Validation of FACBC as an Early Indicator of Sub-clinical Metastatic Disease Among High-risk Prostate Cancer Patients With Presumed Localized Disease
Phase: PHASE2
Conditions: Cancer
Sponsor: Emory University

  
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Validation of FACBC as an early indicator of sub-clinical metastatic disease among high-risk or 
unfavorable intermediate-risk prostate cancer patients with presumed localized disease 
 
Protocol date: June 30, 2017 
 
NCT number: NCT03081884 
 
Early Detection of Occult Metastatic Disease in High-Risk Primary or Unfavorable Intermediate-risk Prostate 
Cancer Patients 
 
 
1. Abstract 
Approximately 50-80% of patients who are considered high-risk or unfavorable intermediate-risk experience 
recurrent disease after being treated with definitive radical prostatectomy, often because of undetected extra-
prostatic metastatic spread. In addition, there is increasing evidence that performing radical prostatectomy in 
patients with high-risk disease or locally advanced disease is feasible and has potential benefit in terms of local 
control, overall survival, and quality of life [1-3]. Thus, improved imaging approaches for early detection of 
occult metastatic prostate cancer at the time of presentation could inform a directed treatment approach that 
would significantly improve patient outcome, including use of extended lymphadenectomy as well as 
postoperative radiation therapy planning. 
 
Amino acid transport is up-regulated in prostate and other cancers. Anti-1-amino-3-[18F]fluorocyclobutyl-1-
carboxylic acid (FACBC) is a synthetic amino acid analog positron emission tomography (PET) radiotracer that 
has demonstrated promising results in the staging and restaging of prostate carcinoma, with high positive 
predictive value (PPV) in the identification of extraprostatic malignancy [4, 5]. Most of the prior studies of 
FACBC were in post-primary treatment recurrence, and this proposed trial will be the first comprehensive study 
to evaluate FACBC PET in detecting occult metastatic disease at initial diagnosis in patients with negative or 
equivocal conventional imaging with the objective of developing a more effective primary treatment plan. 
The goal of this study is to determine if FACBC PET will detect significant occult metastatic disease in patients 
with high risk or unfavorable intermediate-risk primary prostate carcinoma who have negative or equivocal 
conventional imaging such as CT, MR and bone scan. In addition, amino acid regulation has been implicated 
in mTOR pathway signaling; therefore, we believe that FACBC may also play a complementary role with other 
biomarkers of aggressive or metastatic disease. Therefore, a secondary goal is to leverage the utility of 
FACBC as a biomarker of the upregulation of amino acid transport and to correlate FACBC uptake parameters 
with tissue RNA signatures of prostate cancer, and levels of novel serum and urine biomarkers (urine RNA and 
serum phi) as an adjunct to another ongoing study.  
 
Our hypothesis is that FACBC PET imaging will detect occult metastatic prostate cancer at the time of 
presentation, especially nodal disease, in patients with newly diagnosed high risk or unfavorable intermediate-
risk primary prostate cancer who have negative or equivocal conventional imaging. In addition, we hypothesize 
that FACBC as an imaging biomarker may play a complementary role to tissue RNA signatures of prostate 
cancer, as well as urine RNA and serum phi.  
 
 
2. Background and Significance: 
Most patients with prostate cancer present with clinically localized disease, yet after curative radical 
prostatectomy, over 30-50% of patients eventually present with biochemical failure and recurrence [6-8]. This 
is especially so in patients with high or very high risk prostate cancer in which failure rates may approach or 
exceed 50% [8-10]. While this higher failure rate is in part due to the biologic aggressiveness of disease, it is 
also likely that at the time of the initial treatment that metastatic disease was present but not appreciated. 
Despite advances in surgery, cryosurgery and radiation therapy of localized and hormonal treatment of extra-

  
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prostatic disease, nearly all of prostate cancer deaths result from progressive metastatic disease. Thus, the 
presence or absence of extra-prostatic disease will change the therapeutic approach [8]. Imaging is central to 
the differentiation of prostatic from extraprostatic disease. In addition, with locoregional spread or even 
instances of metastatic disease, radical prostatectomy may still have benefit in regards to general health-
related quality-of-life (HRQOL) and overall survival (OS) in this population [11]. Imaging may then play an even 
greater role in formulating individualized therapy plans. 
 
Conventional imaging such as routine CT and MR has demonstrated relatively poor performance in the staging 
of high risk prostate cancer especially in terms of locoregional nodal spread and distant disease [12-16]. While 
FDG PET has been useful in patients with more aggressive castration resistant disease it also has suboptimal 
performance in the routine staging of patients with prostate cancer [17, 18]. FDG-PET is not accurate in the 
differentiation of cancer from inflammation, and generates suboptimal images in the pelvis where small lesions 
can be masked by the accumulation of FDG metabolites from urine accumulation in the bladder [17]. Other 
molecular imaging techniques such as the FDA approved 111Indium-capromab-pendetide radiotracer 
(ProstaScint) also have reported poor diagnostic performance [19-23]. Though newer PSMA ligands are 
promising, they are still early in their translation to routine clinical use [24].  
 
Recent studies suggest that utilizing more advanced imaging such acetate and choline PET has the potential 
to improve early detection of occult metastatic prostate cancer of presumed locally confined primary and 
recurrent prostate carcinoma. Though there is suboptimal sensitivity for microscopic disease, added value has 
been described in higher risk prostate cancer to improve staging, especially in the detection of distant disease 
[25-30]. Schiavina has reported that while not sensitive enough to replace pelvic nodal dissection, imaging with 
choline PET demonstrated better diagnostic performance than clinical nomograms [31]. Yet, the isoform of the 
choline PET radiotracer that is available in the United States is based on carbon-11, which has a 20 minute 
half-life and is impractical without an on-site cyclotron. Though fluorocholine (FCH) with a longer half-life is 
available outside of the United States, intellectual property issues will limit its availability in the US until 2021. 
In addition, FCH has high bladder excretion which may be a limiting factor in image interpretation.  
 
Amino acids are involved in a variety of biologic processes including protein synthesis, and amino acid 
transport is up-regulated in many neoplasms [32-35]. Consequently, radiolabeled amino acids, both natural 
and synthetic, have been utilized for oncologic molecular imaging. FACBC is an investigational synthetic non-
metabolized amino acid analogue positron emission tomography (PET) radiotracer [4, 5, 36-43].  Transport is 
primarily mediated by sodium dependent amino acid transporters, specifically system ASC, with contribution by 
sodium independent system L [44, 45]. FACBC PET has been studied at multiple centers, primarily in the 
restaging of recurrent prostate carcinoma where it has demonstrated significantly better diagnostic 
performance than conventional imaging [4, 5, 39, 46, 47].  
 
FACBC has characteristics that are advantageous in the imaging of prostate carcinoma including little renal 
excretion, and longer half-life of the fluorine-18 radioisotope. Most importantly, FACBC is FDA approved for 
recurrent prostate cancer detection. Thus, FACBC is an ideal PET radiotracer candidate to conduct a study 
determining if advanced molecular imaging provides significant value in the early detection of occult metastatic 
prostate cancer in high risk or unfavorable intermediate-risk patients before radical prostatectomy who have 
negative or equivocal conventional imaging, with the goal of informing a targeted treatment approach including 
extended pelvic nodal dissection and potentially postoperative radiotherapy and/or systemic therapy.  
 
3. Objectives 
Primary Aim- To validate FACBC as an early indicator of occult metastatic disease among high risk or 
unfavorable intermediate-risk prostate cancer patients with presumed localized disease. 
After completion of FACBC PET, detection rate for extraprostatic disease will be determined. In addition, after 
surgery and review of histology, correlation will be made to histologic findings for extraprostatic disease, as 
well as definitive skeletal imaging to determine diagnostic performance as a secondary analysis noted in the 
statistical analysis plan. Reference standards as to ground truth for extraprostatic disease will be established 
with histologic analysis of nodes harvested in extended nodal dissections, extrapelvic and/or skeletal biopsy 
and/or correlation with definitive imaging findings. Thus, for this aim: 1) positivity rate will be calculated for 

  
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FACBC PET for extraprostatic disease as the primary analysis; 2) diagnostic performance of FACBC in the 
detection of extraprostatic disease as confirmed with histology and/or correlative imaging will be determined as 
a secondary analysis.  
 

  
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Secondary Aim- to evaluate the correlation of FACBC uptake in the prostate with presence of FACBC-
detected metastasis.  
With data obtained from the trial we will correlate uptake within known tumor in the prostate to the frequency of 
FACBC extraprostatic positivity. We will use various indices such as SUVmax, SUVpeak, SUVmean, total 
lesion activity, and retention indices of the primary tumor to determine if degree of uptake and uptake 
characteristics of FACBC PET as an imaging biomarker in itself indicate the propensity of the primary prostate 
cancer to metastasize as correlated with the reference standards of this trial.   
 
Exploratory Aim- to evaluate tissue RNA signatures of prostate cancer, as well as urine RNA and 
serum phi parameters that are associated with higher rate of  FACBC positivity in this cohort. 
Urine, tissue and serum samples will be obtained from all study participants for urine and tissue RNA, and 
serum Phi parameters through the Prostate Satellite Tissue Bank (IRB 00045859). With data obtained through 
the trial and in conjunction with other ongoing studies: 
1) We will correlate tissue RNA signatures of prostate cancer, urine RNA and serum phi parameters with the 
detection rate of FACBC studies for extraprostatic disease. 
2) We will also correlate FACBC uptake parameters within the prostate/primary tumor (such as but not limited 
to SUVmax, SUVpeak, SUVmean, total lesion activity, and retention indices as available) with tissue RNA 
signatures of prostate cancer, as well as urine RNA and serum phi parameters.  
3) We will therefore determine if FACBC PET may be used as an adjunct imaging biomarker in combination 
with the novel tissue RNA signatures of aggressive prostate cancer, as well as urine RNA and serum phi 
biomarkers in the detection of more aggressive or metastatic disease. 
4) We will also, at a later time point, correlate uptake within the prostate itself to pathology from Emory 
standard histologic processing, likely on a sextant basis. Specifically, we will correlate presence or absence of 
tumor, inflammation, and BPH with uptake parameters. 
 
4. Study Design 
We will undertake a clinical trial with 88 patients who have been diagnosed with primary prostate carcinoma 
who are considered at least unfavorable intermediate-risk (Grade Group 2 (Gleason score 3+4) with either 
PSA 10-<20 or clinical stage T2b-c, OR Grade Group 3 (Gleason 4+3) with PSA < 20) or high risk per standard 
guidelines (clinical T3a, or Gleason score 8-10, or PSA greater than 20 ng/ml; and/or recurrence probability of 
≥50%) as per clinical assessment, without definitive findings of systemic metastasis on conventional imaging, 
and who are candidates for potentially curable radical prostatectomy and extended pelvic nodal dissection. We 
will employ the Kattan nomograms and other standard instruments as appropriate in making this determination 
[48]. Subsequently, patients will undergo whole body FACBC PET-CT. Typically patients will then undergo 
radical prostatectomy and extended nodal dissection, but if disease is detected preoperatively outside of the 
prostate, this will inform a discussion between the surgeon and patient as to an individualized treatment plan 
which may include targeted nodal dissection and use of postoperative radiotherapy and/or systemic therapy. 
Primary analysis will be centered on detection of occult extraprostatic disease by FACBC PET in high or very 
high-risk patients without definitive findings of systemic metastasis on conventional imaging. While the primary 
endpoint will be FACBC PET occult extraprostatic disease detection, as a secondary analysis we will cross-
tabulate the agreement between FACBC classifications versus extraprostatic disease status as identified by 
extended pelvic nodal dissection and other extraprostatic truth verification. Patients will also be followed for 
long-term outcome, but that is beyond the scope of this current trial.   
 
FACBC radiolabeling: Production will be accomplished by the GE FastLab cassette system. Alternatively by 
automated synthesis developed by J. McConathy and M.M. Goodman [49]. We have prepared greater than 
200 batch productions for tumor imaging in volunteer subjects. Imaging will be performed under the IND held 
by Dr. Schuster and FDA mandated monitoring will be completed. 
 
 
 
 
 

  
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Standard of Care Procedures 
 
1. Conventional imaging: Prior to enrolment in this study, all patients will undergo standard of care 
preoperative bone scan and/or NaF PET, as well as nodal staging with diagnostic CT and/or MR per 
institutional standards. The official report is an important part of the initial evaluation and will serve as 
the basis for recording findings of extraprostatic disease since this will duplicate standard practice. 
Equivocal findings and/or non-definitive findings of systemic metastasis will be considered as negative 
for extraprostatic disease since management is typically not changed unless definitive radiologic 
findings are evident. The interpreter of the conventional imaging will have no access to FACBC imaging 
(and typically will be performed before FACBC). It is anticipated that all the conventional imaging will be 
reimbursed by third party payers.   
 
2. Radical Prostatectomy and Extended Lymph node dissections: Patients will undergo standard of care 
radical prostatectomy and extended or super-extended pelvic node dissection. The surgical plan will 
generally involve nodal dissection of right and left obturator, right and left external iliac, right and left 
internal iliac, right and left common iliac, right and left pre-sciatic, and central pre-sacral with optional 
para-aortic and para-caval regions subject to clinical exigencies. Each group of nodes will be removed 
as a packet, labeled separately and sent to pathology for routine histopathologic examination. If either 
conventional imaging or the FACBC scan demonstrates potential other pelvic or extrapelvic nodal 
disease, the surgeon may choose to extend the nodal dissection to other sites. If this is done, the 
additional nodes will be labeled to indicate the site and they will be also be submitted for pathology 
review. It is noted that some patients with extrapelvic disease may still undergo surgery after a 
discussion between patient and surgeon as to risks, advantages, and disadvantages since there is solid 
evidence that patients may still benefit from this approach [1-3, 11]. Burden of disease will likely be an 
important factor in this decision. In addition, since patient safety is paramount, an individual patient may 
have surgery stopped or altered due to clinical judgement, which will modify nodal basins sampled. 
 
After the FACBC scan described below, and before surgery the diagnostic imager and the surgeon will 
communicate to review findings and to ensure consistency in correlation of findings to nodal packet 
nomenclature. In addition, patients with abnormal though non-definitive findings on conventional 
imaging and/or abnormal and/or equivocal and/or discrepant on FACBC PET-CT in extraprostatic or 
especially extrapelvic locations may also have those sites sampled as clinically appropriate through a 
combination of percutaneous image guided needle biopsy and/or laparoscopic techniques. 
 
3. Serum, urine, and tissue samples will be collected for RNA and other genomic analysis.  
 
Study Specific Experimental Procedures 
1. Fluciclovine PET-CT imaging: PET-CT images will be acquired on a state-of-the-art scanner.  All 
studies will use measured attenuation correction (routinely acquired through the initial CT portion of 
the scan).  All subjects will fast for 4 hours to normalize their neutral amino acid levels. Within 1 
hour prior to scanning, the patient (if able) will drink up to 450 ml of standard oral contrast. IV 
contrast will not be used. After completion of the CT scan, approximately 10 mCi anti-[18F]FACBC 
will be injected into an antecubital vein as a bolus and flushed with normal saline. Scanning will 
commence immediately as technically possible starting with the pelvis at 2.5 min/bed for 2 bed 
positions (from just below ischium to approximately bifurcation); this sequence will be designated, 
early 0-5 minutes. At 5 minutes, 7 consecutive 2.5 minute/frame acquisitions will be obtained from 
the pelvis (below ischium) to approximately the skull base. At 22.5 minutes, a delayed 2 bed similar 
pelvis will then be acquired from the 22.5 to 27.5 mins. Thus, we will have early (effectively 10 min 
multi-time point imaging of the pelvis) and 10-22.5 min imaging from pelvis inlet to skull base. This 
acquisition is similar to a successful protocol with FACBC for primary prostate cancer staging 
employed at Aleris Medical Center in Oslo, Norway (personal communication, F Willoch), but also 
allows us to cover the entire pelvis to the bifurcation and also obtain an exploratory final 5 minutes 
delayed acquisition of the pelvis. The whole body acquisition itself is similar to that employed 
clinically. Scanning will preferably be undertaken arms above the head if possible for the patient. 

  
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Image Analysis of FACBC PET-CT: 
1) Images will be reconstructed with iterative technique and interpreted on a MimVista or similar 
workstation.  
2) Visual inspection of the PET-CT images by a board certified nuclear medicine imager, blinded to 
other imaging, will then occur and results recorded on a case report form. (It is possible that as 
part of clinical duties, the research reader may have interpreted one of the patient’s earlier 
clinical exams. This type of situation is impossible to avoid, but it is highly unlikely that recall of 
an individual exam would be possible with our institutional workflow. Therefore, this situation is 
still considered as blinded for the purpose of this study.) 
3) 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 and background will be recorded. SUV (mean, maximum, peak, total lesion activity) will 
also be documented for the prostate primary lesion(s) as a whole gland ROI at all time points to 
calculate uptake and retention indices. For extra-prostatic sites such as lymph nodes and bone, 
abnormal moderate or intense focal uptake which are present on 5-27.5 minute images will be 
considered prospectively positive (allowing for partial volume effect). Analysis will be 
supplemented by data from early and delayed time point acquisitions of the pelvis and is most 
useful to increase sensitivity for small lesions subject to partial volume effect on PET and also 
increase specificity. These criteria were successfully used in our studies of FACBC in recurrent 
disease [4, 50]. The multi-time point data of the pelvis will also be used for future analysis of 
uptake in comparison to the reference histologic standard likely on  a sextant basis. If possible. 
we will use a segmentation algorithm under development to assist with this analysis. 
4) A final review of the images by the nuclear medicine imager and the urologist will occur to 
ensure that nodal regions are understood in a similar manner and determine if areas of uptake 
will be in the field of operation. For example that internal iliac means the same to the imager and 
the surgeon. 
 
Histologic Assessment: 
 
The histologic examination of the nodal tissue will be done using standard clinical protocols. The surgical 
specimens will be submitted with each of the nodal groups separately identified with appropriate labels. This 
will ensure that the pathology reports will be evaluable for the presence of positive nodes in each of the nodal 
groups, and that it will be feasible to correlate the pathology data with the imaging data. 
 
1) The FACBC readings for nodal groups in each patient will be compared against the histologic results. 
To ensure proper correlation of both FACBC and histologic results, FACBC nodal reads will be labeled 
according to the packets listed in #2 above. This will also guide nodal dissection and labelling of nodal 
tissues for pathologic analysis.  
2) The readings for skeletal disease will also be compared to biopsy and definitive correlative imaging as 
appropriate. Criteria for skeletal metastasis are considered more well established than for lymph nodes 
and therefore biopsy may not be needed in the case of skeletal metastasis if two separate conventional 
imaging modalities such as MR, CT, and/or bone scan are concordant in probability for skeletal 
malignancy [51]. 
3) At a later time point the prostate sextant histologic data will be compared to best matching imaging 
sextant based on automatic or manual segmentation and correlation of uptake indices made with 
tumor, Gleason grade, inflammation, and BPH as well as other potential imaging and histologic 
analysis.  
 
 
Tissue and Data Management: 
 

  
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1) Tissue specimen obtained from participants will be formalin fixed and paraffin embedded by the Emory 
Pathology Department, preserved for future intra-patient genomic comparisons between primary and 
metastatic disease.  
2) Radiological data of participants will be stored on a secured password protected database for future retrieval 
and follow-up as indicated. 
3) Experience from this trial will be used to plan a multicenter trial in cooperation with ECOG-ACRIN, SNMMI-
CTN and Blue Earth Diagnostics (corporate developer of FACBC in the US and the EU) to potentially obtain 
expanded FDA approval of the modality in early detection of occult metastases before primary treatment.  
4) Patients will also be followed for long term outcome measures correlating FACBC findings with PSA and 
clinical recurrence. Though this endpoint is beyond the scope of the current trial, patients will therefore be 
consented for 10 year follow-up through the medical record and via selected contact.   
 
5. Participant selection 
1) Inclusion criteria 
a. High-risk or very-high risk prostate cancer eligible for standard of care surgery 
i. At least clinical T3a disease, and/or Gleason >8, and/or PSA>20, as per clinical assessment 
and routine guidelines 
b. Unfavorable risk intermediate prostate cancer eligible for standard of care surgery 
i. Grade Group 2 (Gleason score 3+4) with either PSA 10-<20 or clinical stage T2b-c, OR 
Grade Group 3 (Gleason 4+3) with PSA < 20. 
c. 18 or years of age or older 
d. Undergone standard of care conventional imaging (CT and/or MR; bone scan and/or NaF PET) 
 
2) Exclusion criteria 
a. Definitive findings of systemic metastasis on conventional imaging. 
 
3) Recruitment: Any attempt to recruit a large cohort of subjects is always a possible limitation. We believe 
with the typical numbers of patients for this clinical question seen at Emory hospitals including ESJH  
hospital per year (approximately 50), we will be able to achieve our target goal of 18 patients per year at a 
conservative 36% recruitment rate. We have an on-site cyclotron and radiopharmacy staff with a proven 
ability to manufacture FACBC. Thus, we have the capacity to scan these subjects. If accrual is lagging, we 
also have the capability to open this trial at our sister institutions, Grady Hospital and the Atlanta VA.  
 
4)  Dropout: We have factored in an extra 2 scans for unforeseen difficulties, but since the endpoint of the 
study is FACBC imaging, even if a patient does not undergo surgery, sufficient data will have been 
obtained for the primary analysis. Therefore patient dropout is not considered to be highly relevant in this 
design. We will seek IRB approval of sufficient patients to allow for screening failures, but these patients 
will not have undergone FACBC imaging. 
 
6. Informed Consent Process 
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 PET scan. 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. 
Consent would also be obtained for RNA, DNA and other genomic analysis on urine and other indicated 
biofluids. 
 
7. Incidental Findings 
 
a.   All incidental findings noted by the imager will be discussed with the attending urologist who is a co-
investigator, and documented in the electronic medical record.  
b.   Incidental findings (such as incidental lung nodule for example) will be disclosed to the patient who 

  
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will then formulate a follow-up plan with the attending urologist including any referrals.  
c.   The urologist 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.  
d.   Language to this effect is present in the consent form. 
 
It is possible that nodes may be missed that are FACBC positive even with nodal dissection leading to an 
overestimation of false positivity of FACBC. If this is suspected, patients may be followed with conventional 
imaging as per routine to clarify the ground truth in specific situations. Also, a patient could then be enrolled in 
an ongoing clinical trial at Emory for PSA failure after prostatectomy (R01 CA169188) to undergo repeat 
FACBC study to determine if abnormality persists. Yet, since the PPV of FACBC has already proven to be high 
for extraprostatic disease and FACBC detection in itself is the primary endpoint, this potential limitation would 
only affect secondary analyses. 
 
FACBC 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 the principal investigator on this study. 
 
8. Compensation for time and effort: 
Each patient will be compensated $50 as per diem for travel expenses for the FACBC scan. 
9. Statistical Analysis and Power Calculation 
In calculating statistical power we have taken realistic suppositions. The prevalence estimate of occult 
metastatic disease, FACBC sensitivity and specificity is extrapolated from reported large series and 
nomograms, as well as data culled from our previous trials and clinical experience [4, 5, 48, 52, 53].  
The primary goal of the study is to estimate the rate of positive FACBC studies in this population for occult 
extraprostatic metastasis. We therefore assumed a 50% prevalence of occult metastasis (metastases not 
definitively evident on routine clinical imaging), 95% specificity, and a conservative sensitivity of 40%. They 
translate to 22.5% FACBC scans to be positive (note that FN included) and 89% PPV. We plan to enroll 88 
patients to have 0.8 power for detecting the rate of positive FACBC to be at least 10%. The number of patients 
with positive FACBC is expected to be 20, and the number is between 12 and 28 with 0.95 probability. In 
addition to the point estimate, 95% CI will be calculated for the rate of positive FACBC and a statistical test will 
be conducted against the null hypothesis of a rate of 10%. 
 
As part of the secondary analysis, we will cross-tabulate the FACBC classification versus extraprostatic 
disease status as detected by extended pelvic nodal dissection as outlined above. Note that the latter is not 
regarded as a gold standard for extraprostatic disease detection since it may still results in substantial false 
negatives. Nevertheless, the percent of positive FACBC among patients with extraprostatic disease detected 
by extended pelvic nodal dissection provides a reasonable estimate of the sensitivity for FACBC. We will 
calculate the corresponding exact 95% confidence interval. In addition, we will evaluate the extent to which the 
FACBC and extended pelvic nodal dissection agree with each other using kappa statistic. This analysis of 
concordance will help guide design of analyses of tissue-imaging concordance in the subsequent, Phase III 
Validation Trial (ECOG-ACRIN), to comprehensively evaluate the diagnostic characteristics of FACBC. 
 
For Aim 2, we will assess associations between FACBC uptake parameters in the prostate and rate of 
extraprostatic disease detection using standard associative statistical tools including logistic regression and 
ANOVA as applicable. 
 
For Aim 3, we will evaluate the association of the tissue RNA signatures of prostate cancer as well as urine 
and serum biomarkers with the rate of FACBC positivity using standard associative statistical tools including 
logistic regression and ANOVA as appropriate. Finally we will correlate FACBC uptake parameters in the 
primary prostate tumor to the tissue RNA signatures of aggressive prostate cancer and urine and serum 
biomarkers using Spearman’s correlation coefficients. 

  
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10. Data and Safety Monitoring and Reporting:  
See http://irb.emory.edu/documents/DSMB-DSMPGuidance.pdf for guidance. 
 
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 scheduled. The GU Oncology Working Group will serve as the Data and Safety Monitoring Board 
(DSMB) only 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.  Urology 
Department Clinical Research Unit Director of Clinical Trials, Mersiha Torlak or a designee will serve as the 
independent internal monitor and will oversee the conduct of this study. The independent internal monitor will 
review pertinent aspects of study conduct including patient safety, compliance with protocol, data collection 
and efficacy.  The independent internal monitor will review the charts of 10% of patients enrolled to the study. 
At a minimum, review is required annually. The independent internal monitor reserves the right to conduct 
additional audits if necessary. The Principal Investigator (PI) or designee is responsible for notifying the 
independent internal monitor about ongoing patient accrual at a minimum on a monthly base.  
Any study specific experimental (not standard of care) procedure related serious adverse event will be 
communicated by the PI to the Emory IRB and the sponsor to the FDA using standard adverse event reporting 
forms. Yearly safety reporting will also be forwarded to the FDA.  A formal DSMB, except as noted above, will 
not be utilized as this is a diagnostic study with minimal risk to the patient. In addition, Blue Earth Diagnostics, 
Ltd, will receive data on safety since they supply FACBC cassettes.  
 
11. Adverse Event Reporting 
Halting a clinical trial due to adverse events is a possibility that must always be considered in any trial. Though 
we have a system in place for adverse event reporting and evaluation, it is extremely unlikely such adverse 
events will occur. The radiotracer is administered in trace pharmacologic amounts like all PET radiotracers. 
Our experience with extensive animal testing and with over 1000 human subjects has failed to demonstrate 
any serious adverse events due to the radiotracer. This lack of adverse events is similar to general experience 
with other PET radiotracers. FACBC is FDA approved for recurrent prostate cancer. But since we will be 
conducting research off-label and to potentially change drug labelling, we will administer the radiotracer drug 
under our existing IND after manufacture at our CSI radiopharmacy. An event greater than 7 days post scan 
will not be considered an AE or SAE since 95% of ligand is eliminated by 7 days.  
 
However, in the event of 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 1000 patients in multiple centers have been 
studied without attributable serious adverse events.  
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. 
  
The Investigator will report all Serious Adverse Events occurring in a subject on the day of or within 28 days 
following the Agent administration to Pharsafer® Associates Ltd (“Pharsafer”) by telephone (+44 1483 
212151), FAX (+44 1483 212178) or e mail (drugsafety@pharsafer.com). Events should be reported to 

  
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Pharsafer within 24 hours of the investigator becoming aware of the events occurrence. Pharsafer will prepare 
an individual single case report (ISCR) in compliance with applicable regulations. A copy of the ISCR will be 
sent by Pharsafer to the Investigator. The Investigator is responsible for informing the ethics committee of 
serious events occurring during the study in compliance with local regulations. Pharsafer 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.  
 
12. Medical Record and Confidentiality 
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 be stored on the HIPAA compliant shared folder at all 
times and should never be stored on any local or portable drives.  
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 Access 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.  

  
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