.0, dated 24 October 2022. amends Protocol Version 7.0, dated 
16 August 2023. 
 
Amendment 7: See changes below 
 
3.4.2 Study Calendar has noted that optional blood collection has been removed from 
ICF for patients consented after August 2023 (MODCR00000250) 
 
6.3 Exploratory Objectives has been updated to note optional blood collection was 
removed from ICF for patients consented after August 2023 (MODCR00000250) 
 
Protocol Version 7.0, dated 16 August 2023. amends Protocol Version 8.0, dated 
08 November 2023. 
 
Amendment 8: See changes below  
 
 
3.4.2 Study calendar added 6-month follow up procedures in the Study Calendar for 
Radical Prostatectomy section