Clinical trial NCT01808222
Conditions: Recurrent Prostate Cancer
Sponsor: David M. Schuster, MD
Start date: 2013-11-01; Completion date: 2017-09-13
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators will perform a study with 25 patients in whom the investigators have a strong suspicion of prostate cancer that has returned to the body after having an initial treatment. The major goal of the investigation is to see whether anti-\[18F\] FACBC PET-CT and MRI imaging individually will be useful in the detection of local and extraprostatic recurrence of prostate cancer. Routine blood test will be done on the day of the FACBC scan and one week later as required by the FDA. All patients will undergo biopsy of the prostate as clinically appropriate per standard of care. If either the FACBC or MRI scans indicate cancer recurrence, the subject's cancer site(s) will also be biopsied as clinically appropriate.

Detailed description:
Prostate cancer is the most common solid tumor, with approximately 200,000 new cases diagnosed per year. Several different local therapies are available for treatment, including surgery and radiotherapy. Significant advances have been made which have improved the cancer control outcomes and treatment. Despite these significant advances, approximately 30% of patients treated with definitive local therapy experience recurrent disease. Recurrent (returning) disease usually displays rising Prostate-Specific Antigen (PSA) (a blood test for prostate cancer). The PSA level is often of limited use in differentiating local recurrence (i.e. recurrence in the prostate bed) from recurrence outside of the prostate bed (extra-prostatic recurrence). Imaging plays a central role in the detection of recurrent prostate carcinoma in the prostate bed and in the differentiation of prostatic from extraprostatic recurrence. There are newer methods of imaging such as magnetic resonance imaging (MRI) and positron emission tomography (PET) with molecular radiotracers that are currently under study for the imaging of post-therapy recurrence.

One PET radiotracer which has shown promise in the staging and restaging of patients with prostate carcinoma is anti-1-amino-3-\[18F\]fluorocyclobutane-1-carboxylic acid (anti-3-\[18F\]FACBC) which is a synthetic amino acid analog. FACBC demonstrated higher accuracy compared with other methods in the restaging of patients with suspected recurrent prostate carcinoma. FACBC has been tested in over 140 subjects in other studies in the Emory system including 128 subjects with prostate cancer.

The investigators will perform a study with 25 patients in whom the investigators have a strong suspicion of prostate cancer that has returned to the body after having an initial treatment. The major goal of the investigation is to see whether anti-\[18F\] FACBC PET-CT and MRI imaging individually will be useful in the detection of local and extraprostatic recurrence of prostate cancer. Routine blood test will be done on the day of the FACBC scan and one week later as required by the FDA.

All patients will undergo biopsy of the prostate as clinically appropriate per standard of care. If either the FACBC or MRI scans indicate cancer recurrence, the subject's cancer site(s) will also be biopsied as clinically appropriate. Biopsy of the suspected recurrence sites will be scheduled at the subjects' convenience as soon as possible after the scans.

Tissue obtained from the biopsy will undergo standard analysis to determine if prostate carcinoma cells are present. The secondary aim is to use left-over biopsy material to determine if there are genotypic differences between prostate carcinoma recurrence confined to the prostate bed and extraprostatic recurrence

Arms: arm 1: Participants receiving a bolus of anti-\[18F\]FACBC injected with PET-CT detection of cancer recurrence.
Interventions: intervention 1: FACBC
Intervention descriptions: intervention 1: Participants will receive a bolus of anti-\[18F\]FACBC injected IV over 1-2 minutes. The dosage will be approximately 10.0 millicuries (mCi) (3.70 x 108 becquerel (Bq)).

Protocol documents:
Prot_SAP_000.pdf: 
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Unique Protocol ID: IRB00061518 
 
NCT01808222 
 
Transmolecular Imaging of Recurrent Prostate Carcinoma with Exploration of Genomic Markers 
differences between Local and Distant Recurrence 
 
Principal Investigator: David M. Schuster, MD 
 
Date: 12/04/2014 
 
 
 
 


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Transmolecular Imaging of Recurrent Prostate Carcinoma with Exploration of Genomic 
Markers differences between Local and Distant Recurrence 
 
 
 
David M Schuster, MD 
Division of Nuclear Medicine and Molecular Imaging 
Department of Radiology and Imaging Sciences 
Ph: (404) 712-4859 
Email: dschust@emory.edu 
 
 
 
 
 
 
 
Co-Investigators: 
Ashesh Jani, MD 
 
Peter Nieh, MD 
 
Viraj Master, MD PhD 
 
Carlos Moreno, PhD 
 
Raghuveer Halkar, MD 
 
Baowei Fei, PhD, EngD 
 
Adeboye Osunkoya, MD 
 
Pardeep Mittal, MD 
 
Courtney Coursey Moreno, MD 
 
Sherif G. Nour, MD 
 
Mark M Goodman, PhD 
 
Zhengjia Chen, PhD 
Omer Kucuk, MD 
Oluwaseun Odewole, MD


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Enrolled n=25  
 
anti-[18F]FACBC Scan of abdomen/pelvis 
 
Multiparametric MRI of abdomen/pelvis 
Image guided prostate biopsy 
and of suspect extraprostatic 
lesions via best modality as 
clinically appropriate 
Correlate uptake of anti-[18F]FACBC 
and MR foci with pathology and 
clinical follow-up 
Tissue 
Provided 
for Aim 2 
and 
Subaim2a  


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Precis/Abstract 
 
Prostate cancer is the most common solid tumor, with approximately 200,000 new cases 
diagnosed per year. Several different local therapies are available for treatment, including 
surgery and radiotherapy [1]. Significant advances have been made in the technical aspects of 
surgery and of radiotherapy that have improved both the cancer control outcomes as well as the 
morbidity of treatment.  
 
Despite these significant advances, approximately 30% of patients treated with definitive 
local therapy experience recurrent disease [2, 3]. The differentiation of local from regional 
and from distant recurrence is of critical importance since salvage techniques can cure 
disease confined to the surgical field. If pelvic nodal involvement is suspected, radiation 
fields can be extended to include the pelvic nodes [4-6]. If a patient is not a candidate for 
salvage radiotherapy, he will likely be treated with systemic long-term hormonal therapy that is 
expensive and can result in significant morbidity, also leading to increased healthcare 
expenditures.  
In addition it has been noted in the literature that there may be genotypic and phenotypic 
differences between prostate carcinoma recurrence in the prostate bed and in extraprostatic 
nodal locations. Exome sequence analyses of prostate cancer metastases have identified 
mutations specific to castrate-resistant metastases including components of the Wnt pathway 
[7], while microarray studies have identified changes in gene expression specific to bone 
metastases including IGFBP2, WHSC2, and CRIM1 [8].  Integrative copy number and gene 
expression analyses have also identified important differences between primary and metastatic 
lesions including components of the AR pathways such as NCOA2 [9] and the polycomb 
complex chromatin suppressor EZH2 [10]. 
Imaging has the potential to play a central role in the detection of recurrent 
prostate carcinoma and in the differentiation of prostatic from extraprostatic recurrence. 
Yet to date, no one method has demonstrated definitive accuracy in this regard. For this 
reason, newer methods such as diffusion weighted MR (DWMR) and positron emission 
tomography (PET) with molecular radiotracers are currently under study for the characterization 
of post therapy recurrence [11-19]. Each of these techniques has its own strengths and 
weaknesses and each interrogates only a portion of the anatomic and imaging biomarker data 
present in recurrent prostate carcinoma. 
The specific hypothesis in this proposal is that a combination of molecular 
interrogation with the synthetic amino acid PET radiotracer anti-[18F]FACBC PET-CT 
combined with multiparametric MR including DWMR will provide a greater degree of 
imaging biomarker data than each technique individually. We believe that such 
transmolecular interrogation will enable us to more accurately diagnose recurrent 
prostate carcinoma within the prostate bed and in extraprostatic locations. We can then 
utilize tissue obtained from this study to examine the second specific hypothesis that 
there are genotypic differences between prostate carcinoma recurrence confined to the 
prostate bed and those that are extraprostatic, and also be useful to elucidate amino acid 
transport uptake mechanisms of anti-[18F]FACBC.  
 
 
 
 
 
 
 


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A. Background and Significance 
 
One in six men will develop prostate cancer [20]. Due to the widespread use of PSA testing, 
cancer is often detected before systemic disease occurs [2]. Depending on clinical presentation, 
therapy is typically approached through locally directed interventions such as radical 
prostatectomy, brachytherapy, external beam radiotherapy or cryotherapy. Yet, approximately, 
30% of patients treated with definitive local therapy experience recurrent disease [2, 3]. 
 
Recurrent disease usually manifests with rising PSA. The differentiation of local from 
extraprostatic recurrence is of critical importance since salvage techniques can cure disease 
confined to the prostate bed. If pelvic nodal involvement is suspected, radiation fields can be 
extended to include the pelvic nodes [4-6]. Systemic disease is treated with hormonal 
manipulation and/or chemotherapy. PSA level is not useful in the differentiation of local from 
extraprostatic recurrence, though the rate of PSA rise may have some value [21].  
 
Imaging plays a central role in the detection of recurrent prostate carcinoma in the 
prostate bed and in the differentiation of prostatic from extraprostatic recurrence. Conventional 
methodology including computed tomography (CT), magnetic resonance imaging (MR), 
transrectal ultrasound, bone scan and 111Indium-capromab-pendetide (ProstaScint) (EUSA 
Pharma, Langhorne, PA) may provide important information, but suffer from less than optimal 
diagnostic performance [22-30]. Newer methods such as diffusion weighted MR (DWMR) and 
positron emission tomography (PET) with molecular radiotracers are currently under study for 
the characterization of post-therapy recurrence [11-19]. MR with superparamagnetic (USPIO) 
particles has shown promise but is not available in the US [19]. The sensitivity of most imaging 
techniques is dependent upon PSA level, doubling time, and velocity [16, 31, 32]. 
 
One PET radiotracer which has shown promise in the staging and restaging of patients 
with prostate carcinoma is anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-
[18F]FACBC) which is a synthetic amino acid analog with little renal excretion and transport via 
sodium dependent and independent pathways [33-35]. In a recent study, anti-3-[18F]FACBC 
demonstrated higher accuracy compared with 111Indium-capromab-pendetide in the restaging of 
patients with suspected recurrent prostate carcinoma [36]. Yet there was suboptimal specificity 
in the prostate bed, especially after non-radical prostatectomy therapy. It is not yet clear if this 
was the result of sampling error during biopsy and/or nonspecific uptake by anti-3-[18F]FACBC 
in non-neoplastic tissue.  
In one study of patients with both primary and recurrent prostate carcinoma, DWMR 
demonstrated significant differences of mean apparent diffusion coefficients (ADC) between 
malignant and benign nodes with an accuracy of 85.6% (sensitivity 86%, specificity 85.3%) 
compared with an MR accuracy of 66.1% based on nodal size alone. Yet there was significant 
overlap of individual ADC values between benign and malignant foci [18]. In addition, less than 
50% of patients had histologic follow-up and 6 month follow-up was accepted as truth in those 
without histologic confirmation. In another recent study in patients with suspicion of recurrence 
after high dose brachytherapy, DWMR was noted to have a sensitivity of 68% and a specificity 
of 95% in the detection of tumor in the prostate bed [37]. Multiparametric MRI achieved the 
highest sensitivity (77%) but with slightly decreased specificity (92%). 
Thus, there may be utility in combining both multiparametric MR and synthetic amino 
acid PET as a hybrid transmolecular technique in the detection and restaging of recurrent 
prostate carcinoma. The data from this study could be used to design a more comprehensive 
study that would lend itself to novel PET-MR hybrid devices which are now commercially 
available.  
There may also be genotypic and phenotypic differences between prostate carcinoma 
recurrence in the prostate bed and in extraprostatic nodal locations. Exome sequence analyses 


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of prostate cancer metastases and integrative copy number and gene expression analyses have 
identified mutations specific to specific metastases [7, 8].  Other authors have also identified 
important differences between primary and metastatic lesions including components of the AR 
pathways such as NCOA2 [9] and the polycomb complex chromatin suppressor EZH2 [10]. 
Furthermore, we have determined in RT-PCR analysis of primary and recurrent prostate 
carcinoma and distant metastases that the amino acid transport (AAT) proteins PAT1, LAT2 and 
ASCT2 as well as LAT1, xCT, LAT3 and ASCT1 are associated with malignancy. In analysis of 
lymph node metastases only, LAT1 and ASCT1 drop below significance. In addition, out of the 
AATs which were associated with malignancy, PAT1 had the highest correlation co-efficient of 
significance of expression to anti-3-[18F]FACBC uptake [38]. 
 
A. Specific Aims 
 
Aim 1. Investigate the ability of anti-[18F]FACBC PET-CT and multiparametric/DW MRI 
imaging individually then together to detect local and extraprostatic recurrence of 
prostate cancer. 
We will undertake a preliminary clinical trial with 25 patients post-definitive non-
prostatectomy therapy for prostate carcinoma and who have suspected recurrence 
based on elevated PSA greater than nadir plus 2 ng/ml with absolute PSA ≥ 4.0 ng/ml 
with any doubling time (DT) or with PSA 2.0-3.99 ng/ml with DT ≤10 months. We will 
perform anti-[18F]FACBC PET-CT with early and delayed imaging, as well as 
multiparametric/DWMR. Each study will be blindly interpreted then fused utilizing 
software registration and co-interpreted. Data from both studies will be used to direct 
biopsies to areas of concern in the prostate bed, and in extraprostatic locations. Results 
will be compared to the standard of pathologic analysis of prostate bed biopsies as well 
as clinical follow-up. The diagnostic performance of anti-[18F]FACBC PET-CT and 
multiparametric/DWMRI will be assessed individually then together. We will also 
determine if there is correlation between synthetic amino acid PET and MR, such as 
SUV and apparent diffusion co-efficient (ADC). 
 
Rationale for AIM 1. 
As has been outlined in the Preliminary Results section of this proposal, anti-[18F]FACBC has 
been demonstrated to 1) have high sensitivity in the detection of recurrent prostate carcinoma 
though with suboptimal specificity in the prostate bed, and 2) the ability to differentiate prostatic 
from extraprostatic recurrence with high accuracy. anti-[18F]FACBC may thus have specific 
advantages for imaging recurrent prostate neoplasia within a clinical setting over conventional 
imaging. Yet, MR, especially with the addition of diffusion weighted imaging, has been reported 
in preliminary studies to provide high accuracy especially in the characterization of prostate bed 
recurrence. We hypothesize that utilization of a transmolecular approach combining synthetic 
amino acid radiotracer PET imaging with multiparametric MR has the potential to identify the 
presence and location of recurrent prostate carcinoma to a higher accuracy than either modality 
alone. Therefore the most comprehensive manner to assess our hypothesis that PET-CT 
imaging with anti-[18F]FACBC in combination with multiparametric MR will lead to 
improved patient care resulting from detection of local and distant recurrent disease 
(Specific Aim #1) is to undertake a prospective clinical trial designed to address these 
issues.  
 


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Secondary Aims 
Aim 2. To determine mRNA differences between prostate carcinoma recurrent in the 
prostate bed and extraprostatic locations and to correlate any difference with 
quantifiable imaging biomarker data such as SUV for anti-[18F]FACBC PET-CT and ADC 
for MR. 
Within the structure of the clinical trial (the same 25 patients) we will obtain sufficient 
tissue to perform mRNA sequencing on samples to exploit differences between the 
genetic profiles of recurrent prostate carcinoma in the prostate bed versus metastases. 
Since approximately 30% of patients with PSA > 4 ng/ml by our experience manifest with 
both prostate bed and nodal recurrence, we believe at least 8-10 patients in whom this 
comparison can be directly made will be available for analysis. This may also occur with 
lower PSA levels with faster DT. We will then correlate any differences in genotypic 
profile with imaging biomarkers from synthetic amino acid PET and MR, such as SUV 
and ADC. 
 
Sub-aim 2a. To evaluate protein expression of previously identified amino acid 
transporters (AATs) that have been implicated in the uptake of anti-[18F]FACBC. 
Also within the context of the clinical trial of 25 patients, we will, whenever there is 
sufficient tissue, determine if candidate amino acid transport (AAT) proteins identified 
from data obtained in an earlier study (Project 1: P-50 ICMIC) are expressed. We will 
perform IHC analysis of up to 7 candidate AAT or co-transporters, specifically PAT 1, 
LAT1, LAT2, 4F2hc, and ASCT2, LAT3 and ASCT1 to understand if the AAT whose 
mRNAs are increased in malignant prostate carcinoma and correlated with anti-
[18F]FACBC uptake are expressed at the protein level by IHC analysis.  
 
Rationale for Aim 2 and Sub-aim 2a. 
As has been outlined in the Preliminary Results section of this proposal, there is 
preliminary data in the literature of gene expression and mutational differences between primary 
prostate carcinoma cells and those prostate metastases [7-9] as well as between bone 
metastases and non-osseous metastases [8]. We propose within the context of this clinical trial 
to provide tissue to further understand these differences both in the ability of prostate carcinoma 
to transport and retain amino acids measured as uptake of anti-[18F]FACBC and expression 
characteristic as studied by multiparametric MR such as ADC parameters on DWMR and 
uptake and retention of Gadolinium. If we can determine that there are gene expression 
differences between malignancy confined to the prostate bed and those that are extraprostatic, 
we can correlate these differences to PET uptake and MR appearance. Furthermore, we may 
also be able to derive incidental genotypic information that could be exploited on subsequent 
unrelated experiments. In addition, we have preliminary evidence based on our earlier research 
that PAT1, LAT2 and ASCT2 as well as LAT1, xCT, LAT3 and ASCT1 were associated with 
malignancy. Out of the AATs that were associated with malignancy, PAT1 expression had the 
strongest correlation coefficient relative to anti-3-[18F]FACBC uptake [38]. We believe that a 
study such as this one provides an ideal opportunity to obtain both prostatic and extraprostatic 
tissue from the same patient in order to test these hypotheses using the patient as his own 
control.  
Our rationale for utilizing patients with PSA ≥ 4 is as follows. A total of 127 patients have 
been studied already in an R-01 study of the diagnostic performance of anti-3-[18F]FACBC 
versus conventional imaging. If the patients are stratified by PSA level as in the table below, 
41/73 were positive in the prostate bed only, 25 in both prostate bed and lymph nodes, and 1 in 
lymph nodes only. Thus, in the 25 patients whom will be studied in this population, 


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approximately 23 will be expected to have disease in the prostate bed and approximately 9 will 
have disease in nodes, most of the latter will also have disease in the prostate bed. This should 
provide sufficient tissue for the above secondary aims. In addition, we have demonstrated that 
greater extraprostatic involvement will occur with shorter DT even at lower PSA levels. Thus the 
addition of PSA 2.0-3.99 ng/ml plus DT ≤ 10 months is a reasonable method to increase 
recruitment while still acquiring tissue from extraprostatic involvement.  
 
 
 
 
 
 
 
We hypothesize that by identification of disease recurrence in the prostate bed and extra-
prostatic locations, we can exploit differences in mRNA analysis to correlate these differences to 
synthetic amino acid transport as well as MR parameters such as ADC mapping, and also better 
understand the relationship of AAT protein expression to anti-3-[18F]FACBC uptake. Therefore 
the most comprehensive manner to obtain tissue to test our hypotheses is within the 
context of this prospective clinical trial.  
 
C1.0 Research Design and Methods (Aim 1) 
 
We will undertake a clinical trial with 25 patients who have undergone definitive therapy for 
prostate carcinoma and who have suspected recurrence based on elevated PSA greater than 
nadir plus 2 ng/ml with absolute PSA ≥ 4.0 ng/ml with any doubling time (DT) or with PSA 2.0-
3.99 ng/ml with DT ≤10 months. We will perform anti-[18F]FACBC PET-CT with early and 
delayed imaging as per the detailed protocol below. All patients will also undergo staging 
including multiparametric MR with diffusion weighted imaging. Other standard of care imaging 
such as bone scan, ProstaScint, CT, and transrectal ultrasound may also be performed per 
clinical judgment. These latter studies including MR are standard of care at our institution and 
will not be charged to the grant. We will investigate the ability of anti-[18F]FACBC PET-CT 
imaging to detect recurrence of prostate carcinoma in the prostate bed and in extraprostatic 
locations validated by pathologic analysis of prostate bed biopsies ideally guided by MR or 
ultrasound fusion of molecular to anatomic data in the prostate bed and percutaneous or 
laparoscopic guided biopsies of nodal and skeletal disease. Within the structure of the clinical 
trial, we will also evaluate the ability of transmolecular imaging with anti-[18F]FACBC PET-CT 
and multiparametric MR in the discrimination of prostatic from extra-prostatic recurrence, 
validated by a combination of pathologic analysis as well as imaging and clinical correlation. 
Though the grant itself extends for one year, patients may be followed up to 5 years to 
determine true negative imaging findings at minimal cost. Finally within the context of the clinical 
trial, tissue will be obtained for Aims 2 and Sub-aim 2a. 
 
 
C1.1 Anti-[18F] FACBC radiolabeling 
Methods. Production will be accomplished by the GE FastLab cassette system. Alternatively by 
automated synthesis developed by J. McConathy and M.M. Goodman [39] as outlined in Figure 
15. The automated radiosynthesis of anti-[18F]FACBC will be carried out in a chemical process 
PSA group 
<4 (n=54) ≥ 4 (n=73) Total(n=127) 
Prostate bed only (+) 27 
41 
68 
LN only (+) 
3 
1 
4 
Both 
8 
25 
33 
Total 
38 
67 
105 


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control unit (CPCU) with a computer interface. The two-step reaction sequence will involve 
incorporation of no-carrier-added potassium [18F]fluoride into a protected triflate precursor and 
deprotection using aqueous hydrochloric acid. The crude reaction mix will be passed in series 
through ion-retardation resin, an alumina-N SepPak®, an HLB cartridge and a 0.22 µm sterile 
filter, and the resulting aqueous solution will be collected in a dose vial. The radiochemical purity 
of the product will be determined by TLC.  Additional chemical solvent purity will be measured 
by Gas Chromatography (GC). The total time for synthesis of anti-[18F]FACBC after delivery of 
18[F]fluoride will be ~70 minutes, and the average decay-corrected yield of anti-[18F]FACBC will 
be 24 ± 4 % (n = 40 runs, average ± standard error) in over 99% radiochemical purity. This 
procedure will provide 140-200 mCi of anti-[18F] FACBC at the end of synthesis. We have 
prepared greater than 100 batch productions for tumor imaging in volunteer subjects.  
 
 
 
 
 
BocHN
CO2CH3
OSO2CF3
BocHN
CO2CH3
18F
H2N
CO2H
18F
a
b
anti-[18F]FACBC
a)K18F, K222, K2CO3; 90C b) 4 NHCl, 120 C
 
C1.2 PET-CT imaging protocol to measure amino acid uptake 
Methods. PET-CT images will be acquired on a GE Discovery 690 Time of Flight (TOF) 16 slice 
PET-CT scanner or equivalent.  All studies will use measured attenuation correction (routinely 
acquired through the initial CT portion of the scan).  All subjects will be required to fast for four 
hours to normalize their neutral amino acid levels. Non-strict fasting is not an absolute 
contraindication and may be overridden on a case by case basis since it is unknown if fasting 
affects FACBC uptake positively or negatively. One hour prior to scanning, the patient will drink 
500 ml of 1.2% (Readi-Cat) oral contrast over 1 hour to maximize conspicuity of abdomen and 
pelvic structures. IV contrast will not be used. Prior to placement in the tomographic gantry, an 
intravenous catheter will be placed for injection of tracer. The subject will be placed in the 
tomograph gantry for completion of the CT scan. Ambient conditions will be a quiet, dimly lit 
room. anti-[18F]FACBC (10 mCi) will be injected into an antecubital vein in a slow bolus infusion 
over 1-2 minutes. At 5 minutes, 4 consecutive 2.5 minutes per frame acquisitions will be 
obtained starting from the prostate level of the pelvis and extending superiorly to the diaphragm. 
At 16 minutes, this process will be repeated. Thus, 4-15.5 minute, and 16-27.5 minute 
acquisitions from the pelvis extending superiorly to the abdomen at the diaphragm will be 
obtained (Figure 1). This imaging schema is based on analysis of our data to date in which early 
and delayed uptake to 30 minutes yields the most diagnostic information. Imaging may be 
carried out with HD mode and respiratory gating or TOF mode with or without respiratory gating. 
 
 
 
 
 
 
 
 
 
Minutes:  5-7.5    8-10.5   11-13.5   14-15.5                  16-18.5 19-21.5 22-24.5   25-27.5 
 
Figure 1: CT of abdomen and pelvis followed by injection of anti-[18F]FACBC then PET scanning 
as above. 
Synthesis of anti-
FACBC 
 


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Summary of PET-CT Scanning Procedure 
1) The patient will be placed in the tomographic gantry for a CT scan of the abdomen-
pelvis to be utilized for anatomic imaging and correction of emission data (approximately 
1 minute).  
2) The patient will then receive a bolus of anti-[18F]FACBC injected IV over 1-2 minutes 
3) The dosage will be approximately 10.0 mCi (3.70 x 108 Bq). 
4) At 5 minutes after initial injection (3 minutes after injection ceases), a 2.5 minute per 
bed position PET acquisition will start at the pelvis with the inferior aspect of the 
acquisition to include the entire prostate or prostate bed.  
5) 4 bed positions will be obtained which should cover pelvis through abdomen to the 
diaphragm.  
6) This sequence will be repeated once. 
7) The entire study including injection of radiotracer should take approximately 30 
minutes. 
 
C1.3 Multiparametric/DW MRI imaging  
 
Pelvic and abdominal MRI through the prostate will be performed on a 1.5 T MR scanner or 
equivalent utilizing a standard clinical protocol (figure 2) including but not limited to the following 
sequences: 
1) Dynamic contrast enhanced (DCE) perfusion protocol of the pelvis (including prostate) with 
delayed post-contrast sequences of the abdomen-pelvis. 
2) High Resolution T2 of the pelvis 
3) SPACE 3-D volumetric images of the pelvis 
4) Diffusion-weighted imaging (DWI) of the abdomen and pelvis 
 
Figure 2.  
 
 
 
 
 
 
 
 
 
 
 
Figure 2. 8mm prostate carcinoma nodule in the right posterior peripheral zone (arrow) on high 
resolution T2 (A), dynamic 3D gadolinium enhanced T1 gradient echo 30 sec (B) and 90 sec MRI 
(C). 
 
 
C 1.4 Image Analysis of anti-[18F]FACBC PET-CT 
Methods. The methods of image analysis to be used for the anti-[18F]FACBC PET-CT are as 
follows: 
1) Images will be reconstructed with iterative technique and hardware fused (PET to CT) on a 
MimVista or similar workstation which enables SUV (mean, maximum, total lesion activity) as 
well as standard size measurements of lesions. An edge seeking conformational volume of 
A 
B 
C 


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interest tool as appropriate (PET Edge, MIMvista, Cleveland, OH) will typically utilized. If this is 
not possible due to anatomy an appropriate 2D or 3D ROI will be utilized.  
2) Visual inspection of the PET-CT images by 2 board certified nuclear medicine imagers who 
will be blinded to all history and other imaging. Each reader will assess images individually and 
any disagreement will be resolved by consensus. Thus, Z score will be calculated. 
3) For anti-3-[18F]FACBC, uptake will be defined according to the following criteria in relation to 
background structures: mild (above blood pool but less than marrow), moderate (above or equal 
to marrow but less than liver), and intense (equal to or above liver). Visual analysis will aided by 
quantitative criteria of SUVmax lesion/SUVmean background. Maximum and mean SUV of each 
focus of abnormal uptake as well as background structures including liver, marrow at L3, aorta, 
and bladder will be recorded. For prostate beds as well as extra-prostatic sites such as lymph 
nodes and bone, abnormal moderate or intense focal uptake over background marrow which 
persist from early to delayed images will be considered prospectively positive. These criteria 
were used to analyze data in our study of anti-[18F]FACBC in recurrent disease [40].  
4) Confidence in interpretation for disease within the prostate bed and outside the bed will be 
recorded with the following scale on a per patient basis and any all recordable lymph nodes: 1-
defiinitvely negative; 2 -probably negative; 3 - indeterminate; 4 - probably positive; 5 – 
definitively positive. 
5) In summary, we will record both visual and semi-quantitative analysis of the prostate 
bed, positive lymph nodes (greater than blood pool), and other structures such as 
skeletal foci on early and delayed time frames. We will use maximum and mean SUV as 
well as standard bidimensional size measurements. We will also record similar 
measurements on background structures such that we may derive uptake ratios. 
 
C1.5 Image Analysis of MR 
The MR studies will be interpreted by an MR imager. (At some point after primary analysis, a 2nd 
interpretation may also be blindly performed and agreement (Z Value) recorded.) Studies will be 
interpreted utilizing standard interpretative criteria for MR and including anatomic criteria, 
perfusion analysis and DWMR criteria. Confidence in interpretation for disease within the 
prostate bed and outside the bed will be recorded for each of these three interpretative 
categories individually and in aggregate with the following scale on a per patient basis and any 
all recordable lymph nodes: 1-defiinitvely negative; 2 -probably negative; 3 - indeterminate; 4 - 
probably positive; 5 – definitively positive. Typically, a combination of abnormality on all relevant 
sequences will result in a “5” (e.g. DCE, DWI, and T2), while no abnormality on any sequence 
will result in a “1”. A combination of suspicious and benign findings on pulse sequences will 
result in a “2”, “3”, or “4” depending on particular findings. 
 
C1.6 Image Analysis of PET-MR 
After individual interpretation of each study, then the PET and appropriate sequences from the 
MR (typically post-contrast abdominopelvic supplemented by other sequences) will be co-
registered using rigid software registration on a MimVista 5.5 or similar workstation. The studies 
will then be analyzed by consensus by one of the 2 nuclear imagers and the primary research 
MR imager. All foci previously recorded by each group as positive or negative will then be 
assessed by the group taking into account all parameters previously employed. New foci may 
also be identified. Confidence in interpretation for disease within the prostate bed and outside 
the bed will then be recorded with the following scale on a per patient basis and any all 
recordable lymph nodes: 1-defiinitvely negative; 2 -probably negative; 3 - indeterminate; 4 - 
probably positive; 5 – definitively positive. Typically agreement on both studies will be recorded 


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as “1” or “5”, and combination of lack of agreement in a “2”, “3”, or “4” depending on particular 
findings. 
 
 
C1.7 Clinical and Histologic Assessment. 
 
Methods. After the anti-[18F]FACBC scan has been obtained and interpreted, the following will 
occur: 
1) All patients with identifiable sites of disease on either PET or MR imaging may undergo either 
ultrasound guided biopsy after fusion with PET and/or MR data (Fei R-01) or MR guided 
techniques as clinically appropriate. If this is not deemed appropriate by the clinical team and 
referring Urologist or Radiation Oncologist, patients will undergo standard TRUS 12-core biopsy 
as clinically appropriate. A 12 core biopsy protocol as clinically appropriate will be used as it has 
greater sensitivity for disease detection, with no increased morbidity.  
2) Patients with abnormal suspicious findings on MR, and/or anti-[18F]FACBC PET-CT may have 
those suspicious lymph nodes or other extraprostatic sites sampled as clinically appropriate 
through a combination of percutaneous image guided needle biopsy, laparoscopic techniques, 
as well as open lymph node dissection when appropriate. With both laparoscopic and open 
nodal dissections, it is standard practice to also sample adjacent imaging negative nodes. Rare 
sites of suspect metastases such as the inguinal nodal regions will be evaluated via a 
combination of physical exam and percutaneous biopsy as appropriate. On a per patient basis, 
suspicious uptake which corresponds to abnormal lymph nodes on MR or PET studies will be 
biopsied per standard of care as clinically appropriate.  
3) All pathologic samples will undergo standard analysis to determine if prostate carcinoma cells 
are present as well as (if there is sufficient tissue) provide tissue for Aim 2 and Sub-aim 2a. 
Specimens will be fixed in neutral-buffered formalin, embedded in formalin, sectioned at 5-
micron thickness and stained with hematoxylin & eosin (H&E) using standard pathology 
procedures.  Board-certified anatomic pathologists from Emory University will perform all 
diagnosis of prostate carcinoma (and when applicable Gleason grading and staging) using 
standard criteria. RNA analysis and immunohistochemistry will be performed at end of study on 
parallel histologic sections of tissue confirmed to contain prostate carcinoma.   
4) All patients may also be followed up as scientifically appropriate at least one year and up to 
five years regardless of initial findings in order to optimize correlation of imaging to clinical 
findings. It is not possible to do a template nodal dissection on all patients regardless of 
findings, and certainly not on nodal imaging negative patients. While it is true that we will not 
biopsy lymph nodes if all the imaging modalities are negative, there will be patients who are MR 
imaging positive but PET negative and visa-versa who will get biopsied. Yet biopsies or 
sampling will typically performed only when there is an identifiable target on anatomic imaging 
and will thus be standard of care. Some patients who undergo open or laparoscopic nodal 
sampling for positive findings will have a limited template dissection of adjacent imaging 
negative nodes (a standard practice). By clinical and ethical necessity, the imaging and biopsy 
negative patients will be confirmed by lack of lymph node progression on imaging as well as 
stable PSA levels. The standard of care outside the trial includes serial PSA measures as well 
as appropriate imaging such as CT or MR and repeat imaging as required.  
5) A Ground Truth Panel composed of two urologists (Nieh and Master or substitute) and a 
radiation oncologist (Jani or substitute) will meet once sufficient data has been collected and/or 
communicated via email. The diagnostic imagers will not be included on this panel but will 
present the data. Truth will be ascertained via the criteria outlined below. If there were initial 
differences of opinion, further discussion will ensue until a group consensus can be achieved.  


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6) Presence or absence of disease in the prostate bed will be confirmed by biopsy only 
overridden by clinical data. For example, a substantial reduction in PSA after prostatic bed 
salvage therapy without a subsequent substantial PSA rise in at least 6 months would not only 
establish presence of presumed prostatic bed disease but also absence of extraprostatic 
disease. Extraprostatic nodal involvement per patient will be typically confirmed by pathologic 
proof or under certain circumstances by response after focal therapy if scientifically justifiable. 
Skeletal involvement will be confirmed with either biopsy or typical appearance on MR [41] or 
other accepted confirmatory imaging such as typical appearance on bone scan or CT. Absence 
of extraprostatic disease will typically be confirmed by either a substantial reduction in PSA after 
prostatic bed therapy without a substantial rise in at least 6 months as above, and/or stable 
appearance on CT or MRI for greater than 1 year without evidence of nodal or bone 
involvement as medically and scientifically appropriate. Because some patients had definitive 
follow-up for the prostate bed but not extraprostatic disease, and visa-versa, the number of 
patients in each sub-analysis may differ.  
7) Patients who are prostate bed positive and extraprostatic negative may get treated with local 
therapy (radiation, cryoablation, salvage surgery, etc.) as appropriate. Most of these patients will 
not initially get hormonal therapy and will be entered into the followup group. It is true that some 
patients with either high Gleason scores, impending or with cord compression and/or pathologic 
fracture, hydronephrosis, and/or rapid PSA doubling time of less than 3 months will require 
hormonal therapy, but this is not the majority of patients (approximately 15-20% worst case 
scenario). The majority of patients (80-85%) will have low to intermediate risk disease and PSA 
recurrence reflecting the prevalence of low and intermediate risk disease in the United States. 
Therefore these patients can be followed off hormonal therapy but with local therapy as needed.  
 
C1.8 Correlation of FACBC and MR to and Clinical Outcome 
 
Upon completion of the study and/or after additional follow-up, each patient may be re-reviewed 
by the same Ground Truth Panel to determine if the predicted findings on anti-[18F]FACBC scan 
and MR individually and in tandem match those of clinical and pathologic findings especially in 
regard to the identification of prostatic versus extraprostatic recurrence. Also at that time uptake 
parameters will be reviewed. At no time this study will interfere with proper therapy as 
determined by the patient’s physicians and the patient. 
 
C2.0 Study Design and Methods (Aim2 and Sub Aim 2a)  
Rationale. We hypothesize that anti-[18F]FACBC uptake is mediated by a LAT protein subtype 
or subtypes.  However, the precise LAT subtype involved in all cases is unknown.  We also 
further hypothesize that there are genotypic differences between recurrent prostate carcinoma 
cells confined to the prostate bed and those that are extraprostatic and that these differences 
can be explored via proper identification of candidate tissue via transmolecular imaging to be 
performed at termination of study or when sufficient tissue has been collected. 
 
Experimental Design. To test the above hypothesis, we will compare mRNA expression of 
recurrent prostate carcinoma tissue within the prostate bed and extraprostatic. In addition we 
will utilize anti-[18F]FACBC avid tissue to confirm that the following AAT subtypes based on 
preliminary data are expressed at the protein level: PAT 1, LAT1, LAT2, 4F2hc, and ASCT2, 
LAT3 and ASCT1. We will study 8-10 samples of each recurrent prostate carcinoma in the 
prostate bed and 8-10 samples of disease outside the prostate bed, preferably in the same 
patient. We predict that one or more AAT subtypes will be relatively overexpressed by IHC in 
FACBC-avid carcinoma.  We also predict that there will be differences in mRNA expression 


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based on these tissue samples between disease confined to the prostate bed and those that are 
extraprostatic. Based upon tissue availability we will perform IHC in the following rank priority: 
First: PAT 1; Second: LAT1, LAT2, 4F2hc; Third: ASCT2, LAT3 and ASCT1. This priority 
ranking is based on our desire to first confirm phenotypic expression of PAT1, since presence of 
this AAT correlated most strongly with anti-[18F]FACBC uptake, followed by LAT1 and LAT2 with 
the heterodimeric associated protein 4F2hc, and ASCT2, LAT3 and ASCT1. 
 
C 2.1 Quantitative next-generation mRNA sequencing  
Methods. For experiments on fixed tissue RNA will be extracted at the Cancer Genomics 
Shared Resource (CGSR) at the Winship Cancer Institute from macrodissected 5 micron 
sections. The CGSR has extensive experience in preparing Total RNA from FFPE tissues [42].  
FFPE RNA extraction will be performed using the Omega Biotech methodology in 96-well 
format on a Kingfisher FLEX Liquid Handler Robot.  FFPE RNA will be quantitated by nanodrop 
spectrophotometry, and tested for RNA integrity and quality by Taqman analysis of the RPL13a 
ribosomal protein.  Samples with sufficient yield (>500 ng), A260/A280 ratio > 1.8 and RPL13a CT 
values less than 31 cycles will be used for preparing sequencing libraries using the TrueScript 
kit (Illumina).  Amplified cDNA libraries will be sonicated to an average length of 250 bp with a 
Covaris E-120 Adaptive Focused Acoustics Instrument.  We will repair the ends of the sonicated 
DNA using the Illumina TrueScript protocol and generate barcoded libraries for RNA-seq 
analysis on an Illumina HiSeq 2000 instrument at the Southern California Genotyping 
Consortium at UCLA.  Agilent Bioanalyzer Nanochip analysis will be performed to ensure the 
integrity of libraries prior to sequencing.  We will obtain 60 million reads per sample of 50bp 
paired-end sequencing reads using the Illumina version 3 kits with three samples multiplexed 
per sequencing lane.   
Fluorogenic quantitative RT-PCR assays will be used to confirm changes identified by 
RNA-seq analysis and performed in triplicate with standard SYBR-Green methodology on the I-
cycler system (Bio-Rad, Hercules, CA, USA) according to published protocols with minor 
modifications [43].  Reaction specificity will be assessed by melting point analyses, in which 
single melting point peaks are required at temperatures predicted by amplicon sequence.  
Reactions without reverse transcription and template will serve as controls for DNA 
contamination and specimen carry-over.  Test gene expression will be normalized to 28S 
ribosomal RNA and referenced to a standard RNA specimen.  Relative normalized gene 
expression of each LAT subtype will be compared in FACBC avid versus non-avid prostate 
carcinoma, with statistical significance assessed by analysis of variance (ANOVA). 
 
C 2.2 Immunohistochemistry  
Methods. Fixed tissue sections (5 μm thickness) will be dewaxed, and steam antigen retrieval 
will be performed at pH 6.5 in a pressure cooker for 20 minutes [44].  Tissue sections will be 
incubated with primary antibodies directed against PAT 1, LAT1, LAT2, 4F2hc, and ASCT2, 
LAT3 and ASCT1. Sections will be deparaffinized and subjected to heat-induced epitope 
retrieval by steaming for 15 minutes.  IHC staining will be performed at the Winship Cancer 
Institute Research Pathology Shared Resource using an automated (DAKO) 
immunohistochemistry stainer and established procedures and protocols. Optimal dilutions for 
all antibodies will be determined empirically using archived sections from prostatectomies and 
blocking reagents recommended by the manufacturers. Immunohistochemical reactions will be 
developed with diaminobenzidine as the chromogenic peroxidase substrate. Sections will be 
counterstained with hematoxylin after immunohistochemistry.  Specificity will be verified by 
negative control reactions without primary antibody. Intensity of the various 
immunohistochemical stains were scored blindly by a board-certified pathologist as follows; 0-


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negative, 1+ (weak), 2+ (intermediate) and 3+ (strong).  The expression of these markers will be 
correlated with FACBC uptake by ANOVA testing 
 
 
C 2.3 RNA-Seq Results and Imaging Findings  
 
RNA-Seq sequencing reads produced from the Illumina HiSeq 2000 will be mapped to the 
human reference genome (hg19) using Bowtie [45] and fragment reads per kilobase (FRPK) 
calculated using TopHat [46].  Only uniquely mapped reads will be retained for analysis.    
Relative changes in mRNA expression will be computed using Cufflinks and Cuffdiff [47] in a 
locally installed Galaxy bioinformatics environment [48, 49] deployed by the Moreno laboratory.   
 
D. Subject recruitment: 
All patients will be recruited from the Emory Healthcare (Drs. Nieh, Master, Rossi and Jani), 
Urology and Radiation Oncology clinics per the inclusion and exclusion criteria below.  
 
Inclusion Criteria:  
 
1. Patients must be 18 years of age or older. 
2. Patients will have been originally diagnosed with localized (Stage T1c, T2, or T3 ) prostate 
carcinoma and have undergone what was considered definitive non-prostatectomy therapy for 
localized disease. 
3. In the case of cryotherapy, external beam radiation, or HiFU the procedure will have occurred 
at least one year in the past. In the case of brachytherapy, treatment will have occurred at least 
2 years in the past to eliminate patients with so-called “PSA bump.”  
4. Patient will have suspicion of recurrent prostate carcinoma as defined by: the ASTRO-RTOG 
Phoenix criteria of elevated PSA greater than nadir plus 2 ng/ml with absolute PSA ≥ 4.0 ng/ml 
with any doubling time (DT) or with PSA 2.0-3.99 ng/ml with DT ≤10 months. 
5. Ability to lie still for PET scanning 
6. Patients must be able to provide written informed consent.  
 
 
Exclusion Criteria: 
1. Age less than 18. 
2. Greater than T3 disease in past and/or treated with prostatectomy. 
3. Less than 1 year since cryotherapy, external beam radiation therapy, or HiFU, or 2 years 
since brachytherapy.  
4. Does not meet above criteria of suspicious PSA elevation 
5. Inability to lie still for PET scanning 
6. Cannot provide written informed consent. 
7. Bone scan findings characteristic for metastatic prostate carcinoma 
8. Less than 1 month since any prior prostate biopsy (to decrease false positive uptake from 
inflammation).  
 
Written informed consent will be obtained before subject participation in the study.  No 
procedures will be performed before written informed consent is obtained.  Participants 
will be assigned an identification number for screening purposes; data collected during 
the screening process will be recorded using that number.   
 


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PET Scan Day:  The following procedures will be performed: 
 
Obtain written informed consent 
 
Inclusion/exclusion criteria review 
 
Vital signs measurements 
 
Clinical laboratory tests (serum chemistries, CBC and urinalysis) 
 
 
To be repeated at one week (+/- 3 days) after scan 
 
 
E. Statistical Analysis 
E.1 Aim 1 
Receiver Operating Characteristic (ROC) analysis will be conducted to instigate the predictive 
power of FACBC PET and MR and determine if a variation in standard criteria or if combined 
criteria better maximizes sensitivity, specificity and accuracy of each technique using Chi-
square test. The predictive accuracy of each technique will be determined using the positive 
predictive value (PPV) relative to the clinical and pathologic findings. The PPV of imaging will be 
assessed by calculating the probability of obtaining clinical and pathological outcomes that 
confirm the predicted positive findings based on the individual and combined scans. A similar 
negative predictive value (NPV) will also be calculated based upon a negative pathologic 
sampling as well as clinical/imaging follow-up at least 1 year or more. Formal hypothesis testing 
will be conducted to obtain inferences regarding differences between the predictive accuracies 
of these two approaches.  
 
Each case will be evaluated as follows:  
 
1) Results of biopsy as well as clinical follow-up will be correlated with prediction of local 
and distant neoplastic involvement by MR and anti-[18F]FACBC PET-CT. 
2) Results of biopsy of lymph nodes or other extra-prostatic sites as well as clinical follow-
up will be correlated with prediction of extraprostatic neoplasia by MR and anti-
[18F]FACBC PET-CT.  
3) Registered PET and MR will be correlated both qualitatively and quantitatively to 
pathologic and clinical results and in the discrimination of prostatic from extra-prostatic 
recurrence. 
4) Thus, truth for presence of disease will be established by biopsy/pathology and/or 
appropriate clinical followup. Truth for absence of disease will be established via 
pathologic sampling as well as standard clinical follow-up for at least 6 months 
and up to five years. We believe there will be enough patients with biopsy and 
clinically followed-up negative lymph nodes to calculate a true negativity rate. 
 
E2.0  Secondary Aims 
Aim 2. and Sub-aim 2a.  
Depending on the normality of data distribution, t-test or Wilcoxon rank sum test will be 
conducted to compare the mRNA differences, genomic differences in gene expression, 
alternative splicing, indels and single base mutations between prostate carcinoma recurrent in 
the prostate bed and extraprostatic samples. Analysis of variance (ANOVA) will be used to 
compare the IHC staining of protein levels between the different categories of FACBC uptake. 
Tukey pairwise comparison will be further conducted when the overall comparison with ANOVA 


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is significant at the significance level of 0.05. Pearson/Spearman correlation coefficients will be 
estimated to measure the associations: 1) between mRNA levels of candidate AAT genes and 
FACBC uptake; 2) between mRNA differences and quantifiable imaging biomarker data such as 
SUV for anti-[18F]FACBC PET-CT and ADC for MR. Multivariate analyses will further be 
conducted, in which general linear model (GLM) will be employed to assess the adjusted 
relationships mentioned above after adjusting for the other covariates.   
 
Sample size and power calculation 
 
The sample size of this study is 25 patients. The power calculation is based on the comparison 
of mRNA differences between the prostate bed and extraprostatic samples using two sided t-
test. At the significance level of 0.05, the sample size of 25 will achieve a power of at least 80% 
to detect one standard deviation or higher difference in mRNA difference between the two 
groups of samples.  
F. Adverse Event Reporting 
 
An adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans whether or not considered drug-related 
 
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 7 days 
post scan will not be considered an AE since 95% of ligand is eliminated by 7days. 
  
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 (June 14, 2010) will be used as a guide address potential AEs subject to 
limitations above and medical and scientific judgment as to plausibility of such criteria in a 
diagnostic radiotracer study. 
 
Adverse Event Reporting 
Any patient death that may be due to the study procedure (i.e. severe radiotracer reaction), 
unanticipated problem, would be promptly reported to the Emory IRB office.  Additionally any 
patient death not associated with the study procedure or serious unanticipated event(s) (i.e. 
radiotracer allergy) will be reported to the Emory IRB and FDA upon continuing review. Protocol 
deviation/non-compliance will be reported according to IRB Policies & Procedures.  This 
radiotracer is studied under IND 72437 and monitoring will be performed per already agreed 
upon FDA guidance. Over 900 patients in multiple centers have been studied without adverse 
events.  
  
G. Safety Monitoring 
This study is being performed under the auspices of FDA IND 72,437. Patients will be monitored 
by the technologists and 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).  They will be followed 
routinely by their referring physician with clinical exams, and the PI will work with the co-
investigators and referring physicians to ensure that the patients continue to follow up as 


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scheduled. In addition, a DSMB who will consist of Drs. Nieh, Schuster, Halkar, and Master will 
meet formally if a drug related serious adverse event has been reported. 
 
Patient safety, study efficacy and compliance will be reviewed at the Urology working group 
meeting. The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute 
will also oversee the conduct of this study (every 6 months or annually – depending on the risk 
level of the protocol). This committee will review pertinent aspects of study conduct including 
patient safety, compliance with protocol, data collection and efficacy. The committee will review 
the charts of 10% of patients enrolled to the study and two of the first 5 patients entered to the 
study. The Committee reserves the right to conduct additional audits if necessary. The Principal 
Investigator (PI) or designee is responsible for notifying the DSMC about the accrual of patients 
when the first 5 have been entered to the study. The PI or designee will also notify the DSMC of 
study status within 2 months before the next scheduled review is due. 
 
Any serious adverse events will be communicated by the PI to the Emory IRB and FDA using 
standard adverse event reporting forms. Yearly safety reporting will also be forwarded to the 
FDA.  A formal DSMB will not be utilized as this is a diagnostic study with minimal risk to the 
patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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