Clinical trial NCT03264456
Conditions: Prostate Cancer
Sponsor: University of Alabama at Birmingham
Start date: 2017-11-08; Completion date: 2020-02-13
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
There is great need for improved preoperative imaging in men with high-risk prostate cancer. Investigators propose to develop and validate an optimized simultaneous PET/MRI protocol for local, regional and whole body preoperative staging in a single imaging session using the amino acid PET tracer, F-18 fluciclovine. Despite advances in the diagnosis and treatment of prostate cancer, the preoperative staging of men with prostate carcinoma (PCa) is currently problematic. Conventional imaging is falsely negative for regional lymph node metastases in a substantial fraction of men. In particular, approximately 35% of men with high-risk prostate cancer will have biochemical recurrence even after optimal surgical resection. A major benefit of simultaneous acquisition of a multiparametric prostate MRI (mpMRI) and F-18 fluciclovine PET includes having the patient undergo a single imaging study which provides both anatomic and molecular characterization of the tumor, including metastases which would potentially be missed by conventional anatomic imaging and size criteria. Additionally, simultaneous acquisition will improve co-registration of the PET and MR data which is valuable for small lesions and in anatomically complex regions. Although the use of fluciclovine in the characterization of the primary PCa remains to be established, the anatomic detail provided by conventional mpMRI will complement the detection of small volume metastatic disease by fluciclovine PET. Additionally, the use of hybrid PET/MRI technology allows for the assessment of dynamic tracer uptake and washout during the whole body and regional PET/MRI scan, which may demonstrate the ability to increase detection of the primary PCa on fluciclovine PET. If F-18 fluciclovine PET/MRI can reliably and accurately detect nodal metastases in high-risk prostate cancer patients, surgeons may use this new technology to develop new treatment algorithms for the optimal management of these patients.

Detailed description:

Arms: arm 1: \[18F\] Fluciclovine PET/MRI for pretreatment staging of high-risk prostate cancer
Interventions: intervention 1: [18F] Fluciclovine PET/MRI intervention 2: [18F] fluciclovine
Intervention descriptions: intervention 1: \[18F\] fluciclovine PET/MRI intervention 2: \[18F\] fluciclovine

Protocol documents:
Prot_SAP_000.pdf: 
Document date: 09/11/2019 
[18F]Fluciclovine-PET/MRI for Staging Newly Diagnosed High-Risk Prostate Cancer and Evaluating 
Response to Initial Androgen Deprivation Therapy 
Samuel J. Galgano, MD1,2, Andrew McDonald, MD2,3, Soroush Rais-Bahrami, MD1,2,4, Kristin K. Porter, 
MD, PhD1, Gagandeep Choudhary, MD1, Constantine Burgan, MD1, Pradeep Bhambhvani, MD1, Jeffrey 
W. Nix, MD2,4, Desiree E. Morgan, MD1,2, Jonathan McConathy, MD, PhD1,2 
1.
Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
2.
O’Neal Comprehensive Cancer Center at UAB, University of Alabama at Birmingham,
Birmingham, AL, USA 
3.
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
4.
Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA
NCT03264456 


1 
Comprehensive Cancer Center 
University of Alabama at Birmingham 
Birmingham, Alabama 
Protocol UAB 1767: 
Pretreatment Staging of High-Risk Prostate Cancer with F-18 
Fluciclovine PET/MRI 
TABLE OF CONTENTS 
1.0 
INTRODUCTION AND STUDY RATIONALE 
2.0 
STUDY OBJECTIVES 
3.0 
INVESTIGATIONAL PLAN 
4.0 
STUDY PROCEDURES 
5.0 
STUDY PARAMETERS 
6.0 
STATISTICAL CONSIDERATIONS 
7.0 
REFERENCES 
Samuel J. Galgano, M.D 
Radiological Society of North America & 
University of Alabama at Birmingham 
Blue Earth Diagnostics  
Comprehensive Cancer Center 
Study Supported By 
1824 Sixth Avenue South 
Birmingham, AL  35294-3300 
UAB 
Tel (205-934-1388); Fax (205-996-0059) 
Study Sponsor 
Principal Investigator 
F-18 Fluciclovine 
Study Agent 
Pending 
IND Number 
Jonathan McConathy, MD, PhD, Soroush Rais- 
Yufeng Li, PhD 
Bahrami, MD, Andrew McDonald, MD, PhD, 
Biostatistician 
John V. Thomas, MD 
Sub-Investigators 
Marianne Vetrano 
Research Nurse Coordinator 
Data Coordinator 


2 
TABLE OF CONTENTS 
1.0 
Introduction and Study Rationale ..........................................................  
4 
1.1 
Overview ....................................................................................................  
4 
1.2 
Background and Rationale ......................................................................  
4 
2.0 
Objectives ...................................................................................................  
6 
3.0 
Investigational Plan ..................................................................................  
7 
3.1 
Study Design ..............................................................................................  
7 
3.2 
Study Population .......................................................................................  
7 
3.3 
Inclusion Criteria ......................................................................................  
7 
3.4 
Exclusion Criteria .....................................................................................  
8 
3.5 
Withdrawal Criteria .................................................................................  
8 
3.6 
Replacement of Patients ...........................................................................  
8 
3.7 
Study Duration ..........................................................................................  
8 
3.8 
Safety Monitoring .....................................................................................  
8 
3.8.1 
Data and Safety Monitoring Plan ...........................................................  
8 
3.8.2 
Ethical Considerations .............................................................................  
8 
4.0 
Study Procedures ......................................................................................  
9 
4.1 
Informed Consent Procedure ..................................................................  
9 
4.2 
Patient Registration ..................................................................................  
9 
4.3 
Initiation of Study .....................................................................................  
9 
4.4 
Drug Information ......................................................................................  
9 
4.5 
Patient Assessment....................................................................................  
9 
4.6 
Imaging Information ................................................................................  
10 
4.6.1 
[18F]Fluciclovine PET Preparation and Injection ................................  
10 
4.6.2 
[18F]Fluciclovine PET/MRI Protocol .....................................................  
10 
4.6.3 
PET/MRI Imaging Interpretation and Storage ...................................  
10 
4.6.4 
Safety Monitoring .....................................................................................  
13 
4.6.5 
Patient Follow-Up .....................................................................................  
13 
5.0 
Study Parameters ......................................................................................  
13 
5.1 
Primary Endpoints....................................................................................  
13 
5.2 
Secondary Endpoints ................................................................................  
14 
5.3 
Exploratory Endpoints .............................................................................  
14 
5.4 
Study Termination ....................................................................................  
14 
6.0 
Statistical Considerations ........................................................................  
14 
6.1 
Study Design ..............................................................................................  
14 
6.2 
Sample Size Determination......................................................................  
14 
6.3 
Definition of Analyzed Study Population ..............................................  
15 
6.4 
Analysis .......................................................................................................  
15 
6.4.1 
Analysis for Primary Endpoints and Specific Aim 1...........................  
15 
6.4.2 
Analysis for Secondary Endpoints and Specific Aim 2 .......................  
16 
6.5 
Data and Safety Monitoring Plan ...........................................................  
16 
6.5.1 
Pre-study Documentation ........................................................................  
16 
6.5.2 
Institutional Review Board Approval ....................................................  
16 
6.5.3 
Informed Consent .....................................................................................  
16 


3 
6.5.4 
Changes in Protocol ..................................................................................  
16 
6.5.5 
Adverse Event Reporting.........................................................................  
17 
6.5.5.1 
General Definitions ...................................................................................  
18 
6.5.5.2 
AE Reporting Requirements ...................................................................  
19 
6.5.5.3 
CAEPR/ASAE for [18F]Fluciclovine ......................................................  
19 
6.5.5.4 
Potential but Unexpected AE for [18F]Fluciclovine .............................  
20 
6.5.5.5 
Review of Safety Information .................................................................  
20 
6.5.5.6 
Adverse Event Reporting.........................................................................  
21 
6.5.5.7 
Expedited Adverse Reaction Reporting Guidelines ............................  
22 
6.5.6 
Protection of Privacy ................................................................................  
22 
6.6 
Data Management .....................................................................................  
22 
7.0 
References ..................................................................................................  
23 


4 
1.0 
Introduction and Study Rationale 
1.1 
Overview 
There is great need for improved pretreatment imaging in men with high-risk prostate 
cancer. We propose to develop an optimized simultaneous PET/MRI protocol for local, 
regional and whole body pre-therapeutic initial staging of high-risk prostate cancer in a 
single imaging session using the amino acid PET tracer, [18F]fluciclovine. This PET 
tracer has recently received FDA approval for use in biochemically recurrent prostate 
cancer, but its utility for staging prior to therapy and for monitoring response to therapy 
has not been established. Despite advances in the diagnosis and treatment of prostate 
cancer, the pretreatment staging of men with prostate carcinoma (PCa) is currently 
problematic. Conventional imaging is falsely negative for regional lymph node 
metastases in a substantial fraction of men. In particular, approximately 35% of men with 
high-risk prostate cancer will have biochemical recurrence even after optimal surgical 
resection. Therefore, we plan to examine patients at high risk for metastatic disease and 
who will predominantly be offered nonsurgical management of their prostate carcinoma. 
We will compare mpMRI alone to simultaneous fluciclovine-PET/MRI in terms of lesion 
detection in pelvic nodal stations. We will also correlate these imaging findings with 
established risk-prediction models to indirectly assess accuracy, as the vast majority of 
these patients will be managed non-operatively in this study. A second follow-up 
[18F]fluciclovine-PET/MRI study will be performed after completion of therapy. This 
repeat study after therapy will be used as part of a standard of truth (i.e. findings should 
resolve with effective therapy) and to generate preliminary data regarding the utility of 
fluciclovine-PET/MRI for assessing response to therapy. 
If this preliminary study suggests a benefit of [18F]fluciclovine-PET/MRI in the 
pretreatment setting, additional larger studies will be designed based on these results. 
Because [18F]fluciclovine and PET/MRI are clinically available and FDA-approved for 
biochemically recurrent prostate cancer, this study has the potential for rapid and 
widespread impact. If [18F]fluciclovine-PET/MRI can reliably and accurately detect nodal 
metastases in high-risk prostate cancer patients, surgeons may use this new technology to 
decide if a high-risk prostate cancer patient is eligible for surgery, to extend the pelvic 
lymph node dissection to include suspicious lymph nodes identified by imaging, and for 
making decisions regarding initiating androgen-deprivation therapy. We will also 
generate preliminary data regarding the utility of [18F]fluciclovine-PET/MRI for 
assessing response to therapy. 
1.2 
Background and Rationale 
Prostate cancer is a common malignancy with an estimated 180,890 new cases and 
26,120 deaths in 2016.1 Screening for prostate cancer is currently performed utilizing 
digital rectal exam and serum prostate specific antigen (PSA). Due to the high frequency 
of indolent prostate cancer, approximately 80% of cancers detected by screening are 
localized to the prostate. For these patients, the 5-year survival is nearly 100%.  


5 
However, there is a substantial minority of patients with high-risk prostate 
adenocarcinoma that are at significant risk for regional nodal and distant metastases at the 
time of diagnosis. In contrast to localized disease, the 5-year survival for patients with 
distant metastatic disease is 29%. Disease risk is stratified with the Gleason score on 
prostate biopsy, PSA, and clinical staging. These values provide estimated risks of organ-
confined disease and extraprostatic disease based on established nomograms and Partin 
tables.2 In these patients who undergo radical prostatectomy and bilateral pelvic lymph 
node dissection, approximately 30% experience biochemical recurrence. The 5-year 
disease-free survival rate drops from 85% of patients with no nodal metastases to 50% in 
those patients with nodal metastases. This is thought to be due to lack of detection of 
small volume metastatic disease not identified on conventional preoperative imaging. 
Because current imaging techniques have limited sensitivity for nodal metastases, many 
high-risk men are assumed to have metastatic disease and not offered potentially curative 
surgery. More accurate pretreatment staging has the potential to alter surgical planning or 
to prompt the earlier use of radiation or systemic therapy to decrease the risk of 
recurrence and improve survival. Through this study, we will generate key preliminary 
data assessing the ability of fluciclovine-PET coupled with simultaneous PET/MRI to 
improve the accuracy of pretreatment staging in men with high-risk prostate cancer. 
 
While prostate MRI is valuable for the detection of occult primary lesions, its sensitivity 
and specificity for the detection of pelvic lymph node metastases is limited to RECIST 
criteria and nodal morphology. It is well known that normal-appearing lymph nodes on 
CT and MRI can harbor small volume metastatic disease not detected based on size and 
morphological criteria. Molecular imaging has great potential to supplement MRI and 
increase diagnostic accuracy, and simultaneous PET/MRI can provide both dedicated 
regional PET and MRI imaging for regional staging as well as whole body staging in a 
single imaging session.  
 
Amino acid metabolism is upregulated by prostate cancer cells, with increased expression 
of the ASCT2 and LAT1 transporters. As a result, multiple amino acid analogues have 
been developed to image prostate cancer. Recently, the 18F-labeled amino acid anti-1-
amino-3-[18F]fluorocyclobutane-1-carboxylic acid ([18F]FACBC, otherwise known as 
fluciclovine) received FDA approval for use in biochemically recurrent prostate cancer. 
Fluciclovine-PET/CT has been shown to be particularly effective for detecting nodal 
metastases and distant metastases in recurrent prostate cancer. Fluciclovine is a transport 
substrate for ASCT2 and to a lesser extent LAT1, but is not metabolized intracellularly or 
incorporated into proteins.3,4 A key advantage to the use of fluciclovine is minimal 
excretion of the radiotracer into the urine, which lends itself well to imaging the pelvis 
without the use of pre-scan urinary bladder catheterization. Studies with fluciclovine have 
focused primarily on biochemical recurrence using PET/CT. Currently, data are scarce 
regarding the role of fluciclovine in patients undergoing initial staging, and there are 
virtually no data using PET/MRI.5 A single study examining the effectiveness of 
fluciclovine PET/CT for detection of nodal metastases demonstrated increased detection 
of sub-centimeter pelvic lymph nodes when compared to conventional imaging.6  
 


6 
Several studies have examined the use of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) 
PET/CT for the evaluation and staging of prostate cancer. FDG-PET/CT has not become 
a mainstay in the pretreatment staging of patients due to low sensitivity and specificity. In 
response, a number of radiotracers have been developed to detect metastatic disease in 
the setting of prostate cancer. The first alternative tracer in clinical use in the United 
States is [11C]choline. Sensitivity for staging patients using [11C]choline is higher than for 
FDG, but remains relatively poor with studies ranging from 45-73%.7-9 A significant 
logistical problem with the use of [11C]choline is the 20 min half-life of the radiotracer, 
thus requiring on-site production by a cyclotron.  
Prostate specific membrane antigen (PSMA) is a transmembrane cellular receptor that is 
overexpressed in prostate cancer cells. Recently, small molecules have been developed 
that bind to the extracellular component of the transmembrane PSMA receptor. These 
agents have been tagged with both 18F and 68Ga for imaging and 90Y and 177Lu for 
therapeutic purposes. Restaging accuracy of fluciclovine and PSMA-PET/CT are superior 
to choline compounds, particularly at low PSA levels, although no direct comparison of 
PSMA ligands and fluciclovine PET are currently available in the published literature.10 
A limitation of PSMA ligands is that approximately 10% of prostate carcinoma and nodal 
metastases are PSMA negative.11-14 PSMA ligands are currently investigational in the 
United States and not available for routine clinical use. 
While other PET tracers remain promising, [18F]fluciclovine has several key advantages. 
[18F]Fluciclovine is more widely available and can be distributed to centers without 
onsite radiolabeling capabilities due to its 18F-label. Initial data suggest that fluciclovine 
is diagnostically superior to [11C]choline. Although PSMA ligands are promising, 
fluciclovine can have much greater near-term impact for pretreatment staging because it 
is FDA-approved By accurately staging high-risk patients prior to treatment, we speculate 
that treatment algorithms can shift, allowing better assessment of surgical eligibility and 
therapy planning. 
PET/MRI is likely the optimal modality to image patients for pretreatment staging of 
prostate carcinoma. In one study, a patient can undergo a multiparametric prostate MRI 
for characterization of the primary lesion and the extent of regional extraprostatic disease 
along with a molecular imaging study to improve the accuracy of regional staging and 
provide whole body staging. In addition, simultaneous acquisition of PET and MRI data 
allows for more accurate coregistration of MRI and PET data which may be difficult to 
achieve with software fusion, a key to detecting non-enlarged lymph nodes and other 
small lesions. 
We will also develop preliminary data regarding the utility of fluciclovine-PET/MRI in 
early assessment of treatment response in this patient population. In men treated with 
radiation therapy and/or androgen deprivation therapy (ADT), early detection of 
treatment failure may identify patients who would benefit from additional local or 
intensive systemic therapy much sooner than is possible with serum PSA measurement 
alone. The favorable properties of PET/MRI are expected to be useful for early treatment 
response assessment as well. Because most of the patients in this study will not undergo 


7 
surgery, many of the post-therapy studies will be in men undergoing radiation therapy 
and/or androgen deprivation hormonal therapy. We will measure changes in fluciclovine 
uptake and MR parameters at a 3-6 month imaging time point and correlate these results 
with clinical follow up including progression-free survival. If fluciclovine-PET/MRI has 
utility for early assessment of response, men at high risk for recurrence based on imaging 
may be offered additional local therapy and/or systemic therapy prior to progression 
based on serum PSA measurements. 
2.0 
Study Objectives 
Specific Aim #1: Determine the concordance of imaging findings for fluciclovine-
PET/MRI and mpMRI of the pelvis and prostate gland. 
Hypothesis #1: Fluciclovine-PET/MRI will identify more regional lymph node 
metastases than mpMRI alone.  
There have been numerous prior studies demonstrating the value of mpMRI for the 
locoregional staging for PCa. Prior studies in the setting of biochemical recurrence have 
demonstrated high sensitivity and specificity of fluciclovine-PET/CT for detection of 
recurrent disease in the prostate bed and extraprostatic disease.15 We expect the 
simultaneous acquisition of mpMRI and fluciclovine PET data to provide valuable 
preoperative staging information, with fluciclovine PET detecting metastatic disease in 
subcentimeter pelvic lymph nodes not identified with mpMRI alone. Additionally, 
fluciclovine-PET/MRI provides whole body staging in regions not evaluated by mpMRI 
and may detect additional distant metastases. 
Specific Aim #2: Determine the correlation between organ-confined disease, lymph node 
metastases, extraprostatic extension, and seminal vesicle invasion on fluciclovine-
PET/MRI with the expected frequencies of these metastases based on established 
nomograms and risk-prediction models as well as follow up fluciclovine-PET/MRI.  
Hypothesis #2: Fluciclovine-PET/MRI will demonstrate metastases in the expected 
frequencies for patients with high-risk PCa and will regress with effective therapy.  
For pretreatment patients with PCa, several clinical risk-predictors (including nomograms 
and Partin tables) utilize serum prostate-specific antigen (PSA), Gleason score, and 
clinical stage to predict organ-confined disease, the presence of extraprostatic extension, 
seminal vesicle invasion, and lymph node metastases.2 Because majority of the high-risk 
prostate cancer population in this study will not undergo prostatectomy, nomograms and 
risk-prediction models combined with follow up fluciclovine-PET/MRI after therapy will 
be used as a surrogate for accuracy. If successful, this research plan will provide key data 
for further studies that will use histopathological confirmation as the reference standard. 
Specific Aim #3: Measure changes in fluciclovine-PET/MRI at 6-12 weeks after 
initiation of therapy and correlate with serum PSA. 


8 
Hypothesis #3: Fluciclovine-PET/MRI parameters including fluciclovine uptake and 
fluciclovine-defined metabolic tumor volumes will change with effective therapy. 
Resolution of fluciclovine-PET/MRI findings after therapy will also be used to help 
confirm true lesions on the pre-treatment imaging. If successful, this research plan will 
provide key data for further studies in for initial staging and monitoring therapy response 
that will use histopathological confirmation and patient outcomes as the reference 
standards. 
For the post-treatment imaging, a repeat fluciclovine-PET/MRI study will be performed 
at 6-12 weeks months after initiation of therapy. The fluciclovine-PET and MR 
measurements will be compared between the pre- and post-treatment studies. Early 
detection of men at high risk for early treatment failure might undergo additional 
treatment prior to PSA rise from nadir. In the small number of patients in this study who 
undergo prostatectomy, the follow up fluciclovine-PET/MRI has the potential to detect 
residual disease that could then be treated with additional local therapy. 
3.0 
Investigational Plan 
3.1 
Study Design 

Prospective IRB-approved study enrolling patients with biopsy-proven
high-risk prostate cancer for pretreatment fluciclovine-PET/MRI prior to
the initiation of treatment and at three month follow-up

All patients will undergo standard-of-care clinical evaluation and imaging
workup with nuclear medicine bone scan and either CT of the abdomen
and pelvis or MRI pelvis

Majority of patients will be non-operative due to high-risk status, but
participation in study does not exclude operative intervention

Treatment team will initially be blinded to results of PET/MRI, but will be
unblinded following standard-of-care imaging and formation of the initial
treatment plan

If study PET/MRI demonstrates a suspicious finding that may preclude a
patient from operative intervention (in a patient being considered for
surgery) or alter locoregional treatment (e.g. radiation therapy), the
treatment team will be alerted to potentially investigate the finding further
(i.e. additional imaging or biopsy)

Findings on PET/MRI relayed to the clinical team may prompt further
investigation on standard-of-care imaging and discussion in the
genitourinary tumor board. If additional imaging and/or tumor board
consensus indicates the need for biopsy, the biopsy can be billed to
insurance as standard-of-care.

A repeat fluciclovine-PET/MRI study will be performed at 6-12 weeks
weeks after initiating therapy (typically radiation therapy, prostatectomy,
and/or androgen deprivation therapy) at the time when serum PSA values
are initially checked to establish response


9 
3.2 
Study Population 

Patients with high-risk biopsy-proven treatment-naïve prostate cancer
3.3 
Inclusion Criteria 

High-risk biopsy-proven treatment-naïve prostate adenocarcinoma
(Gleason score ≥ 8 and/or serum PSA > 20)
3.4 
Exclusion Criteria 

Inability to tolerate or undergo PET/MRI

Previous or current hematologic or lymphatic disorder (including
leukemia, lymphoma, Castleman’s disease, etc.)

Recurrent prostate adenocarcinoma

Known visceral, osseous, or extrapelvic metastases prior to fluciclovine-
PET/MRI

Known allergy to glucagon or gadolinium-based contrast
3.5 
Withdrawal Criteria 

Given that enrollment in this study will involve two imaging exams, no
withdrawal criteria will be used
3.6 
Replacement of Patients 

Given that enrollment in this study will involve two imaging exams, no
replacement of patients will be used
3.7 
Study Duration 

Study enrollment and imaging will take place over 12 months
3.8 
Safety Monitoring 
3.8.1 Data and Safety Monitoring Plan 
Patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. 
Following this discussion, they will be asked to sign the HIPAA form and 
informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited 
to the individuals described in the informed consent document. PET/MRI scans 
will be loaded into a separate password-protected image storage system that will 
not appear on the PACS utilized in clinical practice.  
3.8.2 Ethical Considerations 


10 
Given that the study involves two imaging sessions with PET/MRI and the 
expected age of the enrolled adult patients, ethical concerns regarding additional 
radiation exposure are minimal. The only ethical consideration was the 
availability of the results of the study PET/MRI to the clinicians. Given that the 
PET tracer used (fluciclovine) is FDA-approved for a similar indication in the 
setting biochemical recurrence, it is highly likely that the tracer will behave in a 
similar fashion in these patients prior to therapy given similarities in tumor 
biology. Therefore, a suspicious lesion on the study PET/MRI is expected to 
correlate with metastatic disease. Therefore, if the PET/MRI demonstrates a 
suspicious finding, the treating clinician (including urology and radiation 
oncology) will be alerted, and the decision to pursue biopsy and/or alter the 
patients treatment plan will be based on standard of care imaging and consensus 
after presenting the case at the GU tumor board.  
 
4.0 
Study Procedures 
 
4.1 
Informed Consent Procedure 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation.  Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedure.  The participant must receive a copy of the 
signed and dated consent document.  The original signed copy of the consent document 
must be retained in the medical record or research file.  
4.2 
Patient Registration 
Enrollment in the study will be available after the patient has been seen by their treating 
physician at UAB. The majority of these patients are expected to be seen in Urology 
clinic. However, all patients that meet enrollment criteria are eligible. Registration in the 
study will be performed by a research coordinator from the UAB Department of 
Radiology. Participation in the study is voluntary and choosing not to participate will not 
affect patient care in any way. 
 
4.3 
Initiation of Study 
The PET tracer [18F]fluciclovine is FDA-approved for biochemically recurrent prostate 
cancer and readily available from commercial production sites. Additionally, UAB 
currently is performing clinical PET/MRI scans, including [18F]fluciclovine-PET/MRI. 
Therefore, the study can be initiated immediately following institutional and IRB 
approval. 
 
4.4 
Drug Information 
[18F]fluciclovine is a non-natural amino acid radiotracer that is currently FDA-approved 
PET imaging agent for use in patients with biochemically-recurrent prostate cancer. The 
radiotracer targets both the LAT1 and ACST2 transporters, both of which are upregulated 
in prostate cancer cells. The dosage of radiotracer administered to the patient is 370 MBq 
(10 mCi) intravenously. This results in an effective dose of 8 mSv (800 mrem) to the 
patient, which is equal to 2.7 years of natural background radiation exposure (3 mSv/yr).  
 


11 
4.5 
Patient Assessment 
Identification and workup of patients prior to potential enrollment in the study will follow 
standard-of-care procedures per the treating physician (urology, radiation oncology, etc.). 
For initial staging of high-risk prostate cancer, this will include a nuclear medicine bone 
scan and either a CT abdomen and pelvis or MRI of the pelvis per NCCN guidelines. If a 
patient is determined to be eligible for the, the research coordinator in this study will be 
asked to come to the clinic to discuss potential enrollment in the study. 
 
4.6 
Imaging Information 
4.6.1 [18F]Fluciclovine PET Preparation and Injection 
The injected dose will be 370 MBq (10 mCi) of [18F]fluciclovine. The patient will 
be instructed to avoid strenuous exercise for 24 hours prior to injection and to 
avoid caloric intake for 4 hours prior to injection. PET/MRI imaging will begin 
immediately following injection. Intramuscular injection of glucagon 1 mg will be 
performed immediately prior to the prostate MRI portion of the PET/MRI. 
 
4.6.2 [18F]Fluciclovine PET/MRI Protocol 
 
Whole body imaging 
Positron Emission Tomography Acquisition: The patient will be placed on the 
PET/MRI scanner in the supine position. Initial localizer images will be obtained. 
Dynamic images of the pelvis will be acquired for the first 8 min after 
fluciclovine injection with framing of 3 sec x 20, 10 sec x 12, 20 sec x 6, 180 sec 
x 1.  Subsequently, static whole body images will be acquired from pelvis to skull 
base utilizing approximately eight 14 cm detector beds for 5 minute acquisitions 
per bed position. Correction for randoms, scatter, attenuation and reconstructions 
will be performed per the manufacturer’s recommendations.  
 
Whole Body MRI: Sequences performed will include MR attenuation correction 
(MRAC), axial and coronal T2 single shot fast spin echo, sagittal T1 turbo spin 
echo for skeletal evaluation, and whole body Dixon-derived sequences. 
 
Following whole body PET imaging, a routine multiparametric MRI of the 
prostate gland will be performed at UAB in the PET/MRI scanner per institutional 
protocol, which includes high b-value diffusion-weighted imaging (b2000), small 
field-of-view T2 imaging, and dynamic contrast enhanced T1 images. An 
additional static pelvic PET acquisition will be performed concurrently. 
 
Fluciclovine PET/MRI scans will be performed at two time points: 
 Prior to initiation of treatment 
 At 3-6 months following treatment initiation when routine clinical practice 
is to begin assessing PSA values for response 
 
The study protocol has been submitted to, reviewed, and approved by the UAB 
Radiation Safety Committee. 
 


12 
4.6.3 PET/MRI Imaging Interpretation and Storage 
Images from the PET/MRI will be stored and reviewed using a commercially 
available software package (MIM Encore, Cleveland, OH) and not be available 
for viewing in the institutional PACS or patient’s medical record. This is in an 
effort to blind the treating physicians from making clinical decisions on an 
experimental imaging technique. The prostate MRI images will be sent to clinical 
PACS and the medical record as part of standard-of-care imaging and can be used 
in the clinical-decision making process. No formal interpretation will be 
generated for the [18F]fluciclovine-PET portion of the PET/MRI study, but the 
prostate MRI will have a clinical interpretation by a dedicated abdominal 
radiologist who will also be blinded to the patient enrollment in the study. 
Dedicated study readers from both abdominal imaging and molecular imaging 
will interpret first the prostate MRI alone, and then the fused PET/MRI to assess 
potential added value from the PET/MRI. The study readers will be blinded to the 
results of any additional standard-of-care imaging and clinical evaluation and will 
only have knowledge that the patient has biopsy-proven prostate cancer. 
 
mpMRI images acquired from the fluciclovine-PET/MRI study will be scored 
initially without access to the fluciclovine-PET portion of the study using the 
method described below. Once the results of the MR only portion of the study 
have been recorded, the same reader will be given access to the entire study and 
provide a second set of scores for the combined PET/MRI images. The 
concordance for metastases in lymph node stations will be determined from these 
scores. At least two readers will score each study, and discrepancies will be 
recorded and resolved through a consensus read after finalizing individual 
scoring. 
 
MRI Data Analysis: The MRI images will be qualitatively analyzed. 
 
Qualitative analysis: A visual evaluation of the pelvic lymph nodes with 
suspected metastatic disease will be performed. The number of positive metastatic 
lymph nodes and their nodal stations will be recorded. Nodal stations that will be 
examined include right and left common iliac, internal iliac, external iliac, 
obturator, inguinal, and retroperitoneal (total of 11 stations per patients). 
 
T1/T2 Images 
0 = Normal lymph nodes 
1 = Mild prominence not meeting RECIST criteria for adenopathy (low suspicion) 
2 = Definitely abnormal size or morphology, possible metastasis (intermediate 
suspicion) 
3 = Markedly abnormal size and morphology, likely metastasis (high suspicion) 
 
DWI Images 
0 = Normal diffusion 
1 = Low level of diffusion restriction when compared to adjacent normal 
appearing lymph nodes (low suspicion) 


13 
2 = Slightly higher level of diffusion restriction when compared to adjacent 
normal appearing lymph nodes (intermediate suspicion) 
3 = Definitely higher level of diffusion restriction when compared to adjacent 
normal appearing lymph nodes (high suspicion) 
 
Note: In cases of nonhomogenous intensity on DWI and ADC images, the grade 
will be determined on the basis of the most suspicious area.  
 
 
PET Data Analysis: The PET images will be qualitatively and quantitatively 
assessed. The scoring will be based primarily on the PET data, but the reader will 
have access to the MRI data for anatomic correlation and characterization of 
lymph node morphology. For PET data analysis, a lymph node positive based on 
MRI criteria but negative based on fluciclovine-PET criteria will be scored as 
negative. 
 
Qualitative analysis: A visual evaluation of the pelvic lymph nodes with 
suspected metastatic disease will be performed. As per manufacturer guidelines, 
lymph nodes measuring less than 1 cm in short-axis dimension will be compared 
to blood pool tracer activity. For lymph nodes measuring greater than 1 cm, 
comparison of activity will be made to the activity in the bone marrow of the L3 
vertebral body. The number of positive metastatic lymph nodes and their nodal 
stations will be recorded. 
 
0 = No uptake or uptake lower than appropriate reference (blood pool vs. L3 
marrow) 
1 = Uptake equal to reference (low suspicion) 
2 = Uptake slightly greater than reference (intermediate suspicion) 
3 = Uptake definitely greater than reference (high suspicion) 
 
Quantitative analysis: Nodes scored as intermediate or high suspicion based on 
MRI and/or PET will undergo further quantitative analysis.  
 
Standardized uptake values (SUVs): The maximum SUV will be measured. 
Additionally, the mean SUV and metabolic tumor volume will be measured based 
on a 40% isocontour.   
 
Lesion to blood pool and marrow ratios: Tissue SUV is a simple uptake ratio of 
activity in an area of interest compared to a normalized tissue background level. 
As stated in section B, activity in lymph nodes measuring less than 1 cm in short-
axis dimension will be compared with activity in the blood pool and a 
lesion:blood pool activity ratio will be calculated. For lymph nodes measuring 
greater than 1 cm in short-axis dimension, activity will be compared to activity in 
the L3 vertebral body marrow and a lesion:marrow activity ratio will be 
calculated.. 
 


14 
Dynamic PET analysis: Time-activity curves (TACs) will be generated for 
pelvic lymph nodes scored as intermediate or high suspicion on visual analysis. 
Additionally, TACs will be generated for three reference pelvic lymph nodes 
scored as normal. The maximum SUV at peak fluciclovine uptake, the time to 
peak, and the shape of the TACs over the 8 min dynamic acquisition (rising, 
plateau, washout) will be recorded. This analysis is exploratory as the role of 
dynamic fluciclovine-PET for the initial staging of prostate cancer is not 
established. 
 
KEY ANALYSIS FOR SPECIFIC AIM 1 
Based on the consensus PET and MRI scoring, the total percentage of nodal 
scoring discrepancies will be calculated. Although the total number of patients is 
small, a total of 165 pelvic nodal stations will be examined. In this pilot study, a 
discrepancy between MR-only and fluciclovine-PET/MR greater than 10% would 
motivate a larger study with more rigorous references standards including 
histopathology. 
 
KEY ANALYSIS FOR SPECIFIC AIM 2 
This study will use the nomograms routinely used by the UAB urology service in 
assessing newly diagnosed prostate cancer. The use of nomograms is necessary, 
as we will not routinely obtain histopathological verification in these high-risk, 
nonoperative patients in this study. Expected frequencies of lymph node 
metastases based on patient risk factors will be compared to observed frequencies 
of lymph node metastases in specific aim 1 on mpMRI alone, fluciclovine-
PET/MRI, and assuming that discrepant nodes between imaging modalities (i.e. 
positive on one, negative on other) will be counted as positive, a combination of 
the two modalities that includes discrepant nodes. The assessment that most 
closely matches the expected frequency based on the nomogram will be 
considered most accurate, although small sample size will require larger studies 
for confirmation.  
 
As stated previously, although most patients enrolled in the study will not be 
surgical candidates, participation in the study does not preclude a patient from 
surgery. However, given the known value of [18F]fluciclovine in the setting of 
biochemically recurrent prostate cancer and the similar biological tumor profile 
between treatment-naïve and recurrent prostate cancer, suspicious extraprostatic 
findings will be reported to the referring physician due to the high likelihood of 
representing true positive metastatic disease. In these cases, further imaging or 
biopsy may be indicated prior to proceeding with surgery. The treating physician 
will initially be blinded to the results of the PET/MRI until a treatment plan is 
established through the use of standard-of-care imaging, which may include the 
prostate MRI portion of the PET/MRI but not the fused PET/MRI. Following the 
treatment decision, the physician will be unblinded to the results of the PET/MRI. 
Changes in treatment plan based on the PET/MRI will be tracked.  
 
4.6.4 Safety Monitoring 


15 
Vital signs will be assessed immediately before and after injection of 
[18F]fluciclovine (HR and supine BP).  Patients will be monitored for adverse 
events during injection and after completion of the imaging study   Additionally, 
patient’s vitals (HR and supine BP) will be checked at the completion of the 
imaging study prior to leaving the imaging center. 
 
4.6.5 Patient Follow-Up 
Patients will be instructed to contact the UAB Department of Radiology 
Advanced Imaging Facility if there are any concerns about delayed side effects 
related to the study radiotracer.  Patients will be seen in the clinic if there are any 
concerning study related adverse events requiring further evaluation. 
 
5.0 
Study Parameters 
5.1 
Primary Endpoints 
- 
[18F]fluciclovine PET/MRI results for primary lesion and regional nodal 
metastases 
- 
Concordance between [18F]fluciclovine PET/MRI results and multiparametric 
prostate MRI results 
- 
Detection of organ-confined disease, regional nodal metastases, extracapsular 
extension, and seminal vesicle invasion [18F]fluciclovine PET/MRI in expected 
frequencies based on risk-predictor models and nomograms 
 
5.2 
Secondary Endpoints 
- 
Potential added value in additional metastases detected on [18F]fluciclovine 
PET/MRI versus prostate MRI alone 
- 
Use of follow up [18F]fluciclovine-PET/MRI after initiating therapy to confirm 
initial suspicious findings on the initial pretreatment study 
 
5.3 
Exploratory Endpoints 
- 
Use of [18F]fluciclovine PET/MRI at 3-6 months following initiation of treatment 
to evaluate response to therapy at the time when serum PSA is routinely checked 
following treatment initiation 
- 
Correlate disease burden at 3 month follow up with serum PSA values 
- 
Dynamic radiotracer uptake by the primary lesion and if this changes on the 
posttreatment [18F]fluciclovine-PET/MRI 
- 
Changes in signal characteristics of primary intraprostatic lesion on posttreatment 
mpMRI 
- 
Changes in initial treatment plan with added information provided by fluciclovine 
PET/MRI versus standard-of-care imaging alone 
 
5.4 
Study Termination 
The study will stop enrolling patients once the target number has been reached. 
 
6.0 
Statistical Considerations 
6.1 
Study Design 


16 
This is a prospective pilot trial to determine the potential use of [18F]fluciclovine 
PET/MRI in the pretreatment staging and post-therapy follow-up of patients with high-
risk prostate adenocarcinoma. The primary objective of this study is to determine the 
concordance of imaging findings for fluciclovine-PET/MRI and mpMRI of the pelvis and 
prostate gland. The secondary objective is to determine the correlation between organ-
confined disease, lymph node metastases, extraprostatic extension, and seminal vesicle 
invasion on fluciclovine-PET/MRI with the expected frequencies of these metastases 
based on established nomograms and risk-prediction models. 
 
6.2 
Sample Size Determination 
This is a pilot study that may warrant a larger study with increased power to determine statistical 
significance if expected results are observed. We plan to enroll 15 patients, primarily determined 
by budgetary constraints and feasibility of patient recruitment in one year. No formal power 
calculations were used in the generation of the sample size. The primary end point of the study is 
to estimate percentage of high-risk prostate cancer patients whose metastasis can be detectable 
early by using of [18F]fluciclovine-PET/MRI comparing using standard care of mpMRI imaging. 
According to risk-prediction models and nomograms used in routine clinical practice, 
approximately 20-30% of patients with high-risk prostate adenocarcinoma will be diagnosed 
with nodal metastases. We expect that using [18F]fluciclovine PET/MRI  will achieve similar 
results, e.g. 30% for early detection of metastasis without invasive procedures, and using 
mpMRI will result in less of detection of metastasis, e.g.  20%-25%. A size of 15 will provide a 
two-sided 95% confidence intervals (CI) for point estimate (% of metastasis) from 9.7% to 
58.4% when the true estimate is 30% using Clopper-Pearson method. Table below shows the 
95% CI when the true estimate varies. 
 
Proportion 
(%)(estimate 
of metastasis) 
Sample size  95% CI  
Lower limit 
95% CI  
Upper limit 
20 
15 
4.3 
48.1 
25 
15 
6.9 
53.4 
30 
15 
9.7 
58.4 
  
 
6.3 
Definition of Analyzed Study Population 
Study population is adult males with high-risk treatment-naïve prostate adenocarcinoma 
who meet the inclusion criteria listed above. 
 
6.4 
Analysis 
Since this is a single arm exploratory pilot study, where no formal power calculations 
were performed for the study’s sample size, this study will largely be exploratory and 
descriptive. For all clinical and histological evaluations, as well as imaging parameters 
(SUV), we will generate summary tabulations of the number of observations, mean, 
standard deviation, median, minimum, and maximum for continuous variables, and the 
frequency and percentage for categorical variables. Analyses will be primarily descriptive 
and graphical in nature whereas the proposed sample size for the study limits the 
distributional assumptions of certain analyses. Therefore, non-parametric approaches will 


17 
be considered. For specific aim 1, in order to correlate imaging parameters between 
imaging modalities our correlation analysis will be performed using Spearman’s Rank 
correlation and Wilcoxon signed-rank sum tests.  In order to address specific aim 2, to 
compare observed frequencies of metastases and expected frequencies, a Chi-squared 
analysis will be performed. Given the small sample size, a Yates’ correction may be 
utilized. Due to the small sample size and potential for sparse data, we may use Firth’s 
penalized likelihood approach. Data transfer, management, and analyses will be 
performed using Excel and SAS v9.4. 
 
6.4.1 Analysis for Primary Endpoints and Specific Aim 1: The imaging data 
from [18F]fluciclovine PET/MRI or mpMRI will be categorized from 0 to 
3 indicating likelihood of having metastasis as ‘0’indicating no sign of 
metastasis and >0  indicating there is sign of metastasis.  The number and 
percentage of metastasis identified by either [18F]fluciclovine PET/MRI  
or mpMRI will be calculated along with exact 95% CI using Clopper-
Pearson method. The agreement and concordance of using these two 
imaging results will be evaluated with McNemar test due to correlated 
results from same patients when the result is dichotomized as yes or no,  
or using Spearman’s Rank correlation analysis when the result is measured 
as 0-3.  
 
6.4.2 Analysis for Secondary Endpoints and Specific Aim 2: Serum prostate-
specific antigen (PSA) will be measured for each patient as a clinical risk-
predictor as a validated measure to identify PCa and monitor response to 
treatment. Patients will be identified if they have PCa metastases and 
response to treatment determined by PSA level (expected) and by using 
[18F]fluciclovine PET/MRI (observed) at baseline and 3 months after 
treatment. To compare observed frequencies of metastases and expected 
frequencies, a McNemar test will be performed at baseline and 3 month 
after treatment separately. Further, a generalized estimation equation 
(GEE) method will be used to examine the association of two diagnosis 
methods accounting for correlation between baseline and 3 months 
measurements. Sensitivity, specificity, and accuracy of using 
[18F]fluciclovine PET/MRI will be estimated along with 95% CI.   
Due to the small sample size and potential for sparse data, we may use 
Firth’s penalized likelihood approach. Data transfer, management, and 
analyses will be performed using Excel and SAS v9.4. 
 
6.5 
Data and Safety Monitoring Plan 
6.5.1 Pre-Study Documentation 
This study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); 
consistent with GCP and all applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval 
from the Institutional Review Board for the protocol, written informed consent 
form, subject recruitment materials, and any other written information to be 
provided to subjects before any protocol related procedures are performed on any 
subjects.   


18 
 
The clinical investigation will not begin until either FDA has determined that the 
study under the Investigational Drug Application (IND) is allowed to proceed or 
the Investigator has received a letter from FDA stating that the study is exempt 
from IND requirements. 
6.5.2 Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) 
will be reviewed and approved by the UAB IRB. Prior to obtaining IRB approval, 
the protocol must be approved by the by the UAB Comprehensive Cancer Center 
Protocol Review Committee (PRC).  The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.   
6.5.3 Informed Consent 
All participants must be provided a consent form describing the study with 
sufficient information for each participant to make an informed decision regarding 
their participation.  Participants must sign the IRB-approved informed consent 
form prior to participation in any study specific procedure.  The participant must 
receive a copy of the signed and dated consent document.  The original signed 
copy of the consent document must be retained in the medical record or research 
file.  
6.5.4 Changes in the Protocol 
Once the protocol has been approved by the UAB IRB, any changes to the 
protocol must be documented in the form of an amendment.  The amendment 
must be signed by the Investigator and approved by the IRB prior to 
implementation.   
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to IRB approval.  In this 
circumstance, however, the Investigator must then notify the IRB in writing 
within five (5) working days after implementation.   
6.5.5 Adverse Event Reporting 
As with many IV administered agents, [18F]fluciclovine could cause an allergic 
reaction that could potentially pose a threat to life (anaphylaxis).  This has not 
been observed in limited human exposure to date.  Reasonable precautions should 
be taken, consistent with normal radiologic and clinical facility practice.  The 
patient should be monitored until the PET procedure is completed, and trained 
personnel and emergency equipment should be available per facility standards. 
 
Qualifying Adverse Events (AEs), including Serious Adverse Events (SAEs), as 
defined herein, will be reported via the FDA Adverse Event Expedited Reporting 
System (AERS). For the [18F]fluciclovine IND we will report adverse events 
based on the FDA final rule for IND safety reporting requirements under 21 CFR 
part 312 published on September 29, 2010 and implemented on March 28, 2011.  
This investigational study is not a BA or BE study so 21 CFR part 320 is not 
applicable.  Adverse events will also be reported to the UAB IRB according to 
their requirements. 
 


19 
Reporting of Serious Adverse Events (SAEs) to Blue Earth Diagnostics (BED): 
In addition to reporting of SAEs to the responsible IRB and Health Authority, 
the Principal Investigator or designee will document all SAEs that occur 
following receipt of [18F]fluciclovine (whether or not related to study drug) to 
BED. Such SAEs must be reported within 24 hours of Principal Investigator or 
designee becoming aware of the event.  All SAE information must be recorded 
and faxed or scanned and emailed to: 
 
Blue Earth Diagnostics SAE E mail:  
Drugsafety@pharsafer.com  
Tel:   
 
 
 
 
1-855-AXUMIN1 (1-855-298-6461)  
Fax:   
 
 
 
 
+44 (0) 1483 212178 
 
Additional and further requested information (follow-up or corrections to the 
original case) will be detailed and faxed/emailed to the same address and must 
include the following minimum information: The name and contact information 
of the reporter, the name of the study drug(s), a description of the reported SAE, 
with the subject identified by one or more of the following (subject initials, 
subject number  age, sex), an investigator assessment of study drug causality, and 
any additional data which would aid the review and causality assessment of the 
case including but not limited to the date of onset, severity, the time from 
administration of study drug(s) to start of the event, the duration and outcome of 
the event, any possible etiology for the event, and the final diagnosis or syndrome, 
if known. If BED receives any individually identifiable health information 
collected or produced in the study, BED shall use and disclose only for the 
purpose of complying with applicable laws, provided that all such uses are 
disclosed in the IRB-approved informed consent form.  BED will use all 
reasonable efforts to protect the privacy and security of individually identifiable 
health information and will require its business partners to do so also.  BED will 
not contact any study subjects, unless permitted by the informed consent form. 
 
6.5.5.1 General Definitions (from 21 CFR 312.32 (a)) 
Adverse Event (AE): An Adverse Event is an untoward medical 
occurrence associated with the use of the drug in humans, whether or not 
considered drug related. For this study, the drug is [18F]fluciclovine and 
adverse events would include any events experienced by a study 
participant during the Adverse Event reporting period defined in Table 1 
whether or not it was considered to be related to the [18F]fluciclovine.   At 
the conclusion of the imaging study, the imaging technologist will observe 
the patient and also inquire if they are back to their usual state of health.  
If a negative answer is received, then the physician will be called to 
investigate this report as a possible adverse reaction. 
 
Adverse Reaction:  An Adverse Reaction is any adverse event caused by a 
drug. In this study, the drug is [18F]fluciclovine. 
 


20 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the IND drug caused the adverse event.  For the 
purposes of IND safety reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the adverse 
event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event 
caused by a drug. 
An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed 
at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in 
the current application. 
An adverse event or suspected adverse reaction is considered “serious” if, 
in the view of either the investigator or sponsor, it results in any of the 
following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include: allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does 
not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
Investigational Agent:  An investigational agent is any agent held under an 
Investigational New Drug (IND) application.  For purposes of this study, 
[18F]fluciclovine is the investigational agent. 
6.5.5.2 AE Reporting Requirements 
The investigators on this protocol will report any suspected adverse events 
that occur after [18F]fluciclovine administration and within the specified 
follow-up period to Dr. Galgano and they will work together to determine 
whether there was an adverse event or adverse reaction and the severity of 
the adverse event or reaction. 


21 
 
All AEs will be followed by the investigators until resolution, 
stabilization, scientifically and clinically satisfactory explanation as to 
attribution and etiology is achieved, or until subject is lost to follow up.   
 
6.5.5.3 CAEPR/ASAE for [18F]Fluciclovine 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. The Agent Specific Adverse Event List (ASAEL) would include 
the expected adverse events associated with the use of [18F]fluciclovine. 
At this time, there have rare reported AEs associated with the use of a 
[18F]fluciclovine in clinical studies (≤1% of patients). The most common 
adverse reactions were injection site pain, injection site erythema, and 
dysgeusia. We will continue to update our CAEPR and ASAE lists as this 
study progresses, including by reviewing the literature and our in-house 
data safety monitoring.  If any are found, we will begin an ASAE list.  
Any information on reported AEs for [18F]fluciclovine will be provided by 
the sponsor to all of the investigators on this protocol. 
 
6.5.5.4 Potential but Unexpected AE for [18F]Fluciclovine 
There have rare reported AEs associated with the use of a [18F]fluciclovine 
in clinical studies (≤1% of patients). The most common adverse reactions 
were injection site pain, injection site erythema, and dysgeusia.  
 
Other general risks for PET/MRI imaging include: 
 The injection site may become infected. 
 The dose might be extravasated into tissues surrounding the vein catheter 
leading to localized pain/discomfort. 
 
Radiation risks: [18F]fluciclovine injection contributes to lifetime radiation 
accumulation.  The smallest dosage for imaging and safe handling are 
used for these protocols. The organ and total body doses associated with 
[18F]fluciclovine imaging are comparable to those associated with other 
widely used clinical nuclear medicine procedures. 
 
6.5.5.5 Review of Safety Information 
As required by 21 CFR 312.32(b), the physician investigators will 
promptly review all information relevant to the safety of the drug. The 
physician investigators will also be providing much of this information to 
the local IRB as well for data safety and review monitoring.  The review 
will include determining whether there is a safety event over time and the 
causality.  Reporting will be as described in Table 1. 
 
Characterization of the severity of an Adverse Event:  Adverse events will 
be graded as below. 


22 
 
Grade:  Grade denotes the severity of the AE.  An AE is graded using the 
following categories: 
 Mild 
 Moderate 
 Severe 
 Life-threatening or disabling 
 Fatal 
 
NOTE:  Severity is graded on the Cancer Therapy Evaluation Program 
(CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 
based scale for each adverse event. For example, an abnormal hemoglobin 
value is graded for severity from 1 to 5 [death] based upon where that 
value falls on the CTCAE scale of abnormal hemoglobin values.  
“Severity” is NOT the same as “Seriousness.” All appropriate clinical 
areas should have access to a copy of the most current CTCAE and a copy 
of the CTCAE can be downloaded from (http://ctep.cancer.gov). 
 
Attribution of cause: The physician investigators will determine whether 
an adverse event was related to a medical treatment or procedure.  
Definitions taken from our work with CTEP and NIH give the following 
definitions for “Attribution” that we will adopt for this IND study:  
Attribution is a clinical determination, by the investigator, as to whether 
an AE is related to a medical treatment or procedure.  Attribution 
categories are: 
 Definite:     The AE is clearly related to a treatment or procedure  
 Probable:   The AE is likely related to a treatment or procedure 
 Possible:    The AE may be related to a treatment or procedure 
 Unlikely:     The AE is likely unrelated to a treatment or procedure 
 Unrelated:  The AE is clearly not related to a treatment or procedure 
 NOTE:  Attribution is part of the assessment of an adverse event.  
Determining that an event is ‘unlikely related’ or ‘unrelated’ to a study 
agent or procedure does NOT make the event unreportable, or disqualify 
the event as an AE.  As defined above, an AE is reportable as specified 
herein if it occurred: “during the Adverse Event reporting period 
defined in the protocol, or by applicable guidance, regulation, or policy.” 
 
6.5.5.6 Adverse Event Reporting 
Expedited AE reporting for this study will be done through the Cancer 
Consortium, IRB and FDA and as required by FDA MedWatch. These 
requirements are briefly outlined in the table below.  
 
Table 1.  Reporting Requirements. 
 
Unexpected 
Expected 
 
Adverse Reaction (known or suspected 
attributable to the use of 
AE not 
attributable to 
AE, AR 


23 
[18F]Fluciclovine 
[18F]Fluciclovine 
Serious including life-
threatening (or death) 
Nonserious 
Life-Threatening 
or serious or not 
serious 
None are 
expected for 
[18F]Fluciclovine 
Reporting 
Time 
Requirement 
to the FDA 
Report to FDA ASAP 
and within 7 days of 
discovery of event  
Annual 
Continuation 
Review 
submission 
Annual 
Continuation 
Review 
submission 
Not applicable to 
[18F]Fluciclovine 
Reporting 
Form for the 
FDA 
IND Safety report of 
potentially serious risk 
Annual Reports / 
Case reports  
Annual Reports / 
Case reports 
Not applicable to 
[18F]Fluciclovine 
Reporting 
Time 
Requirement 
to the local 
IRB 
Report to IRB ASAP 
within 10 days of 
discovery of event 
(suspected is defined as 
50% probability 
attributable to 
[18F]Fluciclovine 
study) this also 
includes any increased 
risks with the study 
even without an AE 
At continuation 
review  time 
At continuation 
review time 
Not applicable to 
[18F]Fluciclovine 
Reporting 
form for the 
IRB 
Expedited Reporting 
Form for Unanticipated 
Problems or 
Noncompliance and 
Adverse Event 
Reporting Form 
Form for 
Unanticipated 
Problems or 
Noncompliance, 
Case reports on 
continuation 
form, Data 
Safety 
Monitoring 
Reports 
Form for 
Unanticipated 
Problems or 
Noncompliance, 
Case reports on 
continuation 
form, Data 
Safety 
Monitoring 
Reports 
Not applicable to 
[18F]Fluciclovine 
6.5.5.7 Expedited Adverse Reaction Reporting Guidelines 
Life-threatening (or fatal) adverse reactions must be reported within 7 
days to the FDA.  The FDA should be notified as soon as the adverse 
reaction is discovered by telephone or fax or email.  The instructions and 
forms are available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm  The 
report should be sent ASAP by mail and followed with a follow-up report. 
Individual IND safety reports to FDA are submitted on the Medwatch 
FDA Form 3500A as an “IND Safety Report”.  The form should be sent to 
The Director, Office of Generic Drugs in the Center for Drug Evaluation 


24 
and Research at FDA.  The address and phone numbers are available at:  
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm119100.htm. 
All life threatening adverse reactions reports are submitted to the FDA, 
THE UAB IRB and to all investigators.  A copy of the report is kept on 
file. 
6.5.6 Protection of Privacy 
Patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. 
Following this discussion, they will be asked to sign the HIPAA form and 
informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited 
to the individuals described in the informed consent document. 
6.6 
Data Management 
All patient data will be anonymized and stored on encrypted password-protected 
computers with access only given to members of the research team. Standard precautions 
regarding HIPAA will be taken to avoid any breach in patient privacy. 
7.0 
References 
1.
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl
J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER
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