Clinical trial NCT04750473
Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Invasive Breast Lobular Carcinoma Metastatic Breast Lobular Carcinoma Prognostic Stage IV Breast Cancer AJCC v8
Sponsor: Emory University
Start date: 2021-07-16; Completion date: 2024-03-21
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies how well fluciclovine positron emission tomography (PET)/computed tomography (CT) and PSMA PET/CT work in helping doctors understand and classify invasive lobular breast cancer in patients with invasive lobular breast cancer that is suspicious for or has spread to other places in the body (metastasized). Fluciclovine and PSMA are radiotracers used in PET/CT imaging scans that emit radiation. The PET/CT scan than picks up the radiation being released to create a picture from within the body. Information learned from this study may help researchers learn how to better identify metastatic disease in invasive lobular breast cancer patients which will impact appropriate staging.

Detailed description:
PRIMARY OBJECTIVES:

I. Improve detection of metastasis with fluciclovine F18 (fluciclovine) and gallium Ga 68-labeled PSMA-11 (PSMA) PET versus best standard of care conventional imaging, as confirmed with histology.

II. Determine concordance and discordance of invasive lobular breast cancer (ILC) detection with PSMA versus fluciclovine PET, as confirmed with histology.

EXPLORATORY OBJECTIVE:

I. Establish the role of circulating tumor deoxyribonucleic acid (DNA) (ctDNA) directed to ESR1 and PI3K DNA in characterizing the degree of tumor burden as identified by metabolic amino acid transport and tumor neovasculature receptor imaging.

OUTLINE:

Patients receive gallium Ga 68-labeled PSMA-11 intravenously (IV) and undergo a PET/computed tomography (CT) scan over 30 minutes. On a separate day, patients receive fluciclovine F18 IV and undergo a PET/CT scan over 30 minutes.

After completion of study, patients are followed up in 5-10 business days, and then up to 5 years.

Arms: arm 1: Patients receive gallium Ga 68-labeled PSMA-11 IV and undergo a PET/CT scan over 30 minutes. On a separate day, patients receive fluciclovine F18 IV and undergo a PET/CT scan over 30 minutes.
Interventions: intervention 1: Computed Tomography intervention 2: Fluciclovine F18 intervention 3: Gallium Ga 68 Gozetotide intervention 4: Positron Emission Tomography
Intervention descriptions: intervention 1: Undergo PET/CT scan intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo PET/CT scan

Protocol documents:
Prot_SAP_001.pdf: 
 
Version 1.0;  Page 1 of 28; 29 July 2020
Winship Protocol: X
Improved staging of lobular breast cancer with novel amino acid 
metabolic and tumor neovasculature receptor imaging
PI: David Schuster, MD. Professor and Director, 
Division of Nuclear Medicine and Molecular Imaging
Department of Radiology and Imaging Sciences
Emory University Hospital, Room E152
1364 Clifton Road, Atlanta, GA 30322
404-712-4859; dschust@emory.edu
Co-Investigators:
Sarah Friend, MD
Assistant Professor, 
Department of Hematology and Medical Oncology
Emory University; sarah.c.friend@emory.edu
Manali Bhave, MD 
Assistant Professor,
Department of Hematology and Medical Oncology
Emory University; manali.ajay.bhave@emory.edu
Mylin A Torres, MD
Associate Professor
Louisa and Rand Glenn Family Chair in Breast Cancer Research
Department of Radiation Oncology; Emory University; matorre@emory.edu
Toncred Marya Styblo, MD, MS, FACS
Associate Professor, 
Chair, Emory Integrated Cancer Network
Division of Surgical Oncology, Department of Surgery
Emory University; tstyblo@emory.edu
Saima Muzahir, MD
Assistant Professor
Division of Nuclear Medicine and Molecular Imaging
Department of Radiology and Imaging Sciences
Emory University; saima.muzahir@emory.edu
Anna Holbrook, MD
Assistant Professor
Division of Breast Imaging
Department of Radiology and Imaging Sciences
Emory University;anna.holbrook@emory.edu
Jeffrey M. Switchenko, Ph.D. 
Research Assistant Professor, 
Department of Biostatistics & Bioinformatics, Rollins School of Public Health
Biostatistics & Bioinformatics Shared Resource, Winship Cancer Institute; jswitch@emory.edu
Funding Source: NIH. Applying for R21. Currently internal. 


 
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Table of Contents
1.1 Synopsis .............................................................................................................3
1.2 Schema ...............................................................................................................4
1.3 Schedule of Activities........................................................................................6
2.  Introduction .................................................................................................................7
2.1 Study Rationale....................................................................................................7
2.2 Background..........................................................................................................8
2.3 Potential Risks and Benefits ..............................................................................10
3. Objectives and Endpoints.........................................................................................12
3.1 Study Objectives: ...............................................................................................12
3.2 Study Endpoints:................................................................................................12
4. Study Design ..............................................................................................................13
4.1 Overall Design....................................................................................................13
4.2 Scientific Rationale for Study Design.................................................................14
4.3 Justification for Dose..........................................................................................14
4.4 End of Study Definition.......................................................................................14
5. Study Population........................................................................................................15
5.1 Inclusion Criteria ................................................................................................15
5.2 Exclusion Criteria ...............................................................................................15
6.  Registration Procedures ..........................................................................................16
7.  Study Intervention.....................................................................................................16
7.1 Study Specific Experimental Procedures...........................................................17
8. Study assessments and Procedures. ......................................................................18
8.1 Schedule of Procedures.....................................................................................18
9. Measurement of Effect...............................................................................................19
10. Statistical considerations.........................................................................................20
11. Adverse Events:  List and Reporting Requirements..............................................20
12. Data Reporting / Regulatory Requirements............................................................23
13. Ethics and Protection Of Human Subjects .............................................................23
14. References .................................................................................................................25
APPENDIX A   Abbreviations and definition of terms ........................................27


 
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1.1 Synopsis
Invasive lobular breast cancer (ILC) accounts for approximately 10-15% of breast malignancies [1]. ILC 
has a distinct histology and discohesive growth which makes it difficult to visualize with current imaging 
modalities such as mammography, ultrasound and breast and whole body MR. Suboptimal imaging 
adversely impacts accurate staging upon which therapeutic decisions are based [2]. The metastatic 
pattern of ILC also differs from that of invasive ductal carcinoma (IDC) with a tendency to involve the 
gastrointestinal tract, genitourinary tract, peritoneum, retroperitoneum and leptomeninges. While 
fluorodeoxyglucose (FDG) PET has been shown to clinically upstage patients with locally advanced IDC, 
this is not so with ILC, which has been described as “initially indolent but slowly progressive”. There are 
currently no accurate imaging techniques for staging ILC. Our goal is to address an unmet public 
health need by improved staging of ILC, specifically detection of metastatic disease. 
Amino acid transporters are upregulated in breast cancer cells [3]. We and others have 
successfully imaged breast cancer with fluciclovine (18F) PET, an FDA approved synthetic amino acid 
radiotracer originally developed at Emory for imaging of cerebral glioma and prostate cancer. In 
exploratory studies conducted at Emory and Memorial Sloan Kettering in 39 women with breast cancer 
(13 patients with ILC), fluciclovine PET demonstrated promising results in detection of ILC in primary 
tumors and locoregional metastases [4-6]. Distant disease was not studied. Post-hoc RNA sequencing 
of the Emory cohort reveals that numerous molecular signaling pathways correlate with fluciclovine 
uptake including PI3K/Akt signalling, which mediates a range of biological endpoints necessary for 
cancer growth including cell survival, apoptosis, autophagy, cell cycle progression and angiogenesis. 
Since the pro-angiogenic factor VEGF contributes to Akt activation to improve oxygenation and 
nutrient supply to areas of poor vascularization, attention has turned to neoangiogenesis as an imaging 
biomarker for breast cancer. A different PET radiotracer in clinical trials for prostate cancer, prostate 
specific membrane antigen (PSMA) may also detect breast cancer due to the upregulation of PSMA 
receptors in tumor angiogenesis. Prostate-specific is actually a misnomer as PSMA receptors are 
upregulated in tumor neovasculature in many cancers including breast cancer. Evolving data suggests 
PSMA radiotracers may also have utility in breast cancer, including ILC [7-11].  
Our preliminary data support a key scientific premise that metabolic imaging with fluciclovine (18F) 
PET has shown promise in the detection of ILC. There is also emerging data that tumor neovasculature 
imaging with PSMA PET may improve detection of ILC. We hypothesize that amino acid transport 
metabolic imaging with fluciclovine (18F) PET will improve staging of ILC, particularly for distant 
metastases, compared to conventional imaging. We also hypothesize that receptor directed 
PSMA imaging of tumor associated neovasculature in ILC will reveal unique information to 
complement metabolic interrogation with fluciclovine PET. Improved staging will facilitate more 
appropriate management decisions.
To test these hypotheses with the highest scientific rigor, we propose an early phase feasibility 
trial with fluciclovine and PSMA PET strategies centered on detection of metastasis in patients with 
advanced ILC using histology as the gold standard. As an exploratory aim, we will also correlate the 
occurrence of circulating tumor DNA (ctDNA) directed against ESR1 and PI3K with presence of 
metastasis and tumor burden. We will explore if a multiparametric strategy with ctDNA and imaging will 
help define which patients should undergo molecular imaging and also identify those who may forego 
biopsy if distant lesions are detected on imaging. We expect this pilot trial will generate sufficient 
preliminary data to determine feasibility for a definitive NIH sponsored trial developing more accurate 
staging techniques to help modify current practice for imaging of ILC. 
Specific Aim 1: Improve detection of metastasis with fluciclovine and PSMA PET versus best 
standard of care conventional imaging, as confirmed with histology. We will image 20 patients with 
ILC who have either: a) clinical or imaging suspicion of metastatic disease; or b) proven metastatic 
disease but in whom there is suspicion of an even greater tumor burden that could change therapy 
approach. Abnormal foci which correlate to anatomic lesions previously unsuspected on conventional 
imaging will undergo optional biopsy as clinically indicated in the safest manner possible (if not already 
done) to determine the verified detection rate of metastatic disease.
Specific Aim 2: Determine concordance and discordance of ILC detection with PSMA versus 
fluciclovine PET, as confirmed with histology. We will compare verified detection rates for 
metastasis between fluciclovine and PSMA PET modalities. This may necessitate a second biopsy of a 


 
Version 1.0;  Page 4 of 28; 29 July 2020
distant lesion discordant between the 2 PET techniques. We will also analyze images for biodistribution 
in the primary lesion(s) for both radiotracers.
Exploratory Aim 3: Establish the role of molecular detection by ctDNA mutations including 
PIK3CA, ESR1, HER2, and AKT1 in characterizing the degree of tumor burden as identified by 
metabolic amino acid transport and/or tumor neovasculature receptor imaging [12]. We will collect 
peripheral blood for ctDNA in all patients and determine if ctDNA correlates with presence or absence of 
metastases and tumor burden as identified by fluciclovine (metabolic) and/or PSMA (angiogenesis) PET. 
1.2 Schema
We will undertake a single arm feasibility study with n=20 patients with treatment naïve biopsy proven 
ILC who have either: a) clinical or imaging suspicion of metastatic disease; b) biopsy proven metastatic 
disease but in whom there is suspicion of an even greater tumor burden that could change therapy 
approach. All patients will be recruited from the Winship Glenn Family Breast Cancer Program at any 
Emory facility and they will have already undergone best standard of care conventional imaging (CT or 
MR and possibly bone scan depending on clinical presentation). Standard of care conventional 
imaging typically does not include FDG PET, since FDG PET is not recommended for lobular 
cancer due to low sensitivity. We will then complete both fluciclovine PET and Ga PSMA PET scans 
on the same patient on separate days separated by at least 10 half-lives to allow for radioactive decay. 
There is no need for randomization since each patient will undergo both imaging techniques, and the 
results will be interpreted blindly. Thus, radiopharmacy scheduling will dictate the order of the radiotracers 
to ensure the patient will undergo both imaging modalities in the shortest time frame. Sometimes this will 
mean PSMA is completed first, followed by fluciclovine, and other times the opposite. After interpretation 
of both studies, careful correlation to already obtained conventional imaging will then be done to 
determine if a previously unsuspected anatomic correlate can be identified which would impact therapy. 
One or two metastases (depending on scan findings) will then undergo biopsy in the safest manner 
possible as standard of care (if not already done) to determine the verified detection rate of metastatic 
disease. Uncommonly, definitive imaging such as MR for skeletal or liver lesions may be accepted in lieu 
of biopsy, if biopsy is not feasible. We will then compare verified detection rate of each PET study to 
conventional imaging and to each other. In addition, we will collect peripheral blood for ctDNA in all 
patients and determine if ctDNA correlates with presence or absence of metastases and tumor burden 
as identified by conventional imaging, fluciclovine and/or PSMA PET. Study Specific Experimental 
Procedures will only consist of both PET studies and ctDNA analysis. All other procedures will be 
conducted per standard of care. See Figure 1.


 
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Figure 1: Trial Schema, Flow diagram 
 
Total 20:  Consent/ Screening and Enrollment.
Collect 20 cc peripheral venous blood
Pregnancy test as appropriate
Complete PSMA or fluciclovine (PET 1)
Follow-up assessments of study endpoints and safety
Phone call from study nurse (5-10 business days > PET)
Correlate PET scans to truth standard and conventional imaging.
Pregnancy test as appropriate
 Complete PSMA or fluciclovine (PET 2)
(i.e. If PSMA completed, patient then undergoes fluciclovine and vis versa)
Final Analysis
Compare verified detection rate of both PET scans to 
conventional imaging and to each other (Aims 1 and 2).
Correlate ctDNA with PET results and CI (Aim 3). 
Visit 1; Day 1
PET 1 
1-30 days >
Visit 2; Day 2
PET 2 
1-15 days > 


 
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1.3 Schedule of Activities
a Study intervention is either the PSMA or fluciclovine PET
b Pregnancy test within 24 hours prior to  each PET as applicable
c Uncommonly, definitive imaging such as MR for skeletal or liver lesions may be accepted in lieu of biopsy, if biopsy is not 
feasible.  
d Blood collection may also occur at other visit 
e There will be no further study specific visits beyond visit 2 (except for followup phone call from study nurse at 5-10 business 
days inquiring as to AE which does not require a “visit”). All further followup will be via medical record of subsequent history, 
biopsy/histology, imaging, etc. 
Procedures
Enrollment/
Screening (-60 days)
Study Visit 1
PET 1
(within 30 days of 
enrollment) 
Study Visit 2
PET2
(within 15 days of 
Visit 1)
Follow up e
(Up to 5 years)
Informed consent
X
Demographics
X
Medical history
X
X
Administer study intervention
X
X
Pregnancy test b
X
X
AE Assessment
X
X
Optional biopsy c
X
X
X
Follow medical history
X
Peripheral blood sample (ctDNA)d
X
Complete Case Report Forms 
(CRFs)
X
X
X
X


 
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2.  Introduction 
2.1 Study Rationale 
Lobular breast cancer is a lethal disease. It is difficult to detect and accurately stage, especially distant 
metastases. This difficulty is in part secondary to the discohesive growth pattern due to loss of E-cadherin 
which results in diffuse spread of cancer cells in atypical and sometimes unexpected patterns which may 
resemble inflammation. ILC may not demonstrate significant FDG uptake and also may be present in 
difficult to image locations such as peritoneum and central nervous system [2]. Thus, with ILC there may 
be significant understaging leading to inappropriate therapeutic decisions. Finally, since lobular breast 
cancer is not mass forming as is IDC, response to therapy may be difficult to evaluate. For these same 
reasons recurrent disease is difficult to detect with ILC, thus potentially limiting salvage therapy options. 
Therefore, the scientific justification for improved detection of metastatic disease is compelling.
Fluciclovine
Tumor glucose metabolism, specifically the shift away from oxidative phosphorylation to aerobic 
glycolysis (Warburg Effect), has formed the basis of advanced molecular imaging of breast cancer. Other 
metabolic activity upregulated in breast cancer includes use of amino acids. The amino acid transporters, 
specifically LAT1, ASCT2, ATB0,+ SNAT1 and XCT, are overexpressed in breast cancer and reported to 
be associated with tumor growth, metastasis and hormone receptor status [13-16]. Shennan and 
coauthors demonstrated that certain human breast cancer cell lines, MDA-MB-231 and MCF-7, express 
system L (large neutral amino acid) transporters [17, 18]. In fact, Shennan has also demonstrated that 
growth of cultured human breast cancer cells may be decreased via inhibition of system L transporters 
[14]. Fluciclovine is a synthetic amino acid analog PET radiotracer transported via system L (LAT1) and 
ASCT (ASCT2) and has shown promise in the imaging of prostate and other cancers [19]. Fluciclovine 
uptake has been shown in vitro in breast carcinoma cell lines as well as in animal models of breast cancer 
[16]. This has led to the study of amino acid transport as a basis for superior detection of breast cancer 
by our group. As noted in the preliminary data section of this proposal, we unexpectedly discovered that 
ILC was better detected with amino acid transport-based PET with fluciclovine compared to glycolytic 
based FDG PET. Preliminary studies understandably focused on the detection of primary and 
locoregional disease. We propose to expand this concept to also include detection of distant disease 
which could alter the stage of the patient and thus therapeutic approach. Improved initial staging and 
treatment selection could impact the survival of nearly 40,000 women with ILC per year, and potentially 
enhance the evaluation of therapy response in women living with metastatic ILC.
PSMA
PSMA receptors are upregulated in many cancers besides prostate cancer since tumor associated 
neovasculature has upregulated PSMA expression [8]. It is likely that PSMA cleavage of vitamin B9 (folic 
acid) stimulates oncogenic signaling through glutamate receptors with downstream activation of the PI3K-
Akt-mTOR signaling pathway [20]. Utilizing PSMA as a biologic marker of tumor neovasculature thus has 
a solid scientific underpinning and may yield significant biologic information in reference to lobular cancer. 
Many non-prostate 68Ga-PSMA avid malignancies have been reported in the literature including breast 
cancer, yet there is little information specifically on ILC [10]. Furthermore, if we can demonstrate that ILC 
is sufficiently PSMA avid, there is a possibility that a theranostic approach with Lu-177 PSMA 
radiotherapy may be investigated as is currently occurring with metastatic prostate cancer [21]. In fact, 
there has been one case report of metastatic IDC triple negative breast cancer treated with Lu-177 PSMA 
[11]. While 68Ga-PSMA is FDA approved for prostate cancer, it is not FDA approved for breast cancer. 
Ga-PSMA is currently produced at the Emory Center for Systems Imaging for an ongoing prostate cancer 
trial, and Dr. Schuster holds an IND allowing research applications.
ctDNA
The role of ctDNA specifically in regard to ILC has been little studied, especially the ability of ctDNA in 
predicting distant disease. The premise in this exploratory aim is specifically studying the association of 
ctDNA targeted to ILC with imaging that is more sensitive to ILC compared with FDG PET. If there is an 
association, this would be a significant area for future research since ctDNA expression could then be 
utilized to select patients who should undergo this advanced imaging or serve to improve specificity in 
lieu of confirmatory biopsy if the association with verified detection rate of metastasis was particularly 


 
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robust. Finally, understanding if this correlation is associated with upregulated amino acid metabolism 
and/or tumor neoangiogenesis as characterized by molecular imaging could yield valuable insights into 
the biologic behavior of ILC. 
2.2 Background
Invasive lobular carcinoma (ILC) comprises 10-15% of breast cancer. While mammography, ultrasound, 
breast MRI, and whole body FDG PET form the backbone of breast imaging, there are limitations in the 
imaging of lobular cancer histology, especially for distant disease (figure 1) [22, 23]. ILC is diagnosed at 
a later and more advanced stage compared with IDC and is typically hormone receptor positive [1]. Up 
to 50% of patients with the CDH1 genetic mutation will 
develop ILC [1]. The development of metastatic 
disease is likely facilitated by the loss of E-cadherin in 
most 
ILC 
cells 
[24]. 
Similarly, 
while 
(18F) 
fluorodeoxyglucose positron emission tomography 
(FDG-PET) has also assumed an important role in 
whole body staging, detection of recurrent disease 
and monitoring therapy response, limitations for 
lobular cancer are well described in the literature [2, 
25]. These limitations are secondary to indolent 
growth and diffuse growth patterns, making lobular 
cancer metastasis difficult to distinguish from 
background activity. In a study by Ulaner in 146 
patients with ILC, FDG PET had only a modest effect 
on upstaging and did not reveal additional nodal 
disease. Compared with IDC patients who were 
upstaged in 22% of cases to stage 4 in a separate cohort, only 6% of ILC patients had unsuspected 
distant metastasis that were FDG PET positive [26]. 
Fluciclovine
Due to the limitations of FDG PET for the staging of breast cancer in earlier studies, we have investigated 
molecular imaging targeting other aspects of the metabolome [27, 28]. Amino acids are involved in many 
aspects of human nutrition including the synthesis of proteins. Amino acid metabolism has been 
demonstrated to be upregulated in many tumors [13]. Since amino acid metabolism is also upregulated 
in breast cancer, molecular imaging utilizing natural or synthetic amino acid radiotracers is an attractive 
approach [28, 29]. Emory University is a center of innovation for amino acid transport PET imaging, 
having developed anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F]FACBC or 
fluciclovine), a synthetic amino acid analog PET radiotracer, which was subsequently FDA approved for 
restaging of prostate cancer [30]. Liang reported fluciclovine uptake in breast carcinoma cell lines which 
correlated with malignant potential as well as in orthotopic MDA-MB-231 breast carcinoma xenografts 
[16]. With funds from a Winship Glenn Family Breast Center Pilot Grant in 2014-2015, we studied uptake 
characteristics of fluciclovine in breast carcinoma, confining the study to evaluation of the primary breast 
lesions and locoregional disease. 
A total of 12 patients with 13 primary lesions were studied at Emory [5]. At diagnosis, 9/12 patients 
had primary breast cancer while 3/12 had local recurrence. Of the malignant lesions, there were 7/13 
invasive ductal carcinoma (IDC), 5/13 invasive lobular carcinoma (ILC) and 1/13 invasive metaplastic 
carcinoma with sarcomatous differentiation (IMC). Histologic sampling occurred in 9 locoregional lymph 
nodes (4 benign and 5 malignant). Of the malignant nodes, 3 were ILC and 2 were IDC. Although 
fluciclovine uptake in IDC and ILC were both higher than in benign breast lesions, IDC had higher uptake 
than ILC in the primary tumor. However, this was reversed with nodal disease in which metastatic 
ILC nodes had higher uptake than IDC nodes (ILC mean SUVmax (±SD) of 6.2±0.8; IDC mean 
SUVmax of 3.3±2.6). Interestingly, uptake by fluciclovine in ILC locoregional metastatic disease 
was also greater than uptake in the primary lesion. Figure 2 is an example of a patient with ILC who 
had fluciclovine uptake in a known primary breast lesion and a biopsy proven metastatic axillary node 
reported negative on outside MR and ultrasound. 
Figure 1
Subtle mesenteric infiltration (arrow) 
missed on PET/CT, biopsy proven 


 
Version 1.0;  Page 9 of 28; 29 July 2020
Four patients also underwent clinical FDG PET-CT. Fluciclovine and FDG activity were compared in 8 
biopsy proven lesions (5 malignant and 2 benign primary, 1 node). The malignant lesions included 3 IDC, 
2 ILC and 1 IMC. For ILC, mean SUVmax was 4.6 (±3.5) with fluciclovine compared to 2.6 (±1.0) for 
FDG. This finding was surprising and intriguing since uptake was greater in ILC with fluciclovine 
PET than with FDG. Figure 3 is an example of greater uptake in an ILC intramammary nodal metastasis 
with fluciclovine than with FDG PET-CT. 
In our pilot study, we unexpectedly discovered greater uptake in ILC with fluciclovine than 
with FDG PET, and greater uptake with fluciclovine in metastasis versus the primary lesion, and 
this observation was not limited to our center. Simultaneously, fluciclovine PET was also being 
studied in breast cancer by the Ulaner Group at Memorial Sloan Kettering. Results were published in the 
same issue of the Journal of Nuclear Medicine as our paper along with an accompanying editorial [6, 31]. 
In that series 27 women with locally advanced IDC (n = 19) or ILC (n = 8) underwent fluciclovine PET/CT. 
All primary tumors were radiotracer avid. Fluciclovine PET detected 20/21 patients with axillary nodal 
metastases and also detected pathologically proven extraaxillary nodal disease in 3 patients, including 2 
previously unsuspected internal mammary nodes. In the 4 patients with ILC who underwent FDG and 
fluciclovine PET, primary ILCs demonstrated fluciclovine avidity (median SUVmax, 6.1; range, 4.5–10.9) 
greater than FDG avidity (median SUVmax, 3.7; range, 1.8–6.0). Thus, in total from both cohorts, 13 
patients with ILC were studied. There was greater uptake in ILC lesions on fluciclovine versus FDG 
PET. And while IDC had greater fluciclovine uptake than ILC in the primary breast lesion; in nodal 
metastases, this relationship reversed and ILC in nodal disease had greater fluciclovine uptake 
than IDC. Furthermore, ILC nodal metastasis had greater fluciclovine uptake than in the primary 
ILC breast lesion. ILC also seems to have better correlation with complete metabolic response to 
neoadjuvant chemotherapy as reported in a separate study [4]. Critically, since these were pilot 
studies, only images of the thorax were obtained. Detection of distant disease was not studied. 
Our proposed trial will specifically address the detection of distant disease and locoregional 
staging.   
PSMA
Prostate specific membrane antigen (PSMA) is a Type 2 transmembrane glycoprotein of the M28 
peptidase family and is overexpressed on the cell surface of prostate cancer [32]. The name prostate-
specific is a misnomer, since other cancers including breast cancer have upregulated PSMA receptors 
due to tumor angiogenesis. Most data regarding PSMA PET with breast cancer pertains to IDC. Wernicke 
studied 92 samples in 106 patients with breast cancer [7]. Immunohistochemistry (IHC) for tumor 
associated vascular endothelial cell PSMA receptors revealed staining in 74% of primary and 100% of 
brain metastasis. There was absence of PSMA staining in 98% of normal breast tissue. Wernicke noted 
there was no difference between PSMA staining for IDC and ILC, yet only 10 ILC samples were included. 
In another study of 72 patients with breast cancer, moderate to strong tumor associated neovasculature 
PSMA staining was present in 67% of distant metastasis versus 36% in primary tumor cells [9]. Yet, only 
12 ILC patients were included and it was not clear if these patients had metastases. In a study of 315 
A
B
Figure 3. Coregistered fluciclovine [A] and 
FDG [B] PET-CT in a 54 yr old woman with a 
2.1cm x 1.1cm right ILC. Fluciclovine [A] had 
higher uptake (SUVmax = 7.1) compared to 
FDG [B] (SUVmax = 3.3) in metastasis to an 
intramammary node (arrows).
A
B
Figure 2. CT [A] and coregistered fluciclovine 
PET-CT [B] in a 49 yr old woman with left ILC. 
SUVmax = 3.5 in the primary mass (short 
arrow) and 5.6 in biopsy proven metastasis to 
a 6 x 11mm left axillary lymph node (long 
arrow).


 
Version 1.0;  Page 10 of 28; 29 July 2020
cases by Tolkach of which 64 tumors were ILC, 64.6% of patients with IDC had PSMA staining, versus 
42.2% of those with ILC [11]. Finally, in one of the few imaging studies, Sathekge reported in 81 lesions 
in 19 breast carcinoma patients that PSMA PET visualized 84% of lesions; yet again, only 2 ILC patients 
were included in this cohort. In a major review in the Journal of Nuclear Medicine, Salas-Fragomeni 
argues “this potential application of PSMA-targeted imaging in breast cancer should perhaps be most 
urgently explored, as the need for reliable agents for systemic staging in lobular breast cancer has been 
long-standing” [8]. Our study will address this urgent question, that of the utility of PSMA PET explicitly 
for ILC metastatic disease, as well as that of fluciclovine PET for ILC. 
ctDNA
The absolute number of circulating tumor cells has been associated with metastatic breast cancer [33, 
34]. A more refined technique, that of circulating tumor DNA (ctDNA), holds promise as a “liquid biopsy,” 
since tumor DNA circulating in the blood is more specific for carcinoma. High levels of ctDNA are reported 
to correlate with tumor size, lymph node involvement, histopathological grade, and clinical staging [35-
40]. Though there have been anecdotal reports of ctDNA and ILC or inclusion of a small number of ILC 
related ctDNA in a larger study, ILC has not been systematically studied [41]. Probing the association of 
ctDNA to tumor burden in ILC with two novel imaging biomarkers (amino acid transport/fluciclovine and 
angiogenesis/PSMA) with more sensitivity than FDG PET for ILC will provide biologic insights in the 
context of this exploratory aim.  
2.3 Potential Risks and Benefits
Benefits:
The primary benefit of participation in this study is more accurate identification of metastatic disease 
which may impact appropriate staging and therapy decisions. If occult metastasis are present but are not 
identified on conventional imaging this would lead to understaging and possible futile curative therapy. 
On the other hand, if conventional imaging identifies metastasis which are in fact false positive for 
neoplasia, and which could have been more definitively characterized by molecular imaging, this may 
lead to overstaging and inappropriate withholding of curative therapy. 
Study Specific Procedure Risks:
1) Radiation Risks: The principal risk associated with a radiation dose is the possibility of developing a 
radiation-induced cancer later in life. However, the additional risk of radiation-induced cancer from these 
diagnostic procedures is low compared to the risks from the disease itself as well as systemic therapy or 
radiation therapy. 
Human dosimetry data for fluciclovine from FDA package insert: The (radiation absorbed) effective dose 
resulting from the administration of the recommended activity of 370 MBq (10 mCi) of fluciclovine is 8 
mSv (22 microSv/MBq). For an administered activity of 370 MBq (10 mCi), the highest-magnitude 
radiation doses are delivered to the pancreas, cardiac wall, and uterine wall: 38 mGy, 19 mGy, and 17 
mGy, respectively. 
Human dosimetry data for Ga-PSMA from Joint EANM and SNMMI Procedure Guideline for Prostate 
Cancer Imaging: Version 1.0 [42]. Based on the available studies, the coefficient for effective dose from 
68Ga-PSMA averages is 2.0 × 10−2 mSv/MBq, resulting in an average effective radiation dose of 3 mSv 
for an administered activity of 150 MBq. For a typical dose of 5 mCi (185 MBq) that we will be 
administering, the effective dose equivalent would be 3.7 mSv. The organs with the highest dose are 
urinary bladder wall (0.13-0.173 mSv/MBq) and kidney (0.122-0.262 mSv/MBq).
2) Allergic or other reactions to radiotracer: Although the risk is extremely small, it is possible to develop 
an allergic reaction to the fluciclovine or Ga-PSMA.  This can result in hives, rash, itching and difficulty 
breathing which may require emergency medical treatment. There have been no previous instances of 
allergic reaction. In prior studies with both radiotracers, the risk of adverse events which can be attributed 
to the radiotracer is extremely low, and of minimal medical impact such as burning at IV site or dysgeusia. 


 
Version 1.0;  Page 11 of 28; 29 July 2020
3) Risk related to IV for PET scan: A small amount of radioactive material will be injected by either a 
hand-held needle or a machine. Such injections are generally quite safe, but any injection involves some 
risks. The injection could harm a nerve, artery or vein, or cause infection. The radioactive material could 
also leak from veins, causing swelling and discomfort. 
4) False positive on PET: It is possible that a lesion identified on the experimental PET procedures may 
be false positive, thus potentially leading to an inappropriate change in stage. Yet, no lesion will be acted 
upon which could change therapeutic intent unless confirmed via histology or advanced imaging such as 
MR for certain bone lesions. See below for risks associated with biopsy or MR. 
Non-Study Specific Procedure Risks:
1) Biopsy associated risk: If a suspect lesion is identified on either or both PET scans, definitive histologic 
proof in the safest manner possible will be sought if clinically indicated. Risks of biopsy, though small in 
expert hands, include bleeding, infection and even rarely death. Note that before biopsy is considered, 
careful scrutiny of the already obtained CT or MR will be undertaken to determine if an unsuspected 
anatomic correlate can be identified. This will then prompt a discussion between the patient and primary 
clinician on the benefits versus risks to definitively determine if a metastasis is present which could affect 
therapy. Biopsy will be undertaken in the least invasive manner possible as a standard of care procedure, 
reimbursed by third party payers.  
2) MR: If a lesion is not deemed safe or possible to biopsy, MR may then be performed (e.g. for bone or 
liver). MR, even with the administration of Gadolinium is considered a safe and effective noninvasive 
imaging procedure. In addition to the small possible reactions to contrast material if used, claustrophobia 
while in the magnet is a potential risk, as well as reaction from metal within the body. Yet at Emory, 
special screening is performed before MR to determine if the patient has tattoos or any metal items in 
the body such as implants, pacemakers, clips or shrapnel, to make sure the MRI scan is done safely.


 
Version 1.0;  Page 12 of 28; 29 July 2020
3. Objectives and Endpoints
3.1 Study Objectives:
Our major goal in this proposed investigation is to use advanced molecular imaging to better 
detect metastases in patients with invasive lobular cancer. 
Specific Aim 1: Improve detection of metastasis with fluciclovine and Ga-PSMA PET versus best 
standard of care conventional imaging, as confirmed with histology. We will image 20 patients with 
ILC who have either: a) clinical or imaging suspicion of metastatic disease; or b) proven metastatic 
disease but in whom there is suspicion of an even greater tumor burden that could change therapy 
approach. Abnormal foci which correlate to anatomic lesions previously unsuspected on conventional 
imaging will undergo optional biopsy as clinically indicated in the safest manner possible (if not already 
done) to determine the verified detection rate of metastatic disease.
Specific Aim 2: Determine concordance and discordance of ILC detection with Ga-PSMA versus 
fluciclovine PET, as confirmed with histology. We will compare verified detection rates for 
metastasis between fluciclovine and PSMA PET modalities. This may necessitate a second biopsy of a 
distant lesion discordant between the 2 PET techniques. We will also analyze images for biodistribution 
in the primary lesion(s) for both radiotracers.
Exploratory Aim 3: Establish the role of molecular detection by ctDNA mutations including 
PIK3CA, ESR1, HER2, and AKT1 in characterizing the degree of tumor burden as identified by 
metabolic amino acid transport and/or tumor neovasculature receptor imaging [12]. We will collect 
peripheral blood for ctDNA in all patients and determine if ctDNA correlates with presence or absence of 
metastases and tumor burden as identified by fluciclovine (metabolic) and/or PSMA (angiogenesis) PET. 
3.2 Study Endpoints:
Primary endpoint: 
Determine verified detection rate for metastasis of invasive lobular cancer using fluciclovine PET 
and PSMA PET for imaging (Specific Aims 1 and 2)
Secondary endpoints: 
Correlation of ctDNA results with presence or absence of metastasis (Specific Aim 3)
Correlation of ctDNA results with results of imaging (Specific Aim 3)


 
Version 1.0;  Page 13 of 28; 29 July 2020
4. Study Design
4.1 Overall Design
We will undertake a study with 20 patients with treatment naïve biopsy proven ILC who have either: a) 
clinical or imaging suspicion of metastatic disease; b) biopsy proven metastatic disease but in whom 
there is suspicion of an even greater tumor burden that could change therapy approach. All patients will 
be recruited from the Winship Glenn Family Breast Cancer Program at any Emory facility. All patients will 
undergo Ga PSMA PET followed at minimum of 10 hours (to allow for radiotracer decay) by fluciclovine 
PET. (This may also happen in the opposite order, in which case 20 hours after fluciclovine will be needed 
to allow for decay.) There is no need for randomization since each patient will undergo both imaging 
techniques, and the results will be interpreted blindly. Thus, radiopharmacy scheduling will dictate the 
order of the radiotracers to ensure the patient will undergo both imaging modalities in the shortest time 
frame. Two nuclear medicine physician co-investigators, Drs. Schuster and Muzahir, will independently 
interpret the 20 cases, each reading half (the other reading the other half) of the fluciclovine and PSMA 
images (to avoid bias in always reading the same type of imaging). The readers will be blinded to all 
imaging including the other PET. All suspicious lesions with nonphysiologic activity above background 
for locoregional spread and distant disease will be identified and rated for suspicion of malignancy on a 
6 point Likert scale (where 1 = definitely benign and 6 = definitely malignant). Both the primary lesion and 
all suspected metastases will be measured on an advanced workstation and metabolic uptake 
parameters (SUV, MTV, TLA) recorded. After both studies have been interpreted blindly, the third nuclear 
medicine physician co-investigator, Dr. Ulaner, will blindly interpret deidentified PET studies on every 
patient (alternating for a total of 10 each fluciclovine and Ga-PSMA PET). Afterward, an unblinded 
reconciliation interpretation will take place with all 3 readers. To ensure balance, 10 of the studies will be 
reviewed for consensus first showing Ga-PSMA, then fluciclovine; 10 of the studies will be reviewed in 
the opposite manner. In this manner, a preliminary sense of kappa can be developed between the third 
and the other 2 readers, yet will guarantee the highest degree of patient care as there are currently no 
validated criteria for interpreting fluciclovine or PSMA PET for breast cancer. This approach will help us 
adapt existing prostate specific criteria to that of breast cancer. Concordant and discordant lesions 
between each PET study and conventional imaging will be reported and potential biopsy sites, if any, 
recommended. The most distant and accessible lesion may undergo biopsy in the safest manner possible 
(if not already done) as clinically indicated after discussion between the primary oncologist and patient. 
Preference for biopsy will be given to discordant lesions. Uncommonly, in some lesions not deemed safe 
to biopsy, characteristic appearance on correlative imaging will be accepted as truth (e.g., MRI for certain 
skeletal or liver lesions). In select cases, a second biopsy of a discordant distant lesion may be required. 
For example, if there are 2 potentially impactful lesions which are fluciclovine positive/PSMA negative 
and fluciclovine negative/PSMA positive, respectively. Note that before biopsy is considered, careful 
scrutiny of the already obtained CT or MR will be undertaken to determine if an unsuspected anatomic 
correlate can be identified. This will then prompt a discussion between the patient and the referring 
clinician co-investigator on the benefits versus risks to definitively determine if a metastasis is present 
which could affect therapy. Biopsy may be undertaken in the least invasive manner as standard of care 
as clinically indicated, reimbursed by third party payers. Uptake parameters will be correlated with all 
proven primary, locoregional, and distant lesions. Verified detection rates for metastasis will be calculated 
for each modality. 
In addition, we will collect 20 ml peripheral blood for ctDNA analysis in all patients at visit 1 (or possibly 
2) to be initially processed and stored by Dr. Torres’ lab for off-site specialty analysis. Plasma levels of 
ctDNA will be measured using a targeted 28 gene panel to detect point mutations including mutations in 
PIK3CA, ESR1, HER2, and AKT1, genes associated with hormone therapy resistance and ILC [38, 39]. 
We will examine ctDNA results for association with presence or absence of locoregional metastasis on 
imaging as confirmed with histology, presence or absence of distant metastasis on imaging as confirmed 
with histology, correlation of presence or absence and absolute ctDNA with PET uptake.


 
Version 1.0;  Page 14 of 28; 29 July 2020
4.2 Scientific Rationale for Study Design
Our preliminary data support a key scientific premise that metabolic imaging with amino acid PET has 
shown promise in the detection of ILC. There is also emerging data that tumor neovasculature imaging 
with PSMA PET may improve detection of ILC. We hypothesize that metabolic imaging with amino 
acid transporter PET will improve staging of ILC, particularly for distant metastases, compared to 
best standard of care conventional imaging (usually CT or MR and possible bone scan), and which 
typically does not include FDG PET due to low sensitivity. We also hypothesize that receptor 
directed PSMA imaging of tumor associated neovasculature in ILC will reveal unique information 
to complement metabolic interrogation with fluciclovine PET. Improved staging will facilitate 
more appropriate management decisions.
To test these hypotheses with the highest scientific rigor, we propose a feasibility trial with 
fluciclovine and Ga-PSMA PET strategies centered on detection of metastasis in patients with advanced 
ILC using histology as the gold standard. As an exploratory aim, we will also correlate the occurrence of 
circulating tumor DNA (ctDNA) mutations including PIK3CA, ESR1, HER2, and AKT1 with presence of 
metastasis and tumor burden. We will explore if a multiparametric strategy with ctDNA and imaging will 
help define which patients should undergo molecular imaging and also identify those who may forego 
biopsy if distant lesions are detected on imaging. We expect this pilot trial will generate sufficient 
preliminary data to determine feasibility for a definitive NIH sponsored trial developing more accurate 
staging techniques to help modify current practice for imaging of ILC.
4.3 Justification for Dose
The doses administered for each radiotracer: 10 mCi fluciclovine (18F) and 5 mCi for Ga PSMA are based 
upon well established guidelines referenced below. 
4.4 End of Study Definition
The study will be closed to accrual once all 20 patients have been recruited and scanned with PET. End 
of analysis will occur once sufficient followup data has been collected for each patient to determine study 
endpoints. Study will be formally closed once all manuscripts have been published. Though it is likely 
most relevant standard of care followup will be acquired within 1 year, patients will be consented for 5 
year followup through the medical record in the case of future required analysis. There will be no other 
study specific visits after the second PET scan (visit 2), though the patient will be called by the study 
nurse at 5-10 business days to ensure no delayed AEs occurred. 


 
Version 1.0;  Page 15 of 28; 29 July 2020
5. Study Population
Approximately 1400 breast cancer patients are seen yearly at Winship, with approximately 20% of lobular 
histology (280). Of these, approximately 100-150 are advanced. Thus at a conservative recruitment rate 
of 10% (10-15 patients/year), successful accrual is highly feasible. Lobular cancer tends to present at a 
higher stage. Based on historical averages, we expect that 31% of patients will present with Stage 3 and 
37% of patients with Stage 4 disease. We expect approximately 10% dropout either before completion 
of both PET scans or after PET scanning and before biopsy. 
5.1 Inclusion Criteria
___(Y) 1. Treatment naïve biopsy proven ILC Patients with ILC 
___(Y) 2. Either: a) clinical or imaging suspicion of metastatic disease; or b) proven metastatic disease 
but in whom there is suspicion of an even greater tumor burden that could change therapy approach.
___(Y) 3. Ability and willingness to undergo biopsy if needed per standard of care for possible metastasis 
which could change therapy approach.  
___(Y) 4. Age over 18
Non-English-speaking patients may be considered for enrollment in this trial. Subjects with 
Limited English Proficiency LEP may be enrolled and study team members will use Emory IRB 
approved short forms to conduct the consent process.
5.2 Exclusion Criteria
___(N) 1. Pregnancy. Qualitative or quantitative serum or urine pregnancy test will be done in women of 
childbearing potential within 24 hours before PET1.  
1 A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (if age 
> 55 years);  if the female subject is < 55 years and she has been naturally postmenopausal for  > 1 year her 
reproductive status has to be verified by additional  lab tests ( < 20 estradiol OR estradiol < 40 with FSH > 40 in 
women not on estrogen replacement therapy).


 
Version 1.0;  Page 16 of 28; 29 July 2020
6.  Registration Procedures
Informed consent is required prior to participation in the study. Patients will sign the written informed 
consent, if possible, at the time of enrollment. In instances where this is not possible, verbal informed 
consent will be first obtained in order to instruct the patient to fast in preparation for the fluciclovine PET 
scan (not required for PSMA). However final written informed consent will be obtained before the PET 
scan. Participants will also be assigned an identification number for screening purposes; data collected 
during the screening process will also be recorded using that number. Patients will then be registered in 
OnCore through usual Winship and department of Radiology and Imaging Sciences guidelines. No 
randomization will be performed. Blinding will only take place for initial study interpretation before 
consensus interpretation by Nuclear Medicine imagers. 
7.  Study Intervention
Radiotracer production: Blue Earth Diagnostics, Ltd manufacturers of fluciclovine has pledged support 
with gratis radiotracer unit doses supplied from PETNET Solutions. 
Telix Pharmaceuticals (US) Inc, manufacturer of Ga-PSMA, has pledged support with gratis radiotracer 
kits which will be compounded by the Emory CSI radiopharmacy. 
Fluciclovine
PETNET Solutions, located on the Emory campus, produces commercial doses of fluciclovine which is 
FDA-approved for the detection of recurrent prostate cancer.  Unit doses of this material will be provided 
for the study. The IRB has decided that a formal IND exemption is not required. 
The following is provided as justification for IND exemption: This is an early phase study in which 20 
female patients will undergo fluciclovine and PSMA PET on separate days. We have already studied 12 
female patients with fluciclovine in the past for breast cancer under an Emory IRB approved protocol 
without safety concerns. At the time, the fluciclovine radiotracer was manufactured at the Emory CSI 
radiopharmacy under Dr. Schuster’s existing IND 072437. Yet, we will now be administering FDA 
approved commercial doses supplied by the commercial radiopharmacy PETNET to which our IND would 
not be applicable. Thus, this is off-label research of an FDA approved product for recurrent prostate 
cancer. The patient will undergo pregnancy testing within 24 hours before PET as appropriate per 
Winship and Radiology regulations. Note also that 27 women had also been studied for this indication at 
Sloan Kettering in the past without complication. Three female normal volunteers and a number of other 
female patients with other cancers have been studied with fluciclovine under our IND without complication 
and this data had been used to obtain FDA approval in terms of safety. Thus, we believe an IND 
exemption is in order since: 1) The investigation is not intended to be reported to FDA as a well-controlled 
study in support of a new indication for use nor intended to be used to support any other significant 
change in the labeling for the drug; 2) The drug that is undergoing investigation is lawfully marketed as a 
prescription drug product, and the investigation is not intended to support a significant change in the 
advertising for the product; 3) The investigation is conducted in compliance with the requirements 
concerning the promotion and sale of drugs; 4) The investigation is conducted in compliance with the 
requirements for IRB review and informed consent; 5) The investigation does not intend to invoke 21 
CFR 50.24, a waiver of informed consent in an emergency room setting.
PSMA
68Ga-PSMA will be produced under Dr. Schuster’s IND #143137 via a lyophilized kit produced by Telix 
Pharmaceuticals. Briefly, 68Ga will be eluted from our Eckerd and Ziegler 50 mCi Pharmaceutical Grade 
68Ge/68Ga Generator (or equivalent) located at our in-house radiopharmacy and combined in a vial with 
the premixed lyophilized product including peptide. Our existing PSMA IND #143137 has been amended 
with the study protocol. 


 
Version 1.0;  Page 17 of 28; 29 July 2020
7.1 Study Specific Experimental Procedures
A. Imaging (PET acquisition)
Note that this order may be reversed in certain patients depending on patient and radiopharmacy 
schedule.
PSMA
Patients will undergo PSMA PET-CT after 5 mci (3-7 mCi) IV dose of 68Ga-PSMA. Then after an uptake 
period of approximately 60 minutes, the patient will be encouraged to void. A PET-CT will then be 
completed from pelvis to skull base at approximately 5 minutes per bed position. Fasting is not required 
for this study. 
Fluciclovine
On a separate day to allow for radiotracer decay, and within 15 days of PET Visit 1, a fluciclovine PET-
CT at approximately 4 min post IV injection of 10 mCi fluciclovine will be completed from pelvis to skull 
base at approximately 3 minutes per table position. Fasting except for water (and medications) will be 
required for at least 4 hours before the PET scan. 
B. Circulating Tumor DNA
Step #1 - Blood Draw will typically occur on day of first PET scan. 
1.
20ml of peripheral blood (or two 10 ml Cell-Free DNA BCT Streck tubes) is collected by any 
standard phlebotomy technique from a peripheral access point or from a central line by trained 
personnel.
2.
Tubes are inverted about 10 times immediately after collection.
3.
Samples are then prepared for transportation to the laboratory for processing (within 24 hours).
Step #2 - Plasma Processing (in Laboratory)
1.
Perform this step once for each patient: transfer 1 mL whole blood with a pipette to a pre-labeled 
2 mL cryogenic vial, round bottom, self-standing. This 1 ml will be stored frozen per below as a 
backup sample. Then the remainder gets processed as following. 
2.
Streck tubes are centrifuged at room temperature for 10 min at 1600 (±150) g.
3.
After centrifugation, remove tubes from centrifuge and transfer supernatant of the Streck tubes to 
one fresh 10 ml polypropylene centrifuge tube without disturbing the cellular layer using a 
disposable serological pipette or disposable bulb pipette. 
4.
Centrifuge the plasma in the 10 ml centrifuge tube at room temperature for 10 min at 3000 (±150) 
g.  
5.
After centrifugation, remove tubes from centrifuge and transfer supernatant to a fresh 10 ml 
centrifuge tube without disturbing the cellular layer using a disposable serological pipette or 
disposable bulb pipette. After transferring the plasma to a new 10 ml centrifuge tube as described, 
gently mix plasma and record total plasma volume (~8-10 ml plasma per 20 ml blood).
6.
Transfer 1 ml plasma aliquots with a pipette to 2 ml pre-labeled cryogenic vials.
7.
Place plasma tubes into storage box and freeze plasma in freezer upright in storage box at -80°C 
or colder. Six-hour time storage at -20°C is possible.


 
Version 1.0;  Page 18 of 28; 29 July 2020
Step #3 - Specimen Storage
1.
Sample are maintained continuously at -80°C or colder.
2.
When outside the freezer, such as when transferring to a different freezer in another location or 
preparing for shipment, boxes containing tubes should be covered with dry ice.
3.
Freezer or dry ice specimen storage container temperature must be checked and monitored. 
Document any deviation from protocol.
4.
The freezer or dry ice storage box containing the specimens will either be locked or in a secure 
area accessible only to authorized study staff.
5.
A backup storage plan will be in place in the event of freezer failure.
8. Study assessments and Procedures.
8.1 Schedule of Procedures
See above schedule of activities in Section 1.3 for study specific experimental procedures.
Standard of Care Procedures
1) Conventional imaging is broadly defined as mammography, ultrasound, bone scan, FDG PET, CT 
and/or MR: Any or all of these imaging studies may have been performed as standard of care at 
enrollment. These are not under control of study design. Conventional imaging and reports within 6 
months of enrollment (ideally 2 months) will be reviewed to correlate to PET imaging. No additional 
interpretation will take place. Imaging reports for these studies will be utilized for comparative analysis. 
2) Biopsy: After the PET studies, patients with abnormal findings on the PET scans will have the most 
distant and accessible lesion identified so that the patient may undergo biopsy in the safest manner 
possible (if not already done) as clinically indicated. Preference for biopsy will be given to discordant 
lesions. In some lesions not deemed safe to biopsy, characteristic appearance on correlative imaging will 
be accepted as truth (e.g., MRI for certain skeletal or liver lesions). In select cases, a second biopsy of a 
discordant distant lesion may be required. Note that before biopsy is considered, careful scrutiny of the 
already obtained CT or MR will be undertaken to determine if an unsuspected anatomic correlate can be 
identified. This will then prompt a discussion between the patient and the referring clinician co-investigator 
on the benefits versus risks to definitively determine if a metastasis is present which could affect therapy. 
Biopsy will be undertaken in the least invasive manner as standard of care, reimbursed by third party 
payers.
3) Therapy: All subsequent therapy for breast cancer will be standard of care and beyond the scope of 
this investigation. 


 
Version 1.0;  Page 19 of 28; 29 July 2020
9. Measurement of Effect
Image Analysis: Two nuclear medicine physician co-investigators, Drs. Schuster and Muzahir, will 
independently interpret the 20 cases, each reading half (the other reading the other half) of the fluciclovine 
and PSMA images (to avoid bias in always reading the same type of imaging). The readers will be blinded 
to all imaging including the other PET. All suspicious lesions with nonphysiologic activity above 
background for locoregional spread and distant disease will be identified and rated for suspicion of 
malignancy on a 6 point Likert scale (where 1 = definitely benign and 6 = definitely malignant). Both the 
primary lesion and all suspected metastases will be measured on an advanced workstation and metabolic 
uptake parameters (SUV, MTV, TLA) recorded. After both studies have been interpreted blindly, the third 
nuclear medicine physician co-investigator, Dr. Ulaner, will blindly interpret deidentified PET studies on 
every patient (alternating for a total of 10 each fluciclovine and PSMA PET). Afterward, an unblinded 
reconciliation interpretation will take place with all 3 readers. To ensure balance, 10 of the studies will be 
reviewed for consensus first showing Ga-PSMA, then fluciclovine; 10 of the studies will be reviewed in 
the opposite manner. In this manner, a preliminary sense of kappa can be developed between the third 
and the other 2 readers, yet will guarantee the highest degree of patient care as there are currently no 
validated criteria for interpreting fluciclovine or PSMA PET for breast cancer. This approach will help us 
adapt existing prostate specific criteria to that of breast cancer. Concordant and discordant lesions 
between each PET study and conventional imaging will be reported and potential biopsy sites, if any, 
recommended. 
Correlation of histology with images: Uptake parameters as above will be correlated with all proven 
primary, locoregional, and distant lesions.
ctDNA analysis: Plasma levels of ctDNA will be measured using targeted assays to detect point 
mutations including mutations in PIK3CA, ESR1, HER2, and AKT1, genes associated with hormone 
therapy resistance and ILC [12, 38, 39, 43]. Because ILC are predominantly hormone receptor positive, 
hormone resistance is particularly relevant because it predicts for higher rate of distant metastasis. Dr. 
Mylin Torres, will provide expertise in ctDNA analyses. Deidentified specimens will be shipped to the 
Circulating Tumor Cell Center at Massachusetts General Hospital for fee for service ctDNA processing.    
Correlation of ctDNA results with results of imaging: We will examine ctDNA results for association 
with presence or absence of locoregional metastasis on imaging as confirmed with histology, presence 
or absence of distant metastasis on imaging as confirmed with histology, correlation of presence or 
absence and absolute ctDNA with PET uptake as determined by the following indices: SUVmax, 
SUVmean, SUVpeak, Total Lesion Activity for the index primary, locoregional and distant metastatic 
lesion if any, and correlation to summed indices as a reflection of total metabolic tumor burden. ctDNA 
will also be correlated with CI. 


 
Version 1.0;  Page 20 of 28; 29 July 2020
10. Statistical considerations 
Specific Aims 1 and 2
Analysis plan: The objectives of Aims 1 and 2 are to compare verified detection rates between 
fluciclovine and PSMA PET versus conventional imaging, as confirmed with histology (Aim 1), and 
determine concordance and discordance of ILC detection with PSMA versus fluciclovine PET, as 
confirmed with histology (Aim 2). Paired detection rates will be assessed using McNemar’s test.  
Detection rates will be reported for each method, and 95% confidence intervals will be estimated using 
the Clopper-Pearson approach. Rates of concordant/discordant observations will be reported. The 
Likert rating-scale data also allows for determination of sensitivity, specificity, PPV, NPV and Receiver 
Operating Characteristic (ROC) Area Under the Curve (AUC) values to compare. 
Sample size and power: We will image 20 patients with ILC for this study. This is a small, exploratory 
study, with a goal of obtaining preliminary data to estimate effect size. Thus, there is no power analysis 
for the study aims. If we find a 20% difference in detection rate with a 40% discordant rate, we would 
require 67 patients in a larger study to achieve 80% power with a Type I error rate of 0.05 using 
McNemar’s test. Discordant rates of 50% and 60% with a difference in detection rate of 20% would 
require 83 and 99 patients, respectively, to achieve 80% power. If the difference in detection rate is 
15%, the required sample sizes would range from 118 to 175 for discordant rates of 40% to 60% to 
achieve 80% power.  If the difference in detection rate is 25%, the required sample sizes would range 
from 42 to 63 for discordant rates of 40% to 60% to achieve 80% power.
Exploratory Aim 3
Analysis plan: In Aim 3, ctDNA parameters will be summarized descriptively using mean, median, 
min/max, IQR, and standard deviation. ctDNA will be correlated with PET uptake parameters using 
Pearson’s or Spearman’s correlation coefficient (where appropriate), as well as chi-squared tests, 
Fisher’s exact tests, or ANOVA if any variables are further categorized. In addition, generalized linear 
models will be fit to evaluate the relationship between ctDNA parameters and PET uptake parameters, 
controlling for relevant characteristics.  
Sample size and power: We will image 20 patients with ILC for this study.  This is a small, exploratory 
study, with a goal of obtaining preliminary data to estimate effect size. Thus, there is no power analysis 
for the study aims.  If we find a correlation coefficient of 0.3 between a specific ctDNA parameter and 
PET update parameter, we would need 84 patients to detect that correlation coefficient vs. a null value 
of 0 with 80% power and a Type I error of 0.05.  We would need 46 patients to detect a correlation 
coefficient of 0.4 vs. a null value of 0 to achieve 80% power.
11. Adverse Events:  List and Reporting Requirements 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during a trial (please 
follow directions for routine reporting provided in the full Data Safety and Monitoring Plan (DSMP)). 
Additionally, certain adverse events must be reported in an expedited manner for timely monitoring of 
patient safety and care. The following sections provide information about expedited reporting.
Special note for radiotracers given during this trial: The risk of AEs or SAEs from PET 
radiotracers is exceedingly low. A significant shift from baseline which can be attributable 
to the radiotracer injection and not the patient’s medical condition will be considered an 
unexpected AE. An event greater than 20 hours post scan for fluciclovine and 10 hours for 
Ga-PSMA will not be considered a related to study procedure AE since the radiotracer has 
effectively decayed by 20 hours and 10 hours respectively. Reporting will follow relevant FDA 
and manufacturer guidelines as outlined below.
A serious adverse event is any medical occurrence which is fatal, is immediately life threatening, requires 
hospitalization (or prolongs an existing hospitalization), results in persistent significant disability or 
incapacity, is a congenital abnormality or a birth defect, or is considered medically significant by a 
physician.


 
Version 1.0;  Page 21 of 28; 29 July 2020
The definition of serious adverse event (experience) also includes important medical event. Medical and 
scientific judgment will be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should also usually be considered serious. Examples 
of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse.
Attribution:  The determination of whether an adverse event is related to a study imaging agent.  The 
categories are:
Definite:  The adverse event is clearly related to the study imaging agent.
Probable:  The adverse event is likely related to the study imaging agent.
Possible:  The adverse event may be related to the study imaging agent.
Unlikely:  The adverse event is doubtfully related to the study imaging agent.
Unrelated:  The adverse event is clearly not related to the study imaging agent.
Unexpected Adverse Event:  An adverse event, the nature or severity of which is not consistent with the 
applicable product information.  
Investigational Agent:  A protocol drug administered under an Investigational New Drug Application (IND).  
Commercial Agent:  An agent not provided under an IND but obtained from a commercial source.
Determination of Reporting Requirements
Reporting requirements may include the following considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study imaging agent (attribution), and the prior experience 
(expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not 
hospitalization or prolongation of hospitalization was associated with the event.
Steps to determine if an adverse event is to be reported in an expedited manner:
Step 1: Identify the type of event using the NCI Common Toxicity Criteria for Adverse Event Reporting 
Version 5.0 (CTCAE v5.0). The CTCAE v5.0 provides descriptive terminology and a grading scale for 
each adverse event listed. A copy of the CTCAE v5.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). Additionally, if assistance is needed, the NCl has an Index to the CTCAE v5.0 
that provides help for classifying and locating terms. All appropriate treatment locations should have 
access to a copy of the CTCAE v5.0.
Step 2: Grade the event using the NCI CTCAE  v5.0.
Step 3: Determine whether the adverse event is related to the protocol imaging agent (investigational or 
commercial). 
Step 4: Determine the prior experience of the adverse event. Expected events are those that have been 
previously identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type of event or the severity of the 
event is not listed in the investigator brochure for an investigational agent or the drug package insert for 
a commercial agent.
Step 5: Review Expedited reporting requirements below to determine if there are any protocol-specific 
requirements for expedited reporting of specific adverse events that require special monitoring.
Step 6: Determine if the protocol treatment given prior to the adverse event included investigational 
agent(s), a commercial agent(s), or a combination of investigational and commercial agents.
Reporting Methods:
The Principal Investigator is responsible for evaluating all reports of adverse events which occur in 
patients enrolled on this study and reporting those events which are serious to Telix Pharmaceuticals or 


 
Version 1.0;  Page 22 of 28; 29 July 2020
to Blue Earth  as outlined below and the Emory University IRB according to the guidelines below. SAEs 
must be reported as required by the WCI DSMP.
Expedited reporting requirements:  All grade 4-5 adverse events (unexpected and expected) and grade 
2-3 adverse events that are unexpected must be reported as above within 24 hours of occurrence.
Reporting to Institutional Review Board (IRB):  All SAEs must be reported by the Principal Investigator to 
the Emory University IRB as required by their regulations and the conditions of approval for the protocol.
Reporting to FDA: The Sponsor- Investigator must notify the FDA in a written IND safety report of any 
adverse event which is both serious and unexpected.  Each written notification must be made as soon 
as possible but no later than 15 calendar days of first becoming aware of the event.  Reports should be 
submitted using the FDA Form 3500A (available on the FDA website at www.fda.gov/medwatch.  
Reporting may be done online or via mail or fax.     
Fluciclovine: The Investigator will report all Serious Adverse Events occurring in a subject on the day of 
or within XX days following the Agent administration to Bracco, the parent company for Blue Earth 
Diagnostics (“Bracco”) by telephone (+44 1483 212151), FAX (+44 1483 212178) or e mail 
(drugsafetyus@blueearthdx.com). 
Events will be reportedBracco within 24 hours of the investigator becoming aware of the events 
occurrence. Bracco will prepare an individual single case report (ISCR) in compliance with applicable 
regulations. A copy of the ISCR will be sent by Bracco to the Investigator. The Investigator is responsible 
for informing the ethics committee of serious events occurring during the study in compliance with local 
regulations. Bracco will report the event, if appropriate, to the regulatory authority in compliance with local 
regulations. The sponsor will also report SAEs to the FDA per regulations as noted in Section 10 above.
Ga PSMA: Emory has provided a copy of the detailed Clinical Trial protocol to Telix Pharmaceuticals, as 
amended from time-to-time, as well as a copy of the annual safety reporting (Safety Reporting) involving 
the use of the Kit. Emory shall provide an annual report to Telix, summarizing the Adverse Event (AE) 
profile in relation to the use of the Kit, specifically noting whether there was attribution of the AE (however 
serious) to the Kit.
In the event of a Serious Adverse Event (SAE) or death occurring any time within 7 days after 
administration of 68Ga-PSMA-11 prepared using the Kit, and not related to disease progression, Emory 
shall 
report 
to 
Telix 
Designated 
Contact 
(Bernard 
Lambert; 
(571) 
294 
4646; 
bernard.lambert@telixpharma.com)
(a)
Within seven (7) calendar days of the date of awareness of a life-threatening adverse 
event or death (Date of Awareness), regardless of apparent causality to the use of the 
Kit.
(b)
Within fifteen (15) calendar days of the Date of Awareness, any other SAEs, regardless of 
apparent causality to the use of the Kit.
(c)
Within seven (7) calendar days upon communication of any other safety-related report, 
issues or queries related to the Kit that are either raised by, or communicated to, regulatory 
authorities or ethics committees.
(d)
Within seven (7) calendar days after submission, the Development Safety Update Report 
(DSUR) submitted to the FDA.
Any unexpected fatal (Grade 5) or unexpected, life-threatening (Grade 4) adverse event must be reported 
to the FDA as soon as possible but no later than 7 calendar days of first becoming aware of the event. 
Reports should be submitted using the FDA Form 3500A via fax at 1-800-332-0178


 
Version 1.0;  Page 23 of 28; 29 July 2020
12. Data Reporting / Regulatory Requirements
Patients will be monitored by the technologists and/or study nurse before and after the studies for any 
adverse events/reactions.  They will be given contact phone numbers to call if they experience any 
problems (i.e. problems with the IV site, any allergic reaction symptoms).  Basic monitoring of adverse 
events during the 68Ga-PSMA-11 PET visit will be performed as pursuant to FDA agreement. This will 
consist of direct observation by our study staff during the visit with documentation of any adverse events 
or lack thereof in the electronic medical record. 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute of Emory University 
will oversee the conduct of this study. This committee will review all pertinent aspects of study conduct 
including patient safety, compliance with protocol, data collection and efficacy. 
The DSMC will review the charts of 10% of patients enrolled to the study and two of the first 5 patients 
entered to the study. Reviews will occur annually for studies that are moderate risk. High risk studies will 
be reviewed every 6 months. The committee reserves the right to conduct additional audits if necessary, 
at any time-point. The Principal Investigator is responsible for notifying the DSMC about the accrual of 
patients when the first 5 have been entered to the study. 
The charter for the Winship DSMC is available upon request to the investigator or other study-related 
personnel.  
As with our ongoing clinical trial, for the current proposal we will adhere strictly to Winship’s Data Safety 
Monitoring Plan which is provided in detail at the following link: 
https://winshipcancer.emory.edu/research/clinical-trials-office/data-and-safety-monitoring-
committee.html
Data Safety Monitoring Board: 
Note that our proposed trial is an early phase clinical trial that will be conducted completely within the 
Emory system, so a formal and independent Data Safety Monitoring Board (DSMB) [which is required for 
multi-site studies or Phase III trials] is not required for our proposal. As described above, the DSMC of 
Winship Cancer Institute of Emory University will oversee the conduct of our study.  
Fidelity to Protocol and Data Integrity:
Clinical trial performance and fidelity to the protocol, will be monitored by the DSMC of Winship Cancer 
Institute of Emory University.  Integrity of the data will be maintained by rigorous peer-review internally 
by all the clinical co-investigators in Radiation Oncology, Radiology/Nuclear Medicine, Surgical Oncology, 
and Medical Oncology. 
13. Ethics and Protection Of Human Subjects
The study will be approved by the Emory IRB per standard institutional requirements and informed written 
consent obtained. 
To maintain patient confidentiality, medical records will be accessed only by IRB approved study 
personnel (e.g. CRC). Partial HIPAA waiver will be obtained to allow screening of provider schedules for 
identification of potentially eligible research subjects. Upon medical record review and identification of a 
potentially eligible research subject, patient's full name, MRN, EMPI, and full dates (e.g. DOB, procedure 
dates, admission dates, etc.) will be stored on a screening log and used by study coordinators for the 
subsequent study activities. The screening log will be kept on the HIPAA compliant shared folder and will 
be accessible only to limited IRB approved study personnel (e.g CRC). Sensitive data will always be 
stored on the HIPAA compliant shared folder and will never be stored on local or portable drives that are 
not encrypted per Emory IS standards. 


 
Version 1.0;  Page 24 of 28; 29 July 2020
Each study participant will be assigned a unique study identification (ID) number at the time that informed 
consent is given. Personal identifying information, study data, including the unique study ID, will be 
entered in the Microsoft Database that will be kept on the HIPAA compliant shared folder accessible to 
approved study personnel only. Only de-identified data will be shared with those outside the study team 
to ensure adequate protection of sensitive data.
Study identifiers will be kept indefinitely. 
To maintain participant confidentiality, no identifying information about any of the study participants will 
be published. Any data published (including demographic information about the study sample as a whole) 
will be in aggregate/summary form only. 
Note also that Dr. Gary Ulaner of MSKCC and Dr. Aditya Bardia of the Circulating Tumor Cell 
Center at Massachusetts General Hospital, will only be exposed to deidentified data, samples, 
and images. As such they would not be considered “engaged” in human subjects research. As a 
result, they do not require inclusion on the IRB per our consultation with the Emory IRB.
Incidental Findings
a.   All incidental findings noted by the imager will be discussed with the attending physician who 
is a co-investigator and documented in the electronic medical record. 
b.   The oncologist will educate the patient about the nature of the incidental finding, how to seek 
care from a clinician or specialist, obtaining health insurance to secure treatment, and/or 
referral to a clinical specialist, if one is required. 
c.   Language to this effect is present in the consent form.
PET findings will be used for research purposes within the context of the clinical trial as noted above. All 
incidental findings will be recorded in the clinical research form and emergent incidental findings will be 
communicated to the patient’s physician who is also an investigator on this study.
Compensation for time and effort: Each patient will be compensated $50 as per diem for travel expenses 
per scan (total of $100 for both scans).


 
Version 1.0;  Page 25 of 28; 29 July 2020
14. References
1.
Dossus, L. and P.R. Benusiglio, Lobular breast cancer: incidence and genetic and non-genetic 
risk factors. Breast Cancer Res, 2015. 17: p. 37.
2.
He, H., et al., Distant metastatic disease manifestations in infiltrating lobular carcinoma of the 
breast. AJR Am J Roentgenol, 2014. 202(5): p. 1140-8.
3.
Ulaner, G.A. and D.M. Schuster, Amino Acid Metabolism as a Target for Breast Cancer 
Imaging. PET Clin, 2018. 13(3): p. 437-444.
4.
Ulaner, G.A., et al., Prospective Clinical Trial of (18)F-Fluciclovine PET/CT for Determining the 
Response to Neoadjuvant Therapy in Invasive Ductal and Invasive Lobular Breast Cancers. J 
Nucl Med, 2017. 58(7): p. 1037-1042.
5.
Tade, F.I., et al., Anti-3-18F-FACBC (18F-Fluciclovine) PET/CT of Breast Cancer: An 
Exploratory Study. J Nucl Med, 2016. 57(9): p. 1357-63.
6.
Ulaner, G.A., et al., Initial Results of a Prospective Clinical Trial of 18F-Fluciclovine PET/CT in 
Newly Diagnosed Invasive Ductal and Invasive Lobular Breast Cancers. J Nucl Med, 2016. 
57(9): p. 1350-6.
7.
Wernicke, A.G., et al., Prostate-specific membrane antigen expression in tumor-associated 
vasculature of breast cancers. APMIS, 2014. 122(6): p. 482-9.
8.
Salas Fragomeni, R.A., et al., Imaging of Nonprostate Cancers Using PSMA-Targeted 
Radiotracers: Rationale, Current State of the Field, and a Call to Arms. J Nucl Med, 2018. 59(6): 
p. 871-877.
9.
Kasoha, M., et al., Prostate-specific membrane antigen (PSMA) expression in breast cancer 
and its metastases. Clin Exp Metastasis, 2017. 34(8): p. 479-490.
10.
Sathekge, M., et al., (68)Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients. Eur J 
Nucl Med Mol Imaging, 2017. 44(4): p. 689-694.
11.
Tolkach, Y., et al., Prostate-specific membrane antigen in breast cancer: a comprehensive 
evaluation of expression and a case report of radionuclide therapy. Breast Cancer Res Treat, 
2018. 169(3): p. 447-455.
12.
Desmedt, C., et al., Genomic Characterization of Primary Invasive Lobular Breast Cancer. J Clin 
Oncol, 2016. 34(16): p. 1872-81.
13.
Jager, P.L., et al., Radiolabeled amino acids: basic aspects and clinical applications in 
oncology. J Nucl Med, 2001. 42(3): p. 432-45.
14.
Shennan, D.B. and J. Thomson, Inhibition of system L (LAT1/CD98hc) reduces the growth of 
cultured human breast cancer cells. Oncol Rep, 2008. 20(4): p. 885-9.
15.
Wang, K., et al., Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt 
overexpression. BMC Cancer, 2013. 13: p. 343.
16.
Liang, Z., et al., Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer 
Progression. Nucl Med Mol Imaging, 2011. 45(2): p. 93-102.
17.
Shennan, D.B., et al., L-leucine transport in human breast cancer cells (MCF-7 and MDA-MB-
231): kinetics, regulation by estrogen and molecular identity of the transporter. Biochim Biophys 
Acta, 2004. 1664(2): p. 206-16.
18.
Shennan, D.B., et al., Functional and molecular characteristics of system L in human breast 
cancer cells. Biochim Biophys Acta, 2003. 1611(1-2): p. 81-90.
19.
Schuster, D.M., et al., Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid: physiologic 
uptake patterns, incidental findings, and variants that may simulate disease. J Nucl Med, 2014. 
55(12): p. 1986-92.
20.
Kaittanis, C., et al., Prostate-specific membrane antigen cleavage of vitamin B9 stimulates 
oncogenic signaling through metabotropic glutamate receptors. J Exp Med, 2018. 215(1): p. 
159-175.
21.
Yadav, M.P., et al., Radioligand Therapy With (177)Lu-PSMA for Metastatic Castration-
Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. AJR Am J Roentgenol, 
2019. 213(2): p. 275-285.


 
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22.
Glunde, K., et al., Molecular and functional imaging of breast cancer. NMR Biomed, 2009. 22(1): 
p. 92-103.
23.
Gore, J.C., et al., Magnetic resonance in the era of molecular imaging of cancer. Magn Reson 
Imaging, 2011. 29(5): p. 587-600.
24.
Ferlicot, S., et al., Wide metastatic spreading in infiltrating lobular carcinoma of the breast. Eur J 
Cancer, 2004. 40(3): p. 336-41.
25.
Groheux, D., et al., Performance of FDG PET/CT in the clinical management of breast cancer. 
Radiology, 2013. 266(2): p. 388-405.
26.
Hogan, M.P., et al., Comparison of 18F-FDG PET/CT for Systemic Staging of Newly Diagnosed 
Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma. J Nucl Med, 2015. 56(11): p. 
1674-80.
27.
O'Connor, M., D. Rhodes, and C. Hruska, Molecular breast imaging. Expert Rev Anticancer 
Ther, 2009. 9(8): p. 1073-80.
28.
Schuster, D.M. and R.K. Halkar, Molecular imaging in breast cancer. Radiol Clin North Am, 
2004. 42(5): p. 885-908, vi-vii.
29.
Plathow, C. and W.A. Weber, Tumor cell metabolism imaging. J Nucl Med, 2008. 49 Suppl 2: p. 
43S-63S.
30.
Parent, E.E. and D.M. Schuster, Update on (18)F-Fluciclovine PET for Prostate Cancer 
Imaging. J Nucl Med, 2018. 59(5): p. 733-739.
31.
McConathy, J., 18F-Fluciclovine (FACBC) and Its Potential Use for Breast Cancer Imaging. J 
Nucl Med, 2016. 57(9): p. 1329-30.
32.
Chang, S.S., Overview of prostate-specific membrane antigen. Rev Urol, 2004. 6 Suppl 10: p. 
S13-8.
33.
Paoletti, C., et al., Circulating Tumor Cell Clusters in Metastatic Breast Cancer Patients: a 
SWOG S0500 Translational Medicine Study. Clin Cancer Res, 2019.
34.
De Giorgi, U., et al., Circulating tumor cells and bone metastases as detected by FDG-PET/CT 
in patients with metastatic breast cancer. Ann Oncol, 2010. 21(1): p. 33-9.
35.
Wang, R., et al., Cell-free circulating tumor DNA analysis for breast cancer and its clinical 
utilization as a biomarker. Oncotarget, 2017. 8(43): p. 75742-75755.
36.
Catarino, R., et al., Quantification of free circulating tumor DNA as a diagnostic marker for 
breast cancer. DNA Cell Biol, 2008. 27(8): p. 415-21.
37.
Canzoniero, J.V. and B.H. Park, Use of cell free DNA in breast oncology. Biochim Biophys Acta, 
2016. 1865(2): p. 266-74.
38.
Kodahl, A.R., et al., Correlation between circulating cell-free PIK3CA tumor DNA levels and 
treatment response in patients with PIK3CA-mutated metastatic breast cancer. Mol Oncol, 
2018. 12(6): p. 925-935.
39.
Lupini, L., et al., High-sensitivity assay for monitoring ESR1 mutations in circulating cell-free 
DNA of breast cancer patients receiving endocrine therapy. Sci Rep, 2018. 8(1): p. 4371.
40.
O'Leary, B., et al., Early circulating tumor DNA dynamics and clonal selection with palbociclib 
and fulvestrant for breast cancer. Nat Commun, 2018. 9(1): p. 896.
41.
Zanetti-Dallenbach, R.A., et al., Levels of circulating cell-free serum DNA in benign and 
malignant breast lesions. Int J Biol Markers, 2007. 22(2): p. 95-9.
42.
Fendler, W.P., et al., (68)Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for 
prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging, 2017. 44(6): p. 1014-1024.
43.
Cheng, J., et al., Clinical Validation of a Cell-Free DNA Gene Panel. J Mol Diagn, 2019. 21(4): 
p. 632-645.


 
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APPENDIX A   Abbreviations and definition of terms
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
Akt
Protein kinase B (or PKB)
CRFs
Case Report Forms
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
DSMB
Data Safety Monitoring Board 
DSMC
Data and Safety Monitoring Committee 
DSMP
Data Safety and Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
ESR1
Estrogen Receptor alpha
FCBP
Female of childbearing potential
FDG
fluorodeoxyglucose
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability Accountability Act
ICF
Informed consent form
IDC
invasive ductal carcinoma
IHC
Immunohistochemistry
IL
Interleukin
ILC
Invasive lobular carcinoma


 
Version 1.0;  Page 28 of 28; 29 July 2020
Abbreviation or 
special term
Explanation
IMC
invasive metaplastic carcinoma
IND
Investigational New Drug
IRB
Institutional Review Board
ISCR
individual single case report
IV
Intravenous
MBq
Megabecquerel
mCi
Millicurie
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIH
National Institutes of Health
PET
Positron Emission Tomography
PI3Ks
Phosphoinositide 3-kinases 
PSMA
Prostate specific membrane antigen
RNA
Ribonucleic acid
SAE
Serious adverse event
SUV
Standardized uptake value
TLA
Total lesion activity
VEGF
Vascular endothelial growth factor 

ICF_000.pdf: 
 
 
 
 
 
Informed Consent Form 
 
WINSHIP4933-19: Improved Staging of Lobular Breast Cancer with Novel Amino 
Acid Metabolic and Tumor Neovasculature Receptor Imaging 
 
NCT Number: NCT04750473 
 
 
Document IRB Approval Date: 9/21/2020 


Page 1 of 13
Version Date: 09/15/2020
IRB Form 06162020
 
You Are Being Asked to Be in a Research Study
Concise presentation of key concepts
You are being asked to be in a research study. A research study is designed to answer a 
scientific question. If you agree to be in the study you will be one of 20 people who are being 
studied, at any Emory facility including Saint Joseph’s and Johns Creek’s Hospitals.
Why is this study being done? 
This study is being done to better detect metastasis in a type of breast cancer (called Invasive 
Lobular breast cancer or ILC). You are being asked to be in this research study because you 
have been diagnosed with this type of breast cancer (ILC). 
Do you have to be in the study? 
It is your decision to be part of this research study. You do not have to be in it. Your choice will 
not affect your access to medical care for your condition. Before you make your decision, you 
should take time to learn about the study.
What do I have to do if I choose to participate in this study?
If you are eligible and want to be part of the study, you will participate for the duration of 
treatment (two study visits) and a follow-up period. The researchers will ask you to do the 
following: undergo two imaging tests called PET-CT scans performed on individual days. 
Additionally, during one of the two study visits, approximately 20 mL of blood will be taken for 
research purposes. All of these procedures will be paid for by the study. Based on the results 
of your scans, you might undergo one-two tissue biopsies or additional imaging tests after 
discussion with your oncologist. These biopsies or additional imaging tests will not be paid by 
the study but will be billed to your insurance.  
How is this study going to help you? 
If you are in the study, you will be helping the researchers answer the study question. The 
information we get from this study may help us to better detect metastasis in real-life practice 
and may help us to better treat patients with ILC in the future. 
What are the risks or discomforts I should know about before making a decision?  
The study will take time. The procedure that is being tested may not work any better than 
regular care, and may even cause harm. All studies have some risks.  Some risks are relatively 
small, like being bored or losing time.  Some are more serious – for this study, these include 
common risks associated with radiation exposure, allergic or other reactions to radiotracers 
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Version Date: 09/15/2020
IRB Form 06162020
(used for the imaging tests), biopsy associated risk (ex. bleeding or infection, loss of privacy, 
and breach of confidentiality.  A full list of expected risks, their frequency and severity are in 
the “What are the possible risks and discomforts?” section of this document.
Alternatives to Joining This Study
Since this is not a treatment study, the alternative is not to participate. You do not have to be 
in this study to be treated for your cancer.
Costs
You WILL NOT have to pay for the study procedures, such as the two experimental PET-CT 
scans and the special blood test. All other tests such as possible biopsies will be billed to your 
insurance. 
What Should I Do Next?
Read this form, or have it read to you.  Make sure the study doctor or study staff explains the 
study to you. Ask questions (e.g., about exact time commitment, about unfamiliar words, 
more details on specific procedures, etc.) Make sure you understand which parts are research 
and which are standard care that you would have even if you did not join the study.  Take time 
to consider this and talk about it with your family and friends.
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Page 3 of 13
Version Date: 09/15/2020
IRB Form 06162020
Emory University and Saint Joseph’s Hospital
Consent to be a Research Subject / HIPAA Authorization 
Title: Phase 1 Feasibility Trial: Improved staging of lobular breast cancer with novel amino acid metabolic and tumor 
neovasculature receptor imaging. 
IRB #: STUDY00000675 
Principal Investigator: David Schuster, MD
Sponsor: National Institutes of Health (NIH)
Investigator-Sponsor: David Schuster, MD
Study-Supporter: Blue Earth Diagnostics Ltd. Telix Pharmaceuticals Ltd.
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything you need to think 
about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to take part, you 
can change your mind later on and withdraw from the research study. The decision to join or not join the research 
study will not cause you to lose any medical benefits.  If you decide not to take part in this study, your doctor will 
continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would like to 
participate. You may wish to discuss your decision with family or friends. Do not sign this consent form unless you have 
had a chance to ask questions and get answers that make sense to you.  By signing this form you will not give up any 
legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site 
will not include information that can identify you. At most the Web site will include a summary of the results. You can 
search this Web site at any time.
What is the purpose of this study?
The purpose of this study is to see if studying  body images from PET scans (PET scan with either fluciclovine or GaPSMA) 
will be useful in helping your doctor better understand and classify your breast cancer. Doctors expect also to better 
identify any possible distant spread of the tumor (metastasis) which could impact your care.
PET (Positron emission tomography) imaging or PET scan, is a type of nuclear medicine imaging. Nuclear medicine 
imaging uses small amounts of radioactive material (called radiotracers) to diagnose, evaluate variety of diseases. 
In this study two different radiotracers will be used: fluciclovine and GaPSMA. Radiotracers are injected into the 
vein. After the substance is injected, PET scans are done. The images show color where the radiotracer emits 
radiation, the PET scanner can pick up the radiation being released to create a picture from within the body.
STUDY00000675
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IRB Form 06162020
Fluciclovine was developed here at Emory and has been approved by the FDA (Food and Drug Administration) for 
routine use in people with recurrent prostate cancer. Fluciclovine is not yet FDA approved for breast cancer. This 
study may help in getting fluciclovine approved to be used in people diagnosed with breast cancer.
68Ga-PSMA is also a PET radiotracer and is still under investigation. It is currently not approved by the FDA (Food 
and Drug Administration). We expect it will become FDA approved in the next 1-2 years. PSMA is currently 
produced at Emory Center for Systems Imaging for an ongoing prostate cancer trial. 
We plan to enroll a total of 20 patients in this study.
What will I be asked to do?
You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests 
or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some 
of them recently, they may not need to be repeated. This will be up to your study doctor. After you sign this informed 
consent form and before starting the study procedures

The study team will review your health history

The study team will review your diagnosis of breast cancer (ILC)

The study team will review prior conventional imaging (mammography, breast US, breast MRI, FDG PET-CT).

You will undergo two PET-CT scans (using the radiotracers: Fluciclovine and Ga-68 PSMA) on two separate days.

A 20 ml (4 teaspoons) of blood will be drawn for research tests, typically on day of the first PET scan.
VISIT PROCEDURES
On the day of the Fluciclovine PET scan, 

You will be required to fast (except for water) for 4 hours before the scan.

You will be given oral contrast to drink; this allows the abdominal organs to be better visible.

Images will be acquired approximately 4 min post intravenous injection of fluciclovine.
On the day of the PSMA PET scan,

Fasting is not required for this exam.

You will be given oral contrast to drink; this allows the abdominal organs to be better visible

Imaging will be performed approximately 60 minutes post intravenous injection of PSMA. 

PET scan (Fluciclovine or GaPSMA PET scan):
The scans will be performed at the Emory Center for PET located in the Nuclear Medicine Department on 
the first floor of the Emory University Hospital or in the Winship Cancer Institute or Emory-affiliated site. 
The entire procedure will last about 2 hours, including set up and preparation time. 
Before the fluciclovine PET scan, you will be asked to not eat or drink for four hours. This will allow the 
fluciclovine radiotracer to get in your blood system easier. You will meet with a technologist and doctor 
who are approved to work on this study, and who will be performing the procedures on you. An 
intravenous tube called a catheter (IV) will be inserted in a vein in your arm to be used later for injection 
of the radiotracer (fluciclovine or GaPSMA). One hour prior to scanning, you will drink 1 bottle (500 ml) of 
oral contrast over 1 hour to allow for better pictures of your abdomen and pelvic structures.
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
After placement of the IV for fluciclovine, you will lay down on a mobile couch that will slide into 
the scanner. The scanner has the appearance of a large box containing a large round opening into 
which your body is placed. An initial “transmission” scans lasting about 1 minute in which the 
couch will move. This transmission scan is similar to a CAT scan and is used to correct for the 
effect of your body on the PET scan in order to produce better images. This transmission scan is 
done on the PET scanner and will look no different to you. You will then receive an injection 
through the IV tube of the radiotracer fluciclovine.  A set of PET scans (pictures) will be done over 
thirty minutes. The couch will move. When finished, the IV will be removed.  You will be able to 
leave the PET Center after this time.

After placement of the IV for GaPSMA, you will be brought into a quiet room and you will then 
receive an injection through the IV tube of the radiotracer GaPSMA.  You will wait in the quiet 
room for approximately an hour. After this, you will then lay down on a mobile couch that will 
slide into the scanner. The scanner has the appearance of a large box containing a large round 
opening into which your body is placed. An initial “transmission” scans lasting about 1 minute in 
which the couch will move. This transmission scan is similar to a CAT scan and is used to correct 
for the effect of your body on the PET scan in order to produce better images. This transmission 
scan is done on the PET scanner and will look no different to you. A set of PET scans (pictures) will 
be done over thirty minutes. The couch will move. When finished, the IV will be removed.  You 
will be able to leave the PET Center after this time.
After the two PET exams, abnormal findings on the PET scan will be carefully correlated with already obtained 
CT or MRI to determine if a previously unsuspected abnormality can be identified which may need to be 
biopsied. Before biopsy a discussion between you and your provider (who will also be the co-investigator of this 
study) will take place on the benefits versus risks to definitively determine if a metastasis is present which could 
affect therapy. Biopsy will be undertaken in the least invasive manner as a standard of care. Biopsy will be 
performed for the distant, most accessible lesion. A second biopsy may be needed in some cases to best 
determine if the cancer has spread elsewhere. 
All subsequent therapy for breast cancer will be standard of care. 

About a week after each scan our nurse will call you to make sure you are doing well.

We will continue to follow your case up to 5 years by looking at your medical record and talking with your 
oncologist to best determine if the experimental PET scans were correct about your particular situation. No 
additional study specific visits are required. 
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive any compensation if 
your samples or information are used to make a new product. If you withdraw from the study, data and samples that 
were already collected may still be used for this study.  
What are the possible risks and discomforts?
You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any 
side effects. However, researchers don’t know all the side effects that may happen. Side effects may be mild or 
very serious. In some cases, side effects can be serious, long lasting, or may never go away. In addition, some of 
the side effects may be life threatening and, in rare instances, may cause death.  You will receive radiation from 
diagnostic procedures to evaluate your condition. The principal risk associated with a radiation dose is the 
possibility of developing a radiation-induced cancer later in life. However, the additional risk of radiation-induced 
cancer from these diagnostic procedures is low compared to other risks from the medical therapy.
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The procedures described in this study may cause all, some, or none of the side effects listed here. These are 
common procedures that are considered relatively safe. Previously unknown side effects can also occur. If new 
side effects are reported, you will be told. It is also important that you give us accurate and complete information 
about your past medical history. 
You may also find it uncomfortable to lie motionless during the approximately 30 minutes necessary to complete 
the scan.  If you believe you cannot lie still for 30 minutes, you should not participate in this study.
Although the risk is small, it is possible to develop an allergic reaction to the fluciclovine or GaPSMA.  This can 
result in hives, rash, itching and difficulty breathing which may require emergency medical treatment.  There have 
been no previous instances of allergic reaction. In prior studies with both radiotracers, the risk of adverse events 
which can be attributed to the radiotracer is extremely low, and of minimal medical impact such as burning at IV 
site or a strange taste in the mouth.
Fluciclovine: In previous studies with many hundreds of patients, there were no problems reported. However, it is 
important to report any unusual side effects that you are having such as itching, skin rashes, fever, chills, nausea, 
dizziness, and vomiting. Please also see the risks of radiation exposure below.
GaPSMA: In previous studies, there were no problems reported. However, it is important to report any unusual 
side effects that you are having such as itching, skin rashes, fever, chills, nausea, dizziness, and vomiting. Please 
also see the risks of radiation exposure below.
Contrast Agents: Your CT, PET-CT or MRI procedure may require the use of a contrast agent, which is a substance that 
helps the radiologist interpret the images. The contrast agent will be injected by either a hand-held needle or a machine 
that does the injection. Most contrast agents stay in your body for only a few minutes, but some of them can remain for 
a few hours or days without any harm to you or anyone near you. Contrast agents are generally quite safe, but any 
injection involves some risks. The injection could harm a nerve, artery or vein, or cause infection. The contrast agent 
could affect kidney function or cause an allergic reaction, though these outcomes are rare. The contrast agent could also 
leak from your veins a little, causing swelling and discomfort, which is typically treated with ice packs.
Reproductive Risks: To protect against possible side effects of the study radiotracer, women who are pregnant or 
nursing a child may not take part in this study. If you become pregnant, there may be risks to you, the embryo, or fetus. 
These risks are not yet known. If you are a woman of childbearing ability, you will be given a pregnancy test within 24 
hours of each PET scan.  If you think that you have gotten pregnant during the study, you must tell the study doctor 
immediately.  
Intravenous Catheter: One tube will be placed in your vein (arm or hand.) It is called an intravenous catheter or IV. 
It is placed under sterile conditions by piercing the skin and underlying vein with a needle, over which is threaded 
the IV catheter and then the needle is withdrawn. When the catheter is placed or removed, the site of insertion 
may become sore or bruised. Rarely, bleeding or infection can occur at this site; however, this is highly unlikely. A 
small gauze pad or bandage is placed over the site after the IV catheter is removed. This is similar to what 
happens when one donates blood.
Vein Puncture
You could experience bruising, pain, and rarely infection at the vein puncture site for the blood draw. Care will be taken 
to minimize these risks.
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Risks of Biopsies: Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, pain at 
the biopsy site, bruising, swelling and scarring. Rarely, an infection can occur.
Radiation Risks:
You will be exposed to radiation from nuclear medicine. These procedures are not necessary for your medical care and 
will occur because you participate in this study. The estimated radiation dose that you will receive is equal to or less 
than the annual radiation exposure limit allowed for persons who are occupationally exposed to radiation (for example, 
x-ray technologist, radiologist).  The principal risk associated with a radiation dose is the possibility of developing a 
radiation-induced cancer later in life.  The risk for radiation-induced cancer from this study is minimal.  
New Findings
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  You may be 
asked to sign a new consent form that includes the new information if you decide to stay in the study.
Will I benefit directly from the study? 
Taking part in this research study may not benefit you personally.  We do know that the information from this study will 
help researchers learn more how to better identify metastatic disease in ILC which will impact appropriate staging. The 
study results may be used to help others in the future.
Will I be compensated for my time and effort?
You will get $ 50 for each completed study visit, to compensate you for your time and effort.  If you do not finish the 
study, we will compensate you for the visits you have completed. You will get $ 100 total, if you complete all study visits.  
You may be asked to fill out a tax form, including your Social Security or Taxpayer Identification Number, in order to be 
reimbursed, depending on the amount and method of payment. Some payment methods involve mail coming to your 
house, which may be seen by others in your household. You can decline payment if you are concerned about 
confidentiality, or you can talk to the study team to see if there are other payment options. 
What are my other options?
If you decide not to enter this study, there is care available to you outside of this research study.  You will receive 
standard of care imaging which includes CT, MRI or FDG PET-CT. Your doctor will decide about these different imaging 
tests as which ones to order, depending upon the stage and treatment planning for your cancer. The study doctor will 
discuss these with you.  You do not have to be in this study to be treated for your breast cancer.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and other 
identifying information will not appear when we present or publish the study results.
Study records can be opened by court order.  
Certificate of Confidentiality
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  The Certificate of 
Confidentiality helps us to keep others from learning that you participated in this study.  Emory will rely on the 
Certificate of Confidentiality to refuse to give out study information that identifies you.  For example, if Emory received a 
subpoena for study records, it would not give out information that identifies you.
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The Certificate of Confidentiality does not stop you or someone else, like a member of your family, from giving out 
information about your participation in this study.  For example, if you let your insurance company know that you are in 
this study, and you agree to give the insurance company research information, then the investigator cannot use the 
Certificate to withhold this information. This means you and your family also need to protect your own privacy.
The Certificate does not stop Emory from making the following disclosures about you:

Giving state public health officials information about certain infectious diseases,

Giving law officials information about abuse of a child, elderly person or disabled person.

Giving out information to prevent harm to you or others.
Giving the study sponsor or funders information about the study, including information for an audit or evaluation.
Storing and Sharing your Information
De-identified data from this study (data that has been stripped of all information that can identify you), including your 
de-identified genetic information, may be placed into public databases where, in addition to having no direct identifiers, 
researchers will need to sign data use agreements before accessing the data. We will remove or code any personal 
information that could identify you before your information is shared. This will ensure that, by current scientific 
standards and known methods, it is extremely unlikely that anyone would be able to identify you from the information 
we share. Despite these measures, we cannot guarantee anonymity of your personal data.
Your data [and specimens] from this study may be useful for other research being done by investigators at Emory or 
elsewhere. To help further science, we may provide your de-identified data and/or specimens to other researchers. If 
we do, we will not include any information that could identify you. If your data or specimens are labeled with your study 
ID, we will not allow the other investigators to link that ID to your identifiable information.
We will use your sample and data only for research. We will not sell them. However, the results of this research might 
someday lead to the development of products (such as a commercial cell line, a medical or genetic test, a drug, or other 
commercial product) that could be sold by a company. You will not receive money from the sale of any such product.
In general, we will not give you any individual results from the study of the samples you give us. If we find something of 
urgent medical importance to you, we will inform you, although we expect that this will be a very rare occurrence.
Medical Record
If you have been an Emory and Saint Joseph’s Hospital patient before, then you already have an Emory and Saint 
Joseph’s Hospital medical record.  If you have never been an Emory and Saint Joseph’s Hospital patient, you do not have 
one.   An Emory and Saint Joseph’s Hospital medical record will be made for you if an Emory and Saint Joseph’s Hospital 
provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory and Saint Joseph’s Hospital 
medical record you have now or any time during the study.  
Emory and Saint Joseph’s Hospital may create study information about you that can help with your care.  For example, 
the results of study tests or procedures.  These study results will be put in your Emory and Saint Joseph’s Hospital 
medical record. Anyone who has access to your medical records will be able to have access to all the study information 
placed there.  The confidentiality of the study information in your medical record will be protected by laws like the 
HIPAA privacy rule.  State and federal laws may not protect the research information from disclosure. 
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The results of some study tests and procedures will be used only for research purposes and will not be placed in your 
medical record.  For this study, those items include:

Fluciclovine PET scan or GaPSMA PET scan results (besides basic documentation of scan completion).

Research blood samples
Copies of the consent form/HIPAA authorization that you sign will be put in your Emory and Saint Joseph’s Hospital 
medical record you have now or any time during the study.  
Tests and procedures done at non-Emory and Saint Joseph’s Hospital places may not become part of your Emory and 
Saint Joseph’s Hospital medical record. Also, if you decide to be in this study, it is up to you to let your other health 
providers know. 
In Case of Injury
OPTION 1: If you believe you have become ill or injured from this research, you should contact Dr. Schuster’s research 
nurse (study coordinator) Bridget Fielder at 
. You should also let any health care provider who treats you 
know that you are in a research study.  
If you get ill or injured from being in the study, Emory and Saint Joseph’s will help you to get medical treatment. Neither 
Emory, Saint Joseph’s nor the sponsor have set aside money to pay for this medical treatment.  Your insurer will be 
billed for your treatment costs.  If you do not have insurance, or if your insurance does not pay, then you will have to 
pay these costs.   
For Emory and Saint Joseph’s, the only exception is if it is proven that your injury or illness is directly caused by the 
negligence of an Emory or Saint Joseph’s employee. “Negligence” is the failure to follow a standard duty of care. You do 
not give up any legal rights you may have by being in this study, including any right to bring a claim for negligence. 
Costs
OPTION 2: The sponsor will pay for certain items or services associated with the study.
The study sponsor will pay for certain items and services that you may receive if you take part in this study.  
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor will not pay for your 
regular medical care. If you have insurance, Emory and Saint Joseph’s Hospital will submit claims to your insurance for 
items and services that the sponsor does not cover.  Emory and Saint Joseph’s Hospital will send in only those claims for 
items and services that it reasonably believes your insurance will pay and that the sponsor has not paid. 
The actual amount that you have to pay depends on whether or not you have health insurance and whether or not that 
insurance will pay for any research study costs. Generally, insurance companies will not pay for items and services that 
are required just for a research study. Some insurance companies will not pay for regular medical treatment or 
treatment for complications if you are in a study.  How much you will have to pay for any co-payments, deductibles or 
co-insurance depends on your plan.  Emory and Saint Joseph’s Hospital and the sponsor will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask them what 
they will pay for and what they will not pay for.  You can also ask the study team for help in figuring out what you will 
have to pay. 
If you do not have insurance, Emory and Saint Joseph’s Hospital will review your case as part of its program for low-
income patient care.  The standard policies of that program will apply.  The program will figure out if you have to pay 
any costs for taking part in the study and what those costs will be.
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Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study.  If you leave the 
study before the final planned study visit, the researchers may ask you to have some of the final steps and procedures 
done.
The researchers also have the right to stop your participation in this study without your consent for any reason, especially if 
they believe it is in your best interest or if you were to object to any future changes that may be made in the study plan.  
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that identifies you, your 
“protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, including the 
Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy 
Rules.”  Here we let you know how we will use and disclose your PHI for the study.
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the research study includes:

Medical information about you including your medical history and present/past medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share your 
PHI to provide you with study related treatment and for payment for such treatment.  We will also use and 
share your PHI to conduct normal business operations.  We may share your PHI with other people and places 
that help us conduct or carry out the study, such as laboratories, data management centers, data monitors, 
contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
we may use your PHI to determine your health, vital status or contact information. 
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests or orders that 
require us to disclose your PHI. These include subpoenas or court orders.  
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this document. You do not 
have to sign this form. If you do not sign this form, you may still receive non-research related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research study:

The Principal Investigator and the research staff will use and disclose your PHI to conduct the study and 
give you study related treatment.

Emory and Saint Joseph’s Hospital  may use and disclose your PHI to get payment for study related 
treatment and to run normal business operations. 
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
The Principal Investigator and research staff will share your PHI with other people and groups to help 
conduct the study or to provide oversight for the study.

 Dr. Schuster is the Sponsor of the study.  The Sponsor may use and disclose your PHI to make sure the 
research is done correctly and to collect and analyze the results of the research.  The Sponsor may 
disclose your PHI to other people and groups like study monitors to help conduct the study or to provide 
oversight for the study.  

Your PHI may be used by Blue Earth Diagnostics Ltd.  or Telix Pharmaceuticals Ltd. for regulatory filings 
with the Food and Drug Administration.

The following people and groups will use your PHI to make sure the research is done correctly and 
safely:
o
Emory and Saint Joseph’s Hospital offices that are part of the Human Research Participant 
Protection Program and those that are involved in study administration and billing.  These 
include the Emory IRB, the Emory Research and Compliance Offices, and the Emory Office for 
Clinical Research. 
o
Other researchers and centers that are a part of this study.  
o
Government agencies that regulate the research including:  [Office for Human Research 
Protections; Food and Drug Administration].
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.

Sometimes a Principal Investigator or other researcher moves to a different institution. If this happens, 
your PHI may be shared with that new institution and their oversight offices. PHI will be shared securely 
and under a legal agreement to ensure it continues to be used under the terms of this consent and 
HIPAA authorization.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If you want 
to do this, you must contact the study team: 
Bridget Fielder, RN, MSN, BSEd
1365 Clifton Road, Clinic A, AT 600
Atlanta, GA 30322
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the information you 
already gave them so they can follow the law, protect your safety, or make sure that the study was done properly and 
the data is correct.  If you revoke your authorization you will not be able to stay in the study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, health care 
payers, and health care clearinghouses.  If we disclose your information to people who are not covered by the Privacy 
Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  People who do not have to 
follow the Privacy rules can use or disclose your information with others without your permission if they are allowed to 
do so by the laws that cover them.  
To maintain the integrity of this research study, you generally will not have access to your PHI related to this research 
until the study is complete.  When the study ends, and at your request, you generally will have access to your PHI that 
we maintain in a designated record set.  A designated record set is data that includes medical information or billing 
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records that your health care providers use to make decisions about you. If it is necessary for your health care, your 
health information will be provided to your doctor. 
We may remove identifying information from your PHI.  Once we do this, the remaining information will not be subject 
to the Privacy Rules.  Information without identifiers may be used or disclosed with other people or organizations for 
purposes besides this study.  
Contact Information
Contact Dr. Schuster’s research nurse (study coordinator) Bridget Fielder at 
 

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

if you have questions, concerns or complaints about the research
Contact the Emory Institutional Review Board at 

if you have questions about your rights as a research participant.

if you have questions, concerns or complaints about the research.

You may also let the IRB know about your experience as a research participant through our Research Participant 
Survey at http://www.surveymonkey.com/s/6ZDMW75.
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Consent and Authorization
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in this research study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the signed form to keep.
Name of Subject 
 
Signature of Subject (18 or older and able to consent)
Date              Time
Signature of Legally Authorized Representative  
Date              Time
Authority of Legally Authorized Representative or Relationship to Subject
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
Signature of Person Conducting Informed Consent Discussion
Date              Time
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