Clinical trial NCT03689582
Conditions: Prostate Cancer
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2018-11-13; Completion date: 2020-02-27
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to find out whether imaging of the prostate with a new molecule called 68Ga-PSMA can find prostate cancer. 68Ga-PSMA has been shown in a large number of patients to be useful to find recurring prostate cancer following initial cancer treatment. This study is performed to test 68Ga-PSMA whether it can be used to find prostate cancers that would be considered in need for treatment.

Detailed description:
In this study, two different imaging tests are being compared: a) 68Ga-PSMA Positron Emission Tomography (PET)/Computed Tomography (CT) and b) Magnetic Resonance Imaging (MRI) of the prostate gland. Participants already have received the MRI, and the results were either suspicious of or definitive for prostate cancer. Both tests (MRI and 68Ga-PSMA PET/CT) are expected to show tumor tissue when more aggressive, but one test could be more accurate than the other test.

Another important question is whether these imaging tests will perform as good or better than prostate biopsies in finding all prostate cancer lesions in need for treatment. If imaging would be comparable or better than biopsies, then imaging may be able to replace invasive biopsies for some indications in the future.

To investigate these questions, participants are asked to undergo a 68Ga-PSMA PET/CT before a planned prostate biopsy procedure. After the biopsy procedure is performed, investigators will compare the imaging results from 68Ga-PSMA with those from the MRI and determine which test is more accurate.

Arms: arm 1: PET/CT imaging with 68Ga-PSMA
Interventions: intervention 1: 68Ga-PSMA
Intervention descriptions: intervention 1: Positron Emission Tomography/Computed Tomography (PET/CT) imaging with 68Ga-PSMA:

68Ga-PSMA is an investigational radioactive drug that binds to receptors on prostate cancer cells. The intravenously administered drug dose will be about 5 mCi (range 3-7 mCi).

Protocol documents:
Prot_SAP_000.pdf: 
1 
68GA-PSMA FUSION PET/MRI FOR IMAGE-GUIDED PROSTATE 
BIOPSIES 
Version 4.0 
Dated: June 2, 2020 
Rogel Cancer Center ID:  2018.072 
IND Number: 133858 
Principal Investigator: 
Morand Piert, M.D. 
Department of Radiology, Division of Nuclear Medicine and Molecular Imaging 
Co-Investigators:  
Matthew Davenport, M.D.  
Chandy Ellimoottil, M.D.  
Kirk Frey, M.D., Ph.D.  
Arvin George, M.D. 
Lakshmi Priya Kunju, M.D.  
Jeffrey Montgomery, M.D. 
Simpa Salami, M.D. 
Thomas Chenevert, M.D. 
Dariya Malyarenko, Ph.D 
Prasad Shankar, M.D. 
Suzan Lowe, R.T. 
David Choi, M.D. 
Benjamin Viglianti, M.D., Ph.D. 
Study coordinator: 
James Pool, CRA 
Study statistician: 
Timothy Johnson, Ph.D. 
NCT03689582


2 
 
1 
SYNOPSIS 
 
Title 
68GA-PSMA   FUSION   PET/MRI   FOR   IMAGE-GUIDED   PROSTATE 
BIOPSIES 
Principle Investigator Morand Piert, MD 
Study Center 
Michigan Medicine 
Primary Objective(s) 
To determine the sensitivity and specificity of mpMRI alone, and mpMRI in 
combination with 68Ga-PSMA PET (i.e., fusion PET/MRI), for the detection 
of primary Gleason ≥3+4 PCa. Our primary outcome will be to determine 
whether the positive likelihood ratio (LR) for 68Ga-PSMA PET-MRI is at 
least 1.28 greater than that of standard-of-care mpMRI. 
Secondary 
Objective(s) 
(1) Safety 
(2) Frequency of extraprostatic extension, lympho-nodal and/or other 
metastatic disease positive on 68Ga-PSMA and not identified by 
conventional imaging 
Exploratory Objective Exploratory assessment of radiomics texture analyses of mpMRI and 68Ga- 
PSMA PET identified lesions 
Test drug(s) 
Name of active ingredient 
Dose 
Route of administration 
Duration of treatment 
68Ga-PSMA 
3.0 – 7.0 mCi 
Intravenous 
Once 
Indication 
Prostate cancer 
Diagnosis and main 
criteria for 
inclusion 
Subjects must fulfill the following criteria: 
Males (≥ 18 years of age) with prior mpMRI resulting in at least one PI- 
RADS 3-5 lesion with clinical need for a prostate biopsy procedure can 
participate, if one of the 2 criteria apply: 
(1) Known Gleason 6 or 7 prostate cancer undergoing active 
surveillance or in the confirmation phase of active surveillance, or 
(2) Rising PSA with either a) no prior biopsy or b) single or multiple 
negative prior biopsies. 
Exclusion criteria 
Any criterion will result in ineligibility: 
(1) Prior prostate biopsy within 12 weeks prior to enrollment 
(2) Acute prostatitis within the last 6 months 
(3) Current non-urologic bacterial infection requiring active treatment 
with antibiotics 
(4) Active other malignancy (except basal cell or squamous cell skin 
cancer) within the last 2 years 
(5) Body weight greater than 350 lbs (158 Kg) 
(6) Inability or unwillingness to receive a prostate biopsy procedure 
(7) Unable to lie flat, still, or tolerate a PET/CT scan 
(8) Unable to provide own consent 
(9) Concurrent severe and/or uncontrolled and/or unstable medical 
disease other than prostate cancer (e.g. poorly controlled diabetes, 
congestive heart failure, myocardial infarction within 6 months prior 
to study participation, unstable and uncontrolled hypertension, 
acute renal failure of any intensity, chronic renal or hepatic 
disease, severe pulmonary disease) 
(10) Prisoner 
Study phase 
Phase 2 
Study design 
Open label, single-center, single-dose, diagnostic imaging efficacy study 


3 
 
 
Methodology 
Participating subjects already underwent a clinically indicated prostate MRI 
resulting in at least one PI-RADS 3-5 lesion performed within 3 months 
prior to recruitment. 
Research imaging: 68Ga-PSMA PET/CT. 
Fusion of mpMRI and 68Ga-PSMA PET and biopsy target selection from 
mpMRI and 68Ga-PSMA PET. 
Prostate biopsy procedure (clinically indicated): standard biopsy and 
additional targeted biopsies to obtain pathological proof. Biopsy targets are 
selected from mpMRI and 68Ga-PSMA PET. 
Type of control 
Not applicable 
Number of subjects 
100 
Safety Assessments 
Patient vital signs will be taken before and after the administration of the 
radiopharmaceutical. The patients will also be asked to report adverse 
events. 
Plan for statistical 
analysis 
Visual and semi-quantitative assessment of PET/CT images: Descriptive 
statistics, frequency tables. 
We employ mixed effects logistic regression model to estimate the positive 
likelihood ratio (LR) of the combination of 68Ga-PSMA-guided plus mpMRI- 
guided biopsy (fusion PET/MRI) for the detection of primary Gleason ≥ 3+4 
cancer is higher than for mpMRI-guided biopsy (using PI-RADS version 2) 
alone. 


4 
 
2 
TABLE OF CONTENTS 
 
              Overall Table of Contents 
 
Page Number 
1 
SYNOPSIS .................................................................................................................... 2 
2 
TABLE OF CONTENTS .............................................................................................. 4 
        Overall Table of Contents ................................................................................ 4 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................... 6 
LIST OF DEFINITIONS ........................................................................................................... 7 
4 
BACKGROUND INFORMATION ............................................................................... 8 
        Introduction ........................................................................................................ 8 
4.1.1 
Significance of PSMA and preliminary data for PET 
imaging with 68Ga-PSMA ............................................................... 9 
4.1.2 
Radiomics ...................................................................................... 10 
5 
STUDY OBJECTIVES AND PURPOSE ................................................................. 11 
6 
OVERALL STUDY DESIGN AND PLAN ................................................................ 12 
        Study rationale ................................................................................................ 12 
6.1.1 
Rationale for administered radioactivity doses ......................... 12 
        Study timeframe ............................................................................................. 12 
        Risks and benefits to subjects ...................................................................... 12 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 13 
        Procedures for enrolment .............................................................................. 13 
        Inclusion criteria .............................................................................................. 13 
        Exclusion criteria ............................................................................................ 13 
        Withdrawal and termination criteria ............................................................. 13 
7.4.1 
Subject withdrawal ....................................................................... 13 
7.4.2 
Study termination .......................................................................... 14 
8 
TREATMENT OF SUBJECTS .................................................................................. 15 
        68Ga-PSMA ...................................................................................................... 15 
8.1.1 
Investigational medicinal product preparation .......................... 15 
8.1.2 
Treatment administration ............................................................. 15 
        Method of numbering subjects ..................................................................... 15 
        Blinding ............................................................................................................ 15 
        Prior and concurrent therapy ........................................................................ 15 
        Treatment compliance ................................................................................... 15 
9 
TREATMENT PERIOD .............................................................................................. 16 
             9.1     68Ga-PSMA PET/CT ....................................................................................... 16 
        Post-Treatment Period .................................................................................. 17 
9.2.1 Target identification ............................................................................ 17 


5 
 
9.2.2      Prostate biopsy procedure ........................................................... 17 
9.2.3      Pathological Evaluation ................................................................ 18 
9.2.4 
Clinical decision making .............................................................. 18 
9.2.5 
Image interpretation and correlation with standard of truth...18 
        Lesion localization variables ......................................................................... 19 
9.3.1 
Overall lesion localization rate .................................................... 19 
9.3.2 
Cancer lesion localization rate .................................................... 19 
9.3.3 
Visual assessment of lesion contrast and scoring ................... 19 
9.3.4 
Extra-prostatic lesions.................................................................. 19 
9.3.5 
Semiquantitative assessment: SUV, SUVR ............................. 19 
        Adverse event monitoring ............................................................................. 19 
9.4.1 
Adverse events ............................................................................. 20 
9.4.2 
Serious adverse events ............................................................... 20 
9.4.3 
Adverse event and serious adverse event reporting ............... 20 
9.4.4 
Expedited reporting ...................................................................... 21 
        Other variables ............................................................................................... 22 
9.5.1 
Demographic data ........................................................................ 22 
9.5.2 
Medical and surgical history ........................................................ 22 
9.5.3 
Prior and concurrent medication ................................................ 22 
9.5.4 
Appropriateness of measurements ............................................ 22 
10 
DATA HANDLING AND QUALITY ASSURANCE ................................................. 23 
      Clinical data management ............................................................................ 23 
     Archiving .......................................................................................................... 23 
11 
STATISTICAL METHODS AND PLANNED ANALYSIS ...................................... 24 
      General statistical considerations ................................................................ 24 
     Subject characteristics ................................................................................... 24 
11.2.1 
Demographic and other baseline characteristics ..................... 24 
11.2.2 
Pharmacodynamical data ............................................................ 24 
11.2.3 
Development of decision rules ................................................... 24 
12 
STATISTICAL EVALUATION ................................................................................... 25 
      Sample size determination ........................................................................... 25 
     Significance Level ........................................................................................... 25 
12.3     Rules for excluding subjects from analysis ................................................ 26 
12.4    Withdrawal from assessment and replacement ......................................... 26 
12.5    Analysis Plan .................................................................................................. 26 
12.5.1 Analysis Population ................................................................. 26 
12.5.2 Analysis of Primary Endpoints ................................................. 26 
12.5.3 Analysis of Secondary Endpoints ............................................ 26 
12.5.4 Analysis of the Exploratory Objective ............................................ 27 
13 
REFERENCES ........................................................................................................... 28 


6 
 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
68Ga-PSMA 
Gallium-68 labelled prostate-specific membrane antigen (PSMA-HBED-CC, or PSMA-11) 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALARA 
As low as reasonably achievable 
AS 
Active surveillance 
BP 
Blood pressure 
BPH 
Benign prostate hyperplasia 
CRF 
Case report form 
CRPC 
Castrate resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
DICOM 
Digital imaging and communications in medicine 
FWHM 
Full width at half maximum 
GC 
Gas chromatography 
GCP 
Good clinical practice 
HPLC 
High-performance liquid chromatography 
i.v. 
Intravenous 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Internal review board 
LC 
liquid chromatography 
MRI 
Magnetic resonance imaging 
mpMRI 
Multi-parameter MRI 
OSEM 
ordered-subset expectation maximization 
p.i. 
post injection 
PCa 
Prostate cancer 
PET 
Positron emission tomography 
PET/CT 
Hybrid PET with CT 
PET/MRI 
Positron emission tomography with magnetic resonance imaging 
PI 
Principal investigator 
PI-RADS 
Prostate Imaging Reporting and Data System 
pPCa 
Primary prostate cancer 
PSA 
Prostate-specific antigen 
ROC 
Receiver operating characteristic 
SAE 
Serious adverse event 
SD 
Standard deviation 
SID 
Stable isotope dilution 
SUV 
Standardized uptake value 
SOG 
Study operation guide 
TBR 
Tumor-to-background ratio 
TRUS 
Transrectal ultrasound 
VOI 
Volume of interest 


7 
 
List of Definitions 
 
Mass dose 
Amount of 68Ga- labeled drug substance (“hot” fraction of 
the active compound, 68Ga-PSMA), plus non-radioactive 
drug substance, expressed in µg 
Radioactive dose 
Amount of active 68Ga- labeled drug substance (“hot” 
fraction of the active compound, 68Ga-PSMA), expressed in 
MBq 
Impurities 
Everything not considered in the Mass dose, e.g. by- 
products, degradation products, radiolysis products 
Total quantity 
Mass dose plus impurities (for a study following the 
microdosing concept the total quantity must remain ≤ 100 
µg/human) 


8 
 
4 
BACKGROUND INFORMATION 
 
              Introduction 
 
Primary prostate cancer (PCa) represents a broad spectrum of disease, ranging from indolent to aggressive 
and death-causing illness. The highly heterogeneous nature of PCa provides a significant challenge for clinical 
disease management.1,2 Organ-confined PCa is an overdiagnosed and overtreated disease, which may result 
in life-changing side effects.3 This overtreatment is in part related to the inability to accurately identify PCa with 
elevated risk. Standard of care management of rising prostate-specific antigen (PSA) levels followed by 
standard systematic (non-targeted) prostate biopsies is unsatisfactory and leads to the detection of low grade 
prostate cancer at high rate while - at the same time - missing many significant (Gleason score ≥ 3+4) 
cancers.4 The positive predictive value of the standard prostate biopsy is only approximately 30% at a PSA 
level > 4.0 ng/mL.5 Accordingly, the recommendation by the United States Preventive Services Taskforce 
(USPSTF) against PSA screening in 2012 has led to a reduction of the number of PSA tests and prostate 
biopsies being performed.6 While this will likely reduce the costs associated with low-risk PCa, it may 
inadvertently cause a reverse stage migration to more men presenting with advanced disease. It was 
estimated that omitting PSA screening may lead to a doubling of metastatic disease rates as early as 2025, 
which would generate many avoidable cancer deaths.7 
 
Clearly, a highly accurate, ideally non-invasive, precision imaging test to differentiate low-risk disease from 
intermediate/high-risk PCa is needed. Accurate imaging allows subsequent tissue verification (via targeted 
biopsy) of suspicious lesions. Multiparametric magnetic resonance imaging (mpMRI) at 3 Tesla — due to its 
ability to detect clinically significant PCa and minimize detection of clinically insignificant disease — has been 
advocated for this task.8 In fact, mpMRI applying the Prostate Imaging Reporting and Data System (PI-RADS 
version 2) scoring criteria9 have demonstrated rising detection rates of significant PCa with increasing PI- 
RADS scores when combined with targeted prostate biopsies. Image-guided (targeted) prostate biopsies based 
on mpMRI clearly outperform non-targeted biopsies.10,11 However, the performance of this approach remains 
suboptimal for the task of identification of significant disease with high precision.12,13 In the recent       
multicenter paired-cohort PROMIS trial of 740 men, the sensitivity of mpMRI for clinically significant prostate 
cancer was 93%, but the specificity was only 41%, indicating a high false positive rate.11 When mpMRI is 
compared to whole-gland pathology from prostatectomy specimens, results are less encouraging. Combining 2 
recent studies with a total of 275 subjects (performed at highly experienced institutions), the sensitivity for 
identification of any Gleason ≥ 7 PCa was below 80%, while at the same time a significant number of low-risk 
cancers were falsely “overstaged” (specificity 54 – 68 %).12,14 Furthermore, interpretation of mpMRI, even when 
using standardized reporting methods (PI-RADS), is difficult and requires considerable training. Among highly 
experienced prostate MRI specialists, inter-observer variability using PI-RADS classifiers remains too high (к= ~ 
0.5-0.6).15 
 
Optimizing the performance of mpMRI—in particular, improving the specificity—is important. We recently 
published an interim analysis on 36 subjects with 52 mpMRI-identified lesions (Likert scale: low, intermediate, 
high risk) that showed the addition of 18F-choline PET/CT to mpMRI significantly improves the identification of 
Gleason ≥ 3+4 PCa over mpMRI alone.16 Pathology was obtained from mpMRI-guided plus 12-sample 
standard biopsies. Our unpublished final results obtained from 56 subjects with 90 mpMRI-identified lesions 
(40 low, 30 intermediate, 20 high risk) indicate that 18F-choline significantly improved the differentiation 
between clinically significant PCa (Gleason ≥ 3+4) and low-risk or benign disease in men assigned an 
intermediate-risk score by mpMRI. Furthermore, we were able to demonstrate that the combination of 18F- 


10 
 
choline PET with mpMRI was cost-effective (respective manuscripts have been submitted for publication in 
“Radiology”). 
While these results demonstrate that precision imaging utilizing a combination of molecular (PET) data with 
mpMRI is can be superior to mpMRI alone, the chosen radiotracer (18F-choline, as 18F-choline PET/CT) is 
ultimately not sufficient for the diagnosis of primary PCa because elevated choline uptake is commonly seen in 
benign prostatic hyperplasia (BPH) nodules.17 Under these circumstances, future approval for 18F-choline by 
the U.S. Food and Drug Administration (FDA) for initial staging of PCa is highly unlikely and alternative 
strategies are needed. 
 
4.1.1 
Significance of PSMA and preliminary data for PET imaging with 68Ga-PSMA 
 
In recent years, 68Ga-labeled ligands to PSMA have shown great promise for PET imaging of recurrent PCa. 
Particularly important is the fact that radiolabeled small molecules binding to PSMA are capable of identifying 
PCa at very low PSA levels, opening the door for early targeted treatment of disease recurrence.18-22 There is 
also substantial evidence that 68Ga-PSMA outperforms 11C/18F-choline for this indication.23-26 In contrast to 
111In-capromab-pendetide (ProstaScint), these ligands bind to the extracellular domain of this transmembrane 
glycoprotein and are internalized due to the enzymatic activity of PSMA, which leads to trapping of diagnostic 
(and therapeutic) radionuclides based on PSMA expression. 
 
PSMA is expressed physiologically in the prostate at low levels as a cell surface protein, and is 
overexpressed in PCa, particularly in metastatic castration-resistant PCa. In fact, there is growing evidence 
that PSMA expression increases as a function of tumor aggressiveness and Gleason scores,27,28 which is a 
highly useful feature for the differentiation of significant from indolent primary PCa. Accordingly, 68Ga-PSMA 
provides excellent target-to-background contrast suitable for PET/CT imaging of PCa.18,29 
While data are still limited, several retrospective reports indicate utility of 68Ga-PSMA PET/CT to diagnose and 
localize primary PCa. 19,26,30,31 In a small series with 20 patients receiving 11C-choline and 68Ga-PSMA PET/CT, 
both tracers identified all biopsy-proven significant primary PCa, but 68Ga-PSMA lesion uptake was significantly 
higher than that of 11C-choline, facilitating lesion detection.26 Most importantly, 68Ga-PSMA standardized uptake 
values (SUV) increase with Gleason grading, an important prerequisite for the identification of significant 
disease. In fact, a drastic increase in 68Ga-PSMA uptake is found for Gleason ≥ 3+4 PCa relative to     low-
grade disease and benign prostate, with little overlap between groups.32 In addition, 68Ga-PSMA also appears 
to have utility for lymph node staging.33 Based on our pilot data (Figure 1) and as demonstrated by Eiber et 
al.,19 hybrid or fusion 68Ga-PSMA PET/MRI seems to be particularly useful for the localization and staging of 
primary disease within the prostate gland with a precision necessary for successful image-guided targeting at 
biopsy. The current literature regarding this topic is summarized in Bailey et al.34 
 
The immunohistochemical (IHC) expression of PSMA has been linked to aggressive features in localized 
(primary) PCa. PSMA overexpression has been associated with a higher rate of local recurrence after 
prostatectomy, 35 further substantiating a potential link of 68Ga-PSMA uptake and aggressiveness. This is an 
important requisite of 68Ga-PSMA when considering patient management within an active surveillance 
population, particularly since PSA and PSA kinetics are insufficient predictors of aggressive disease.36 In 
addition, PSMA is also a promising target for PCa-specific radionuclide therapies.37 
68Ga-PSMA is not completely specific for PCa, as IHC PSMA expression has been found in the neo- 


10 
 
vasculature of regenerative and reparative conditions.38,39 Also, recent case reports indicate elevated 68Ga-
PSMA uptake in pulmonary infections (tuberculosis), non-prostatic malignancies (lung cancer, lymphoma),40,41 
benign neoplasms,42 and trauma. Nonetheless, in Figure 1, we demonstrate the utility of 68Ga-PSMA for the 
distinction of cancer and inflammation in the prostate. While both mpMRI scans in the figure were reported 
prospectively as high risk for aggressive PCa (PI-RADS 5), elevated 68Ga-PSMA uptake was seen only in 
PCa, but not in the site(s) of granulomatous inflammation. 
 
Though the vast majority of aggressive 
prostate cancers express PSMA and display 
increasing IHC staining intensities with 
increasing Gleason scores,28 a small subset of 
aggressive PCa appears to lack PSMA 
expression. Accordingly, the potential for 
absent 68Ga-PSMA uptake in aggressive 
primary PCa needs to be considered. 
 
4.1.2 
Radiomics 
 
Traditionally, medical images are treated as 
pictures intended solely for visual 
interpretation, which undercuts their 
information rich nature as mineable data.43 
Most human cancers exhibit strong molecular, 
morphological and phenotypic differences that 
are not easily assessable with standard image 
analysis techniques.44 Comprehensive 
quantification of imaging features, called 
radiomics, can extract such image metrics 
(intensity, shape, texture, etc.) into 
mathematical classifiers of the tumor 
diagnostic or prognostic phenotype from single 
or hybrid anatomical and functional images.45- 
50 An example is shown in Figure 1. This is 
particularly useful in case of PCa, which often 
presents as heterogeneous multifocal disease 
of varying clinical significance.51 Fehr et al. 
showed that texture features from mpMRI 
could achieve good classification of Gleason 
patterns.52 Radiomics not only serves 
classification purposes, but can also aid in 
understanding the underlying biology of the 
observed imaging phenotype and the risk 
variations among the different foci of the 
disease, subsequently informing clinical 
staging and effective image-guided therapeutic 
intervention in PCa.53 
 
Since the utility of radiomics analyses are 
unknown for the combination of 68Ga-PSMA 
and mpMRI, we will retrospectively assess its 
value to identify significant primary PCa.


11 
 
5 
STUDY OBJECTIVES AND PURPOSE 
 
 
The primary study aim is the prospective comparison of standard-of-care mpMRI vs. combined 68Ga-PSMA 
PET and mpMRI (68Ga-PSMA fusion PET/MRI) for the detection and risk-stratification of clinically significant 
primary PCa. 
Following (clinical) mpMRI and (research) 68Ga-PSMA PET/CT imaging, we will perform targeted and standard 
12-sample prostate biopsies. Biopsy targets will be defined from mpMRI and 68Ga-PSMA PET; mpMRI 
interpretation will be done in accordance with PI-RADS v2. 
 
Primary objective: We will determine the sensitivity and specificity of mpMRI alone and mpMRI in combination 
with 68Ga-PSMA PET (i.e., fusion PET/MRI) for the detection of primary Gleason ≥3+4 PCa. Primary outcome 
measure: determination whether the positive likelihood ratio (LR) for 68Ga-PSMA PET-MRI is at least 1.28 
greater than that of standard-of-care mpMRI. Reference standard will be pathology defined as targeted plus 
standard prostate biopsy, and prostatectomy, when available. 
 
Secondary objective: We will determine the safety of 68Ga-PSMA. We will also determine frequency and 
location of 68Ga-PSMA positive lesions, such as potential extra-prostatic extension, lympho-nodal and/or 
distant metastatic disease positive on 68Ga-PSMA but not identified by conventional (standard) imaging. While 
histological verification would be desirable, the decision for or against tissue verification will depend on clinical 
decisions making only, and not be required due to study participation. 
 
Exploratory objective: We will evaluate whether radiomics classifiers (obtained from mpMRI and 68Ga-PSMA 
identified targets) could improve identification and risk stratification of significant PCa. Reference standard will 
be pathology defined as targeted plus standard prostate biopsy, and prostatectomy, when available. 
 


12 
 
6 
OVERALL STUDY DESIGN AND PLAN 
 
 
 
              Study rationale 
 
6.1.1 
Rationale for administered radioactivity doses 
 
For 68Ga-PSMA, we will use the administered radioactivity dose ranges described in the literature. The 
administered dose may vary between 110 – 370 MBq (equivalent range of 3.0 – 7.0 mCi. The amount of 
radioactivity per subject is in accordance with the radiation protection principle “as low as reasonably 
achievable (ALARA)”, whilst ensuring image quality that is suitable for the planned analyses 18,20. 
 
              Study timeframe 
 
The recruitment period for the study is expected to last up to 4 years. The duration of patient participation in 
this study will end with the clinically indicated biopsy procedure. 
 
              Risks and benefits to subjects 
 
There are no expected direct benefits to subjects who participate in this trial. However, participants may benefit 
under certain conditions. First, if targeted biopsies identify a significant prostate cancer lesion not identified on 
standard biopsies or MRI, the patient would potentially benefit from the detection of such disease. Second, 
patients who will undergo subsequent definitive treatment may benefit if imaging identifies aggressive features 
such as extraprostatic spread or nodal metastases that otherwise would not have been identified. Also, the 
treatment team will be notified about the study imaging results in case of any other unexpected relevant 
abnormal findings. Accordingly, treatment decisions can be made on the basis of 68Ga-PSMA scan results. 
The risks to subjects mainly relate to the procedures employed for i.v. injection of the investigational 
radiotracers. Also, there are risks due to the placement of an i.v. catheter for drug injections as intravenous 
injections as well as small amounts of blood withdrawn. These are known to carry a small risk of infection and 
hematoma (infrequently occurring). There is also a small increase in risk due to additional prostate biopsy 
cores obtained with the clinically indicated prostate biopsy procedure. This risk is limited as we will not select 
more than 2 additional lesions for targeting. 
As the study will be performed as a microdosing study, risks concerning the tracer mass are not to be 
expected. All subjects will be subject to small amounts of research-related ionizing radiation. 
 
There is also a possibility of breach of confidentiality. 
 


13 
 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
              Procedures for enrolment 
 
Subjects will be recruited at Michigan Medicine. 
 
              Inclusion criteria 
 
Male subjects (≥ 18 years of age) with prior mpMRI (within 3 months of recruitment) resulting in at least one PI-
RADS 3-5 lesion with clinical need for a prostate biopsy procedure can participate, if one of the 2 criteria apply: 
- 
Known Gleason 6 (3+3) or 7 (3+4, 4+3) prostate cancer undergoing active surveillance or in the 
confirmation phase of active surveillance, 
 
or 
- 
Rising PSA with either a) no prior biopsy or b) single or multiple negative prior biopsies. 
 
              Exclusion criteria 
Subjects cannot participate in this study if any of the following applies: 
 
- 
Prostate biopsy within 12 weeks prior to enrollment 
- 
Acute prostatitis within the last 6 months 
- 
Current non-urologic bacterial infection requiring active treatment with antibiotics 
- 
Active other malignancy (except basal cell or squamous cell skin cancer) within the last 2 years 
- 
Body weight greater than 350 lbs (158 Kg) 
- 
Inability or unwillingness to receive a prostate biopsy procedure 
- 
Unable to lie flat, still, or tolerate a PET/CT scan 
- 
Unable to provide own consent 
- 
Concurrent severe and/or uncontrolled and/or unstable medical disease other than prostate 
cancer (e.g. poorly controlled diabetes, congestive heart failure, myocardial infarction within 6 
months prior to study participation, unstable and uncontrolled hypertension, acute renal failure 
of any intensity, chronic renal or hepatic disease, severe pulmonary disease) 
- 
Prisoner. 
 
 
Subjects who received a 68Ga-PSMA PET/CT and subsequent (clinical) TRUS-guided targeted biopsy, and are 
again in clinical need of a prostate biopsy can again take part in the study to receive repeat 68Ga-PSMA 
PET/CT imaging. 
 
              Withdrawal and termination criteria 
 
7.4.1 
Subject withdrawal 
 
There are no formal withdrawal criteria for this study.  During the conduct of the study, the investigator will 
review for signals that would indicate the need for withdrawal of a subject. 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study at any time. 
Investigators also have the right to withdraw subjects from the study in the event of illness, AEs, or other 
reasons concerning the health or well-being of the subject, or in the case of lack of co-operation. 


14 
 
 
Should a subject withdraw after administration of the radiotracer, or should the investigators decide to withdraw 
the subject, all efforts will be made to complete and report the protocol-stipulated observations up to the time of 
withdrawal as thoroughly as possible.  A final evaluation at the time of the subject’s withdrawal should be made 
and an explanation given of why the subject is withdrawing or being withdrawn from the study. The reason and 
date and time of withdrawal must be noted in a case report form (CRF). If the reason for withdrawal is an AE, 
monitoring will continue until the outcome is established. 
 
7.4.2 
Study termination 
 
The principal investigator reserves the right to terminate the study on safety grounds at any time. On 
termination of the study, the investigators will assure that adequate consideration is given to the protection of 
enrolled subjects’ interests. Termination of the study will be considered in the event of significant adverse safety 
findings occurring at any time during the performance of the study. Should termination be necessary, the     
IRB, the local health authority, and any other relevant local or national health authority (FDA) will be notified. 
 
8 
TREATMENT OF SUBJECTS 
 
In nuclear medicine imaging, it is important to record sufficient numbers of (true) positron annihilation events in 
VOIs in order to produce images of good quality, which can reliably be interpreted and deliver reproducible 
results. The number of recorded events increases with the duration of the acquisition period. Furthermore, for a 
given duration of image acquisition and for a given imaging time post injection, image quality increases with the 
administered radioactivity over a wide range of radioactivity doses. Therefore, the injected radioactivity should 
be high in order to obtain good images. On the other hand, higher radioactivity doses cause higher radiation 
exposure to the subjects, which is to be avoided. The optimum radioactivity dose is defined as the lowest dose 
that provides high image quality for a given duration of image acquisition and for a defined imaging time post 
injection. 
 
              68Ga-PSMA 
 
8.1.1 
Investigational medicinal product preparation 
 
Gallium-68 labeled PSMA-11 (or PSMA-HBED-CC) is a radiopharmaceutical that will be produced under 
cGMP. 
 
8.1.2 
Treatment administration 
 
The amount of 68Ga-radioactivity administered for a single study will range between 3.0 and 7.0 mCi. 
 
              Method of numbering subjects 
 
At screening, subjects will be given screening code numbers (starting from sc001, ect.). Once enrolled, 
subjects will be assigned unique subject numbers. Subject identification numbers will start from 001 to the 
maximum recruitment number. 
 
              Blinding 
 
This will be an open-label study and no blinding will be performed. 


15 
 
 
              Prior and concurrent therapy 
 
Any prior, concurrent, or procedural medications or therapy given to or taken by the subject within 21 days 
before and up to the time of PET imaging will be recorded in the CRF along with the indication. Either the 
generic or the trade name may be recorded. 
 
              Treatment compliance 
 
Subjects will receive radiotracers under direct supervision of qualified study personnel.  Each administration 
volume and total amount of radioactivity injected will be checked, and the details—including date and time of 
injection—will be recorded. 


16 
 
9 
TREATMENT PERIOD 
 
Informed consent will be obtained.  All subjects must satisfy one inclusion criterion and none of the exclusion 
criteria listed. Signed and dated informed consent must be obtained from all subjects before any study-specific 
procedures are performed. The consent document may be sent to a potential participant prior to obtaining 
consent for their information. A screening visit will be performed within 2 months before radiotracer 
administrations, however can be performed on the day of PET/CT imaging. Subjects will be permitted to 
continue taking any routine or necessary medication. 
 
The following data will be collected on study-specific CRFs. 
 
• 
Date of birth 
 
• 
Weight 
 
• 
Height 
 
• 
Concurrent medications 
 
• 
Medical history and concurrent diseases 
 
• 
Report and date of most recent histological tissue evaluation from any known prostate cancer 
 
• 
Results of screening tests 
 
Personal data (including contact information) will be collected with the subject’s permission and only to the 
extent that is necessary for the purposes of the study. 
Vital signs (pulse, respirations, systolic and diastolic blood pressure) are recorded. A cannula (or indwelling 
catheter) will be placed into a vein, preferably in the antecubital region, for tracer administration. 
The injection site will be examined for any abnormal findings before dosing.  In the interests of comfort, 
subjects will be advised to empty their bladder and, if necessary, complete a bowel movement before being 
positioned on the scanner table. 
 
9.1 
68Ga-PSMA PET/CT 
a) 68Ga-PSMA-11 PET preparation and injection: 
 
The injected dose will be 111-259 MBq (3-7 mCi) of 68Ga-PSMA-11 PET. PET imaging will begin 50- 
100 minutes after injection.  Scan time per bed position will be determined based on expected count 
statistics related to the administered dose. 
b) Patient preparation: no fasting is required. 
 
c) PET protocol: Scan coverage will extend from mid-thigh to the base of the skull, starting from the mid- 
thighs to prevent urinary bladder radiotracer accumulation at the start of PET imaging. Scan time per 
bed position will be determined based on expected count statistics, which is determined mainly by the 
administered dose. Scan time will therefore be between 15 and 40 minutes. In certain circumstances, 
coverage may be extended to the toes.  Contrast may be administered as needed. 
d) Patient monitoring: Vital signs will be assessed immediately before and after injection of 68Ga-PSMA-11 
(HR and supine BP).  Patients will be monitored for adverse events during injection and for two hours 


17 
 
after radiotracer administration.  Additionally, patient’s vitals (HR and supine BP) will be checked at the 
completion of the imaging study prior to leaving the imaging center. 
 
e) Patient follow-up: Patients will be contacted by phone one to three days after 68Ga-PSMA-11 PET to 
assess for the development of delayed adverse events. Patients will be seen in the clinic if there are 
any concerning study related adverse events requiring further evaluation. 
 
9.2 
Post-Treatment Period 
 
We will adhere to the follow-up procedures specified in IND #133858. Patients are encouraged to self-report 
any possible side effect to the study team. 
9.2.1 
Target identification 
 
In-vivo imaging (PET and/or MRI) will be reviewed by participating investigators for intraprostatic lesions 
suspicious for significant prostate cancer. After registration of imaging data to the T2-weighted MRI, the 
responsible radiologists (Dr. Davenport and Dr. Piert, or designees) will determine potential target areas for 
image-guided (targeted) prostate biopsy within the T2-weighted MRI (reference space). Candidate targets are 
the known PI-RADS 3-5 lesions, where higher PI-RADS scores will be preferentially selected. Any PI-RADS 5 
lesion will be targeted for biopsy (unless there are more than 3). 68Ga-PSMA positive lesions not identified by 
mpMRI as PI-RADS 3-5 will be considered as well. Currently available preliminary retrospective data suggest 
that a suitable threshold for 68Ga-PSMA positivity (defining significant disease) would be ≥ 2 standard 
deviations above prostate background.32 
 
To limit the burden to the subject, no more than 3 target locations will be selected for biopsy. If more than 3 
targets are present (from both PET and/or MRI), the most suspicious 3 are selected; in case of a tie, the 
largest will be selected. The selected targets are then transferred to the navigated ultrasound workstation used 
for targeted prostate biopsies. 
 
Radiomics analysis results will not be used to identify targets for prostate biopsies. 
 
9.2.2 
Prostate biopsy procedure 
 
Prostate cancer subjects recruited for this study are expected to receive tissue sampling for clinical (diagnostic) 
purposes. Accordingly, all subjects already had a prior mpMRI indicating presence of a prostate lesion 
potentially representing prostate cancer (PI-RADS 3-5). 
 
Targeted (fusion) prostate biopsies based on TRUS-MRI guidance are routine clinical practice at Michigan 
Medicine. While typically all biopsy targets are sampled, it is at the discretion of the physician performing the 
prostate biopsy which of the selected targets are biopsied. Typically, a total of 2 sample cores are obtained 
from each target. However, to account for biopsy cores missing the target area the exact number of biopsy 
cores obtained from a given target is at the discretion of the physician performing the prostate biopsy 
procedure. 
 
The histological results of the biopsy will be compared to PI-RADS scores and respective visual and quantitative 
radiotracer uptake measures. 
 
Patient monitoring after the prostate biopsy procedure will be done according to standard of care. The patient 
will receive specific instructions and guidance for minor and more serious adverse effects. 
 


18 
 
9.2.3 
Pathological Evaluation 
 
The histological confirmation serves as standard of truth. All biopsy cores obtained, whether targeted or 
standard, will be assessed for diagnosis. 
Routine histology of all prostate biopsy cores will be performed according to the established institutional 
guidelines. Biopsy samples will be processed for routine histological assessment (hematoxylin/eosin (HE) 
stain) using the paraffin embedding process and 3 µm sections. Each tumor focus will be assigned a primary 
and secondary Gleason grade and staged according to recent American Joint Committee on Cancer (AJCC) 
guidelines. Some cuts may remain unstained for later immunohistochemistry (IHC) for PSMA and/or other 
additional PIN cocktail (cocktail of basal markers and AMACR) IHC, when deemed necessary for clinical 
purposes 54. 
 
9.2.4 
Clinical decision making 
 
Once the results of the pathological evaluation of the prostate biopsies are available, - in consultation with the 
patient - the treating physician (or treatment team) will decide the further clinical management. If the decision 
for treatment is made and the patient decides to receive prostatectomy at our institution (Michigan Medicine), 
an effort will be made to analyze the location of tumor lesions within the resected prostate specimen and to 
register pre-biopsy PET and MRI imaging with pathology. If feasible, the prostate specimen may undergo 
additional (research) MRI to facilitate the registration process 55. 
 
9.2.5 
Image interpretation and correlation with standard of truth 
 
PET and MR imaging will be assessed visually. Abnormalities found on MRI and 68Ga-PSMA PET will be 
selected as targets for image-guided biopsies. 
Once prostate biopsies are obtained, the location of each biopsy is retrospectively associated with a matching 
region on pre-biopsy imaging (facilitated via image co-registration) and semi-quantitative PET data are 
obtained and compared with the standard of truth (Gleason score histology). Accordingly, we will determine 
whether a selected target was true positive, false positive, true negative or false negative on imaging (MRI and 
68Ga-PSMA PET) relative to pathological proof. Please note that the location (in 3D space) of a given biopsy 
core is known from ALL biopsies, whether obtained as standard or targeted core. This is possible because the 
navigated ultrasound workstation (i.e. UroNav, Invivo) used will record the biopsy core location (trajectory and 
core length within the gland) in 3D for all cores obtained 55,56. 
Accordingly, the sensitivity and specificity for the detection of low-grade (Gleason 3+3) and significant PCa 
(Gleason ≥ 3+4) is determined for both modalities, 68Ga-PSMA PET (based on uptake measures) and mpMRI 
(based on PI-RADS scores). 
 
              Lesion localization variables 
 
9.3.1 
Overall lesion localization rate 
 
The total number of focal lesions detected on 68Ga-PSMA PET/CT images will be recorded and compared to 
mpMRI. 
 
9.3.2 
Cancer lesion localization rate 
 


19 
 
The number of cancer lesions, as verified in histopathology, detected will be recorded and compared with co- 
localized lesions on 68Ga-PSMA PET and mpMRI. 
 
9.3.3 
Visual assessment of lesion contrast and scoring 
 
The investigator will visually assess the 68Ga-PSMA PET/CT images. Using a scoring system (no increased 
uptake = 0, mild uptake = 1, moderate uptake = 2, high uptake = 3, relative to background) the accumulation of 
68Ga-PSMA in each target volume will be assessed. 
 
9.3.4 
Extra-prostatic lesions 
 
We will also determine frequency and location of 68Ga-PSMA positive lesions. Such lesions could be extra- 
prostatic tumor extension, lympho-nodal and/or distant metastatic disease not identified by conventional 
(standard) imaging. As clinically indicated (clinical relevance, accessibility, risk), an attempt will be made to obtain 
pathological proof of such lesions. The decision for or against a biopsy is made by the treating physician in 
consultation with the patient, and not demanded by the study. 
 
9.3.5 
Semiquantitative assessment: SUV, SUVR 
 
The standardized uptake value (SUV) is defined as follows: 
 
SUV = activity (Bq/cm/[(body weight (g)/injected activity (Bq)] 
An even distribution of the tracer in the body results in an SUV = 1. 
SUVRs can be obtained by calculating the ratio of SUV in a lesion and the SUV of a corresponding reference 
tissue, such as non-cancerous/non-inflammatory tissue of the same organ, blood, or muscle. 
 
              Adverse event monitoring 
The presence of any pre-administration event (baseline signs and symptoms present just before radiotracer 
administrations) will be recorded in the CRF. 
 
The following information will also be recorded in the CRF: 
 
• 
The date of evaluation 
• 
The onset time 
• 
The resolution time or duration 
• 
Action taken 
• 
Status of symptom 
• 
Intensity 
Of these events, only events that increase in intensity after radiotracer administrations will be recorded as AEs 
in the CRF. 
 
9.4.1 
Adverse events 
 
For this study, an AE is defined as any untoward medical occurrence in a clinical investigation subject after 
administration of the radiopharmaceutical products. An AE does not necessarily have to have a causal 
relationship with administration of the radiopharmaceutical product. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated 


20 
 
with the use of 68Ga-PSMA, whether considered related to that product, or not. Only symptoms/signs that begin 
or worsen in severity and/or frequency after 68Ga-PSMA administration/use will be recorded as AEs in the CRF. 
The AE profile of 68Ga-PSMA in humans has been established. No major adverse events have been reported 
in the literature. Therefore, major adverse events are extremely unlikely to occur. However, study personnel 
will remain vigilant at all times to the occurrence of AEs, particularly those that may be life-threatening. 
Personnel who are trained in the acute management of anaphylaxis and other emergencies and who have 
access to appropriate clinical supplies will be immediately available while the subject is confined to the study 
center. Treatment of serious AEs (SAEs) will consist primarily of the support of vital functions. 
 
The subjects will be closely observed and questioned for any kind of AE during the study procedures and at 
follow-up appointments throughout the study period with non-leading questioning (e.g., “How do you feel?”). 
The subjects will be instructed to immediately report any symptoms and signs to the study staff (i.e., between 
formal observations). 
 
9.4.2 
Serious adverse events 
 
An SAE is defined as any AE that: 
 
• 
Results in death 
• 
Is life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is another important medical event.* 
 
(*Other important medical events are those that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical intervention to prevent one of the outcomes listed above.) 
 
9.4.3 
Adverse event and serious adverse event reporting 
 
All AEs should be recorded using acceptable diagnoses, if possible. If an AE has already been reported, it is 
not necessary to report each individual sign and symptom of that AE as a separate AE. Grade refers to the 
severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
SAEs will be recorded in the CRF if they occurred as follows: 
 


21 
 
• 
After a subject first received 68Ga-PSMA and throughout the subject’s follow-up period*, whether or not 
the AEs considered related to the tracer injections, and 
• 
After the subject’s follow-up period, if a causal relationship to 68Ga-PSMA cannot be ruled out. 
 
(*Follow-up period is defined as the protocol-stipulated period or, for subjects prematurely withdrawn from a 
study, the duration of a subject’s participation.) 
All serious and non-serious AEs must be followed for a final outcome until the end of the follow-up period.  An 
outcome of “unknown” is not considered to be an acceptable final outcome.  An outcome of “not yet resolved” 
is an acceptable final outcome for non-serious AEs at the end of a subject’s participation in a study, and for 
SAEs at database lock. 
 
The PI will report all SAEs to local health authorities, the IRB, and investigators as required by local 
regulations. 
 
9.4.4 
Expedited reporting 
 
Expedited Reporting to the Food and Drug Administration 
As the study is being conducted under an IND, the Sponsor-Investigator is responsible for determining whether 
or not the suspected adverse reaction meets the criteria for expedited reporting in accordance with Federal 
Regulations (21 CFR §312.32). 
 
The Investigator must report in an IND safety report any suspected adverse reaction that is both serious and 
unexpected. The Sponsor-Investigator needs to ensure that the event meets all three definitions: 
• 
Suspected adverse reaction 
• 
Unexpected 
• 
Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited IND 
safety report. 
 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after the Investigator 
determines that the suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)). 
 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later than 7 
calendar days after the Investigator’s initial receipt of the information (21 CFR 312.32(c)(2)). 
 
Any relevant additional information that pertains to a previously submitted IND safety report will be submitted to 
FDA as a Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 
312.32(d)(2)). 
 
              Other variables 
9.5.1 
Demographic data 
 
The subject’s demographic data (gender, age, ethnicity and race, weight, height) will be recorded at screening. 
 
9.5.2 
Medical and surgical history 
 
The subject’s relevant medical and surgical history (i.e., a condition that is either active at enrolment or 
adversely impacts the subject’s medical condition at enrolment) will be recorded at screening. Also, relevant 


22 
 
medical and surgical history may be viewed and recorded from digital patient records and optionally obtained 
from physicians involved in the care of the subjects. 
 
9.5.3 
Prior and concurrent medication 
 
Information about medications taken by the subject during the study period will be recorded. 
 
9.5.4 
Appropriateness of measurements 
 
All assessments and measurements are considered appropriate and regarded as standard medical practice. 
 
10 
DATA HANDLING AND QUALITY ASSURANCE 
 
           Clinical data management 
 
All adverse events will be followed with appropriate medical management until resolved.  Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  For selected adverse events for which administration of the investigational drug was stopped, a re- 
challenge of the subject with the investigational drug may be conducted if considered both safe and ethical by 
the Investigator. 
This trial will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer Center 
Data and Safety Monitoring Plan. The study team will meet every 3 months or more frequently depending on 
the activity of the protocol. The discussion will include matters related to the safety of study participants 
(SAE/UaP reporting), validity and integrity of the data, enrollment rate relative to expectations, characteristics of 
participants, retention of participants, adherence to the protocol (potential or real protocol deviations) and data 
completeness. At these regular meetings, the protocol specific Data and Safety Monitoring Report form will be 
completed and signed by the Principal Investigator or by one of the designated co-investigators. 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Rogel Cancer Center Data 
and Safety Monitoring Committee every 3 months for independent review. 
 
           Archiving 
 
All study documentation at the investigators’ site will be archived for a minimum of 7 years following completion 
or discontinuation of the study. 


23 
 
11 
STATISTICAL METHODS AND PLANNED ANALYSIS 
 
           General statistical considerations 
 
Statistical analysis will be performed as specified in the statistical analysis plan. 
 
All subjects who complete the study without major changes versus protocol will be included in the evaluation of 
pharmacodynamics / pharmacokinetics. 
 
           Subject characteristics 
A table will be provided with the following information: 
 
• 
Number of subjects enrolled 
• 
Number of subjects included in the efficacy analysis 
• 
Number of subjects withdrawn from the study and the reason for withdrawal. 
Demographic information (age, height, weight) will be summarized using descriptive statistics. 
Medical histories will be summarized by counts and percent.  Concurrent medications will be recorded and 
coded using a standard classification system and grouped by primary and secondary classes, if applicable. 
 
11.2.1 
Demographic and other baseline characteristics 
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for quantitative 
variables) will be presented. Frequency tables for qualitative data will be provided. Medical history findings will 
be summarized. 
 
11.2.2 
Pharmacodynamical data 
Quantitative data will be described by the following summary statistics: arithmetic mean, standard deviation, 
median, minimum and maximum. Frequency tables will be provided for qualitative data. 
 
11.2.3 
Development of decision rules 
Since mpMRI has already been performed prior to 68Ga-PSMA PET/CT, and since suspicious lesions have 
been found and rated according to PI-RADS, the addition of 68Ga-PSMA can lead to a) a change or 
confirmation of the mpMRI-defined PI-RADS risk score of a given lesion, or b) identification of additional lesions 
not identified on mpMRI. Since mpMRI has a high sensitivity, but relative low specificity for significant PCa, we 
anticipate that modification of the mpMRI risk score will be the main source for a change in management. 
Currently, all PI-RADS 3, 4 or 5 lesions found at mpMRI are targeted for biopsy. Particularly problematic is that 
while PI-RADS 3 lesions are very frequent, their probability for significant PCa disease is low. The second most 
likely outcome, PI-RADS 4, has a roughly 50% chance to result in significant disease. If absence of 68Ga-
PSMA uptake in such lesions is associated with lack of significant disease, hybrid 68Ga-PSMA PET/MRI could 
replace invasive biopsy procedures and avoid side effects for prostate biopsies in many men. On the other 
hand, if focally elevated 68Ga-PSMA uptake would be found to correlate with significant disease, such 
potentially lethal disease could be found at earlier time points and with higher precision. Accordingly, the data 
are acquired to subsequently develop an evidence-based decision rule to inform which patients would a) 
benefit from a prostate biopsy procedure, and b) benefit most from 68Ga-PSMA in addition to mpMRI. 


24 
 
12 
STATISTICAL EVALUATION 
 
Accrual potential: At the University of Michigan, over 800 patients receive a prostate biopsy per year (812 in 
2016, 652 in 2015, 444 in 2014). The number of navigated TRUS-MRI fusion (targeted) prostate biopsies is 
rapidly increasing and reached 310 in 2016. In 2016, the Department of Radiology performed 960 mpMRI 
studies, of which about 60% (576) had a PI-RADS score ≥3.  
Prevalence of significant PCa: Among all patients with PI-RADS score ≥3, the incidence of Gleason ≥ 3+4 PCa is 
15% for PI-RADS 3, 55% PI-RADS 4, and 80% PI-RADS 5. At our center, the sensitivity/specificity for Gleason ≥ 
3+4 is 96.5/59.7% for PI-RADS ≥3, and 78.9/78.9% for PI-RADS ≥4. The patient population for this trial will 
closely resemble a recently retrospectively investigated surveillance population from 2 centers in the state of 
Michigan (n=207) of men with clinical stage T1/T2 Gleason 3+3 PCa. The distribution of PI-RADS grading was at 
follows (unpublished data): PI-RADS 1-2 (37%), PI-RADS 3 (19%), PI-RADS 4 (31%), PI-RADS 5 (13%). This 
incidence of PI-RADS scores ≥ 3 is used in Table 1 to estimate the incidence of Gleason 3+3 vs. ≥ 3+4 vs. 
benign findings in the trial population. Since we will only select patients with prior mpMRI resulting in PI-RADS 3-
5, we will be able to select a specific relevant patient population with a sufficient risk for significant disease 
(defined as Gleason ≥ 3+4 PCa). 
Disease incidence in study population: We estimate the potential impact of molecular imaging in addition to 
mpMRI for this trial on the basis of our prior 18F-choline PET/MRI trial.16 Our final (submitted) data included 90 PI-
RADS 3-5 lesions in 56 subjects resulting in 30 “positive” (Gleason ≥ 3+4) and 60 “negative” (Gleason 3+3 or 
benign). Using a logistic regression model with two predictors—MRI suspicion score and a 18F-choline lesion-to-
background ratio of ≥ 1.58 (AUC = 0.95) —strongly favored the combined model over the mpMRI model alone 
(AUC = 0.83, p < 0.001). The selection of all PI-RADS ≥ 4 lesions for the prediction of Gleason ≥ 3+4 PCa 
resulted in an excessive number of false-positive (n = 27 [FP]) and false-negative (n=3 [FN]) cases. When 
selecting PI-RADS 5 lesions only, 3 FP and 11 FN cases would have resulted, which indicates missing too many 
significant cancers. The addition of 18F-choline PET to mpMRI resulted in 5 FP and 5 FN cases.  
Compared to the selection of all PI-RADS ≥ 4 lesions (high sensitivity, poor specificity), the combined 18F-choline 
PET/MRI model resulted in an improvement of the specificity by +38% with only a modest reduction in sensitivity 
(-10%). Implementation of this rule would have reduced the number of targeted lesions for biopsy by roughly 50% 
(from 51 to 25), exemplifying the cost-saving potential of a PET/MRI strategy. Given that 68Ga-PSMA and 18F-
choline have different molecular targets (68Ga-PSMA has higher specificity for PCa than 18F-choline), and that the 
18F-choline trial investigated a high-risk patient population, these 18F-choline results are not directly transferable 
to the use of 68Ga-PSMA PET/MRI such as is being investigated in this proposal. Furthermore, any future 68Ga-
PSMA PET/MRI rule would likely be constructed differently. For sample size estimates in this trial, we therefore 
project conservatively that the sensitivity of mpMRI would minimally increase (by 2%, mainly from correctly 
identifying significant cancers rated as PI-RADS 3), while the specificity would increase by only 15%. Given the 
known superiority of 68Ga-PSMA over 18F-choline, as well as the known increase of PSMA-expression with 
increasing aggressiveness (Gleason scoring), we have no reason to assume that the performance of 68Ga-PSMA 
would be inferior to 18F-choline for the identification of significant PCa. As a result, these sample size estimates 
are quite conservative.  
In conclusion, we are confident that the necessary number of subjects can be recruited with sufficient prevalence 
of significant PCa in this trial. The inclusion criteria will ensure a sufficient potential for positive imaging findings 
with 68Ga-PSMA PET/CT, and a very high probability of successful targeting with image-guided biopsy.16 
 
Table 1. Estimated incidence of Gleason 3+3 vs. ≥ 3+4 vs. benign biopsy results in the trial population 
Maximum PI-
RADS risk score 
per subject 
Number of  
subjects (%) 
No prostate  
cancer 
Benign % 
Total maximum 
grade  
Gleason = 3+3 % 
Total maximum 
grade  
Gleason ≥ 3+4 % 
3 
30 
16 (53%) 
10 (33%) 
5 (17%) 
4 
49  
9 (27%) 
13 (27%) 
26 (53%) 
5 
21 
1 (5%) 
3 (14%) 
17 (81%) 
Total (N) 
100 
26 
26 
48 
 


25 
 
 
Primary objective: Mixed-effects logistic regression is used to evaluate the primary objective, the diagnostic 
performance of mpMRI and PET. The outcome is Gleason ≥ 3+4 or not, and predictors are PI-RADS v.2 score 
and 68Ga-PSMA PET uptake. We employ a mixed effects model to account for within-subject correlation 
among one or more biopsied lesions. We will test the null hypothesis that the regression coefficient of PET is 
equal to zero versus an alternative hypothesis that it is not equal to zero, assessing whether 68Ga-PSMA PET 
is an important factor to identify aggressive PCa. We also compare predictive accuracies of (1) PI-RADS ≥3 
only and (2) PI-RADS ≥3 plus 68Ga-PSMA PET models by examining the confidence intervals of a predictive 
performance measure: positive likelihood ratio (positive LR). 
Secondary objectives: We are not expecting any adverse events related to the administration of the 
radiotracer. However, frequency tables will be generated to display the safety profile of 68Ga-PSMA 
(secondary objective). 
 
We will also record the frequency and location of extra-prostatic 68Ga-PSMA positive lesions (such as extra- 
prostatic extension, lympho-nodal and/or distant metastatic disease) not identified by conventional (standard) 
imaging. Formal statistical evaluation is not planned as the frequency of such findings is expected to be low. 
 
Exploratory objective: We will evaluate whether radiomics classifiers (obtained from mpMRI and 68Ga-PSMA 
identified targets) could improve identification and risk stratification of significant PCa. Reference standard will 
be pathology defined as targeted plus standard prostate biopsy, and prostatectomy, when available. The 
performance of the different classifiers in detecting significant PCa will be evaluated by using the area under 
the receiver-operating characteristic (ROC) curve (AUC) using pathology as gold standard.57 
 
           Sample size determination 
 
Sample size calculation was made for the primary objective only. We assess potential differences between the 
predictive performances of the two models (1) and (2), while maintaining ethical and economic considerations. 
We consider the positive likelihood ratio (positive LR) as a performance measure, which is defined by a ratio of 
sensitivity to 1-specificity. A higher positive LR means greater predictive information of positive test results 
irrespective of disease prevalence. Based on preliminary data obtained from mpMRI, we assume that the 
sensitivity and specificity of model (1) are both given by 0.789. For model (2), we assume conservatively that 
the sensitivity will be increased by 0.02 (2%) and that the specificity would improve by 0.15 (15%). In this 
scenario, the positive LR of model (1) is given by 3.74 and the positive LR of model (2) is calculated as 5.02. In 
order to detect the 1.28 difference in positive LR between the two models, we need at least 100 subjects, 
including at least 38 of 100 subjects with a histological diagnosis of significant PCa. The sample size was 
estimated as described in the literature. 58 
 
           Significance Level 
 
All statistical tests will use a 0.05 significance level. 
 
12.3           Rules for excluding subjects from analysis 
 
All dosed subjects will be included in the analyses unless otherwise specified. The PI will make any decisions 
regarding whether any subjects or any individual values belonging to a subject who violates the protocol will be 
excluded from the evaluations when the protocol violation is considered to have a negative impact on the 
scientific aspects and interpretation of the study results. The PI will also make a decision whether recruited 


26 
 
subjects with incomplete assessments will be substituted with additional subjects beyond the total recruitment 
goal. 
 
12.4             Withdrawal from assessment and replacement 
 
Subjects who show major protocol deviations, e.g. deviations leading to the loss of essential data for the 
evaluation of the diagnostic efficacy can be withdrawn and replaced. The decision regarding withdrawal and 
replacement will be made by the principal investigator consulting with the study team. 
 
12.5 
 Analysis Plan 
 
12.5.1 
Analysis Population 
Patients with histopathology correlates will be analyzed for the primary aim.  All remaining patients will be 
analyzed for the secondary endpoints. 
 
12.5.2 
Analysis of Primary Endpoints 
PET images will initially be interpreted by a board certified nuclear medicine physician or a board-certified 
radiologist experienced in reading PET at the time of the imaging study at Michigan Medicine. Upon request, 
case report forms and coded 68Ga-PSMA PET/CT imaging data will be provided to the FDA for review. 
 
Intraprostatic lesions identified by mpMRI as PI-RADS 3-5 will be graded visually on a two-point scale as either 
positive or negative for elevated 68Ga-PSMA uptake relative to prostatic gland uptake (0=Negative or 1= 
Positive). 
 
Any focal intraprostatic elevated 68Ga-PSMA uptake relative to prostatic gland that was not identified by 
mpMRI (as PI-RADS 3-5) but was targeted at biopsy will also be evaluated visually as either positive or 
negative (0=Negative or 1= Positive). 
 
All subjects with histopathology correlates will be analyzed for the primary aim. Sensitivity and specificity, 
positive and negative predictive values, and accuracy (along with the corresponding two-sided 95% confidence 
intervals) will be determined on a per-subject and per-lesion basis for 68Ga-PSMA-11 PET and mpMRI 
regarding the detection of Gleason ≥ 3+4 cancer. Standard reference of truth is histopathology from all 
individual biopsy cores, targeted and standard cores. 
 
12.5.3 
Analysis of Secondary Endpoints 
All subjects receiving 68Ga-PSMA will be included in the safety analysis. 


27 
 
Any extraprostatic lesion will be judged as positive if the lesion is visually positive with uptake greater of equal 
to 2 standard deviations above local background. 
 
12.5.4 
Analysis of the Exploratory Objective 
Radiomics analyses will be performed retrospectively, thus after prostate biopsies have been performed. 
Accordingly, radiomics analysis results will not be used to identify targets for prostate biopsies. 
Radiomics analysis consists of two steps: (1) Image feature extraction and (2) Model building of discriminant 
classifiers.50 We plan to extract intensity, texture and morphological features from 68Ga-PSMA PET and 
mpMRI46 into mathematical models using advanced machine-learning methods while accounting for 
confounding effects from clinical parameters (stage, age, histology, etc.).59 For feature extraction we will 
assess co-registered T1w, T2w, ADC, DCE MRI, and 68Ga-PSMA PET volumes. Specific image features 
related to tumor heterogeneity include: (a) first-order histogram intensity variations (mean, min, max, variance, 
skewness, etc.); (b) shape (eccentricity, solidity, etc.), and (c) texture features (second order histogram 
metrics), which relate intensity to local spatial distribution using matrix methods such as the gray-level co- 
occurrence matrices (GLCM) and others such as neighborhood gray-tone difference matrix (NGTDM), run- 
length matrix (RLM), and grey-level size-zone matrix (GLSZM) features on PET,46 PET/CT,60 and separate or 
fused PET/MRI.61 Image pre-processing of VOIs involves feature enhancement (denoising/deblurring) and 
rescaling to isotropic voxels.46,50 
 
We will explore advanced statistical learning methods to build maximally discriminant classifiers of significant 
PCa (Gleason ≥ 3+4). Different machine learning classifiers using linear generalized models (Elastic net), 
support vector machine (SVM), random forests (RF), and deep learning (convolutional neural network (CNN)) 
techniques may be enployed.62,63 
 
Methods based on statistical resampling and information theory will be used to guard against over-fitting and to 
evaluate generalizability to out-of-sample data.64 Feature-based classifiers (LASSO, SVM, RF, NN, DNN) and 
featureless classifiers (CNN) may be applied as well. 


28 
 
13 
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