Conditions: Prostatic Neoplasms
Keywords: Prostate Cancer Imaging Technology Oncology Prostate Biopsy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if using Positron Emission Tomography (PET) scan and transrectal ultrasound (TRUS) guided biopsy together (creating a 3-dimensional ultrasound) will detect prostate cancer more accurately than the standard 2-dimensional approach which uses only the TRUS to guide the biopsy.

Detailed description:
The objective of the proposed study is to evaluate a molecular image directed, three-dimensional (3D) ultrasound guided biopsy system in human patients. Prior studies have shown that Positron Emission Tomography (PET)/Computed Tomography (CT) imaging with the PET molecular imaging agent, a synthetic amino acid, anti-1-amino-3-\[18F\]fluorocyclobutane-1- carboxylic acid (FACBC), is more sensitive than the FDA-approved prostate specific membrane antigen single-photon emission computed tomography (SPECT) radiotracer in prostate cancer detection. FACBC images showed higher focal uptake in tumor foci than in normal prostate and thus could be ideal information to direct targeted biopsy of the prostate. This targeted biopsy system has a unique feature that PET/CT images can be registered with 3D ultrasound images, as a result, a suspicious PET lesion is superimposed over the real-time ultrasound data; and the fused image is then used to direct biopsy needles to tumor targets.

The hypothesis of the study is that PET/ultrasound fusion targeted biopsy can detect more cancer per core than the standard 12-core TRUS guided biopsy.

The specific aims include:

1. To perform PET/CT directed, 3D ultrasound-guided biopsy and determine if fusion targeted biopsy can detect more cancers than 2D transrectal ultrasound (TRUS)-guided biopsy
2. To develop the workflow for performing deformable registration and fusion of PET/CT and 3D ultrasound images of human patients

Thirty six patients, who have suspicion of recurrent prostate cancer after definitive therapy such as radiotherapy, will be recruited into this study. At least half of the patients will have positive imaging findings and will undergo 2D TRUS-guided biopsy as well as PET/ultrasound fusion biopsy. The proposed study will be the first-in-human trial that uses PET/CT imaging to direct 3D ultrasound-guided biopsy of the prostate. The multimodality imaging approach will combine the high sensitivity from PET and real-time information from ultrasound for improved cancer detection.

Arms:
arm 1: All participants with suspected recurrence of prostate cancer will have the FACBC PET-CT scan performed. Participants with abnormal FACBC PET-CT scan results will have a PET/ultrasound fusion targeted prostate biopsy followed a standard of care prostate biopsy. arm 2: All participants with suspected recurrence of prostate cancer will have the FACBC PET-CT scan performed. Participants without abnormal FACBC PET-CT scan results will have a standard of care prostate biopsy.

Interventions: intervention 1: FACBC PET-CT Scan intervention 2: Three-dimensional ultrasound-guided biopsy intervention 3: Standard transrectal ultrasound (TRUS) guided biopsy
Intervention descriptions: intervention 1: One hour prior to scanning, participants will drink one glass (450 ml) of oral contrast to allow for better pictures of abdomen and pelvic organs. The participants will have their temperature taken before and after the injection of the FACBC. Blood pressure and pulse will be taken every 15 minutes during the PET scan.

Participants will lie on a scanning bed and the bed will move slowly through the PET/CT scanner. This portion usually takes about one minute. Following this the FACBC will by administered by an intravenous (IV) catheter and the PET scan portion of the exam will begin. The table moves slowly through the scanner and many sets of PET-CT images are produced. When the imaging is complete, the scanner will send the results to a computer. The computer then generates a number of images that will be reviewed by a specially trained radiologist. intervention 2: A lubricated rectal probe will be inserted and a local anesthetic to numb the prostate will be administered. The ultrasound probe allows visualization of the prostate in two-dimensional (2D) images. The probe connects to a computer that will link to the FACBC PET-CT scan results that the participant has already had performed. These combined images will provide a three-dimensional (3D) image from the FACBC PET-CT scan previously obtained as well as real-time, 2D ultrasound images, resulting in an improved visualization tool to target the biopsy needle to a suspicious lesion.

The needle tip position for each biopsy sample will be recorded on the real-time ultrasound images; this information allows the physician to either re-biopsy the same area for a follow-up examination or not to re-biopsy the same region if the original biopsy was negative.

This biopsy process is estimated to take about 10 minutes. intervention 3: A lubricated ultrasound probe of about 2.5 cm in diameter is gently inserted into the rectum and a local anesthetic to numb the prostate is administered. The ultrasound probe allows visualization of the prostate in two-dimensional (2D) images and allows for the placement of a biopsy needle that collects samples of the prostate. Usually, a total of 12 biopsy specimens are collected. The procedure takes about 20 minutes. This TRUS-guided biopsy is considered as the standard method for prostate cancer diagnosis.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Targeted Fusion Biopsy of the Prostate 
 
Protocol version date: March 29, 2018 
 
NCT02744534


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Targeted Fusion Biopsy of the Prostate 
 
 
David M. Schuster,M.D.Emory University  
Department of Radiology and Imaging Sciences   
School of Medicine, Emory University, Atlanta, GA 
Phone:  (404) 712-4859 
E-mail: dschust@emory.edu 
 
 
 
Co-Investigators: 
 
Mark Goodman, PhD 
 
Viraj Master, MD PhD 
 
Peter Nieh, MD 
 
Baowei Fei,PhD, EngD 
 
 
Protocol Number: RAD 294-15 
IND # 72,437 (Dr. David Schuster) 
Protocol version date: 03/29/2018 
Phase of the study:  n/a 
 
 
 
 
 
 
 


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Schema 
 
 
Patient Enrolled N=36
anti-[18F]FACBC PET scan of abdomen/pelvis
Positive FACBC Scan?
Standard TRUS-guided Biopsy
Standard TRUS-guided Biopsy 
and Targeted Fusion Biopsy
No
Yes
Data analysis and comparison between the two biopsy approaches
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Precis/Abstract 
 


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Every man over the age of 45 is at risk for prostate cancer. Two-dimensional (2D) transrectal 
ultrasound (TRUS) guided biopsy is the standard method for prostate cancer diagnosis. A critical 
problem of this TRUS-guided biopsy approach is its significant sampling error and its low sensitivity 
(24%-52%). Current biopsy approaches may miss up to 30% of prostate cancer. Nevertheless, more 
than 1.2 million prostate biopsies are performed each year and the biopsy cost is more than two 
billion dollars. Innovative image-guided, targeted biopsy technology that can improve cancer 
detection can have a significant impact on the management of this disease that affects one in six 
men.  
 
The objective of the proposed study is to evaluate a molecular image directed, three-dimensional 
(3D) ultrasound guided biopsy system in human patients. At our NIH-funded Emory Molecular and 
Translational Imaging Center, it has been shown that PET/CT imaging with the PET molecular 
imaging agent i.e., FACBC, is more sensitive than the FDA-approved PSMA SPECT radiotracer in 
prostate cancer detection. FACBC images showed higher focal uptake in tumor foci than in normal 
prostate and thus could be ideal information to direct targeted biopsy of the prostate. This targeted 
biopsy system has a unique feature that FACBC PET/CT images can be registered with 3D 
ultrasound images, as a result, a suspicious PET lesion is superimposed over the real-time 
ultrasound data; and the fused image is then used to direct biopsy needles to tumor targets.  
 
The hypothesis of the study is that FACBC PET/ultrasound fusion targeted biopsy can detect more 
cancer per core than the standard 12-core TRUS guided biopsy. The specific aims include: 1) To 
perform FACBC PET/CT directed, 3D ultrasound-guided biopsy and determine if fusion targeted 
biopsy can detect more cancers than 2D TRUS-guided biopsy; and 2) To develop the workflow for 
performing deformable registration and fusion of FACBC PET/CT and 3D ultrasound images of 
human patients, Thirty six patients, who have suspicion of recurrent prostate cancer after definitive 
therapy such as radiotherapy, will be recruited into this study. At least half of the patients will have 
positive imaging findings and will undergo 2D TRUS-guided biopsy as well as PET/ultrasound fusion 
biopsy. The proposed study will be the first-in-human trial that uses PET/CT imaging to direct 3D 
ultrasound-guided biopsy of the prostate. The multimodality imaging approach will combine the high 
sensitivity from PET and real-time information from ultrasound for improved cancer detection.  
 
This early-phase clinical trial will help transform the field from the current “blind” biopsy to future 
“targeted” biopsy and result in the change of prostate cancer management. The new biopsy 
technology can have an immediate impact on patient care by improving the detection and diagnosis 
of prostate cancer.   


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1. Background and Significance 
 
1.1. What is the clinical problem?    
Systematic transrectal ultrasound (TRUS)-guided prostate biopsy is considered as the standard 
method for prostate cancer detection. The current biopsy technique has a significant sampling 
error and can miss up to 30% of cancers (Hricak 2005). Not only is the volume of the biopsy 
sample small but the presence of prostate cancer (PCa) is involving only a small part of the prostate 
in the early stages of the disease. As a result, a patient may be informed of a negative biopsy result 
but may in fact be harboring an occult early-stage cancer. It is a difficult challenge for physicians to 
manage patients with false negative biopsies who, in fact, harbor curable PCa as indicated by 
biochemical measurements such as rising prostate specific antigen (PSA), as well as patients 
diagnosed with early-stage disease. Another important challenge facing physicians is patients 
diagnosed on biopsy as having premalignant lesions, i.e., high grade prostatic intraepithelial 
neoplasia, and, in particular, atypical small acinar proliferation (ASAP). This biopsy result is clinically 
significant as there is a 40%–80% chance of finding cancer on repeat biopsy if there is ASAP 
(Iczkowski et al 1998). As there might be coexisting cancer, especially with ASAP, where the 
pathologist finds only a small amount of histological “atypia” but not enough material to confidently 
diagnose cancer, such patients require a repeat biopsy soon after the first one. For ASAP patients, 
it is vital to rebiopsy the same area. Unfortunately, two-dimensional (2D) ultrasound provides only 
a vague location of the abnormal findings, and it is not possible to be certain that the same area has 
been sampled by the repeat biopsy. As a negative result does not preclude the possibility of a missed 
cancer and due to patient anxiety, a third biopsy may be requested, and etc. On the other hand, due 
to the increasing number of younger men with potentially early and curable PCa who undergo 
repeated biopsies, it is important not to re-biopsy the same area if the original biopsy was negative. 
Because of the biopsy sampling error and uncertainty associated with the current approach, both the 
patient and physician face significant challenges in making treatment decisions.  
 
1.2.  What is the potential impact of the research?   
As reported by the Prostate Cancer Foundation, this disease affects 1 in 6 American men. In 2008, 
186,320 American men were diagnosed with prostate cancer, which accounts for approximately 25% 
of all cases in men (Jemal et al 2009). Of the newly diagnosed prostate tumors, greater than 75% of 
the patients present with clinically localized disease. In the United States, more than 1.2 million 
TRUS-guided prostate biopsies are performed annually and these biopsies exceeds two billion 
dollars annually (Beck 2009). However, most of the biopsies (70-80%) show negative results 
including numerous false negatives. Novel biopsy technology is needed in order to reduce those 
unnecessary biopsies and thus to reduce medical cost and save patient’s time. The proposed 
research is to develop new “targeted” biopsy technology in order to replace current “blind” 
biopsy. If successful, the targeted biopsy would improve the cancer detection rate. As many patients 
would not need repeated biopsies, the total number of prostate biopsies could be reduced by more 
than 30%; this could save more than half billion dollars annually in just the biopsy costs. Furthermore, 
it will also reduce the potential morbidities of life-threatening sepsis and transrectal bleeding, both of 
which are associated with the biopsy procedures. As molecular information from PET/CT will direct 
the biopsy needle to a suspicious tumor target, the biopsy results will provide vital information for both 
the physicians and the patients in order to make optimal treatment decisions. For example, a patient 
may select active surveillance i.e. watchful waiting if the biopsy result shows a low-grade, non-
clinically significant tumor. An accurate biopsy can help to reduce their anxiety that often increases 
due to possible sampling error and the uncertainty associated with the current biopsy technique. As a 
false negative result may delay treatment, an accurate biopsy is extremely important for those active 


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surveillance patients because they rely on the biopsy result in order to follow up the disease without 
any radical treatment.   
 
2. Objectives 
 
Every man over the age of 45 is at risk for prostate cancer. Systematic transrectal ultrasound 
(TRUS)-guided biopsy is the standard method for a definitive diagnosis of prostate cancer. However, 
a critical problem is its significant sampling error and low sensitivity (39-52%). A negative biopsy does 
not preclude the possibility of a missed cancer. Due to the increasing number of younger men with 
potentially early and curable prostate cancer, this problem must be addressed. Two limitations are 
associated with the current biopsy approach: (1) Two-dimensional (2D) ultrasound imaging does not 
provide accurate location information in three dimensions; and (2) ultrasound imaging has difficulty to 
differentiate carcinoma from benign prostate tissue. This "blind" biopsy approach can miss up to 30% 
of prostate cancers. Nevertheless, more than 1.2 million prostate biopsies are performed in each 
year; and the biopsy cost is more than two billion dollars. Most (70-80%) biopsies show negative 
results including numerous false negatives. Those unnecessary biopsies not only increase medical 
cost national wide but also increase the risk of potential complications associated with the biopsy 
procedures. As a negative biopsy is not completely reassuring, both the physician and the patient 
face significant challenges in making treatment decisions. Innovative biopsy technology that can 
improve cancer detection can have significant impact on the management of this disease that affects 
1 in 6 men.  
 
2.1. 3D ultrasound has advantages over conventional 2D ultrasound for biopsy guidance   
A 2D ultrasound image represents a thin plane at an arbitrary angle in the body, yet the anatomy is 
3D, hence the physician must integrate multiple images in his/her mind. This practice is inefficient 
during interventional guidance, and may lead to variability and incorrect localization of lesions. 
Because of manually controlled scanning, it is difficult to localize the same image plane and 
reproduce it at a later time for follow-up studies. When using 2D transrectal ultrasound for needle-
guidance, physicians have restricted anatomical reference points for guiding the needle to target 
sites. Any motion of the probe during the procedure may cause the prostate image to change or 
deform to a prohibitive extent. These variations make it difficult to establish a consistent frame of 
reference for needle guidance. On the contrary, 3D ultrasound imaging provides volumetric 
representation of an object and offers images along any cross sections. The intuitive presentation by 
3D ultrasound allows more accurate lesion localization and treatment planning (Fenster et al 
2003;Shen et al 2008). Our 3D TRUS-guided system can record and display the 3D locations of 
biopsy cores, which is not possible with a conventional 2D image-guided system (Bax et al 2008). 
Existing 3D US-guided prostate biopsy systems include the TargetScan® prostate biopsy system 
(Envisioneering Medical Technologies, St. Louis, MO); which uses a side-firing TRUS imaging system 
containing flexible biopsy needles to perform a templated biopsy (Andriole et al 2007), and the 
Voluson prostate biopsy system (General Electric, Fairfield, CT), which is a 3D hand-held ultrasound 
imaging system with a 5.9 MHz endorectal probe (Long et al 2007). Unlike the two systems, our 
system can make use of any manufacturer’s end-fire TRUS probe and thus can be easily adapted by 
most of current biopsy systems.  
 
2.2.  Multiple modality images will be combined to improve cancer detection   
Although ultrasound imaging is a preferred method for image-guided biopsy because it is performed 
in real time and because it is portable and cost effective, current ultrasound imaging technology has 


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difficulty to differentiate carcinoma from benign prostate tissue. Hence, MR spectroscopic imaging 
(MRSI) is playing an increasing role in prostate cancer management (Manenti et al 2006;Mueller-
Lisse et al 2007). MR spectroscopy metabolite profiles of biopsy tissues can help direct treatment 
plans by assessing PCa pathologic stage and aggressiveness (Cheng et al 2005). MRSI has been 
shown to be valuable for depicting locally recurrent PCa after radiotherapy (Coakley et al 2004). 
Choline MRSI can depict prostate carcinoma with a high degree of sensitivity and specificity (Swindle 
et al 2003). Combined MRI and MRSI allow metabolic and structural evaluation of prostate cancer 
and improve the diagnostic accuracy for localizing and detecting the disease (Carlani et al 
2008;Hasumi et al 2002;Kurhanewicz et al 2002).  
Various PET imaging agents have been developed for prostate cancer detection and staging, 
these include 18F-FDG (Schoder et al 2005), 11C-choline (Hara et al 1998;Schilling et al 2008), 18F-
fluorocholine (DeGrado et al 2001), 11C-acetate (Oyama et al 2003), 11C-methionine (Nunez et al 
2002), and other PET agents. 18F-FDG is widely used in cancer applications. However, they have low 
sensitivity in the primary staging of prostate cancer and poor detection of abdominal-pelvic nodes 
because of excretion of tracers in the ureters, bladder, and bowel. At our Emory Molecular and 
Translational Imaging Center, PET imaging with the new molecular imaging tracer FACBC has shown 
very promising results for detecting and localizing prostate cancer in humans as reported by our 
group (Schuster et al 2007). Our clinical trials on FACBC are currently supported by the National 
Cancer Institute (NCI). As shown in our preliminary results, FACBC PET images show focal uptake at 
the tumor and thus could be ideal information to direct targeted biopsy. One innovation of the 
proposed research is the combination of FACBC PET images and 3D ultrasound for targeted biopsy. 
The multimodality imaging approach will combine the high sensitivity from PET and real-time 
information from ultrasound in order to improve the cancer detection rate. 
 
3. Specific Aims 
 
Central Hypothesis: FACBC PET/ultrasound fusion guided biopsy can detect more cancer per core 
than the standard 12-core TRUS-guided biopsy. The specific aims include: 
 
Aim 1:  To perform FACBC PET/CT directed, 3D ultrasound-guided biopsy and to determine if 
fusion targeted biopsy can detect more cancer per core than standard TRUS-guided 
biopsy. 
 
We will recruit 36 patients who have suspicion of recurrent prostate cancer after definitive therapy 
such as radiotherapy or other non-prostatectomy focal therapy such as cryotherapy. Based on our 
clinical experience, at least half of the patients (N 18) will have positive imaging findings in the 
prostate bed. These patients will undergo a standard 12-core systematic biopsy followed by 
PET/ultrasound fusion targeted biopsy at the same setting. Patients with negative scan will undergo 
the standard biopsy. We will determine (i) whether fusion targeted biopsy can detect more cancer per 
core than the standard biopsy; (ii) whether the addition of targeted biopsy to systematic biopsy 
increases the rate of diagnosis of Gleason 7 or greater cancer. 
 
The patient will be in the same setting for the standard TRUS-guided biopsy and the PET/TRUS 
fusion targeted biopsy. The same setting allows us to directly compare the accuracy of the two biopsy 
approaches for the same patients. This sequential study is supported by the literatures. For example, 
the NIH team led by Dr. Peter Pinto is one of the pioneer groups in the field of MRI/TRUS fusion 


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targeted biopsy. In their study, “Patients in the trial underwent a standard of care 12-core TRUS 
biopsy and MRI/US fusion guided biopsy in the same setting.” (P.A. Pinto, P.H. Chung, A.R. 
Rastinehad, A.A. Baccala, Jr., J. Kruecker, C.J. Benjamin, S. Xu, P. Yan, S. Kadoury, C. Chua, J.K. 
Locklin, B. Turkbey, J.H. Shih, S.P. Gates, C. Buckner, G. Bratslavsky, W.M. Linehan, N.D. Glossop, 
P.L. Choyke, B.J. Wood, "Magnetic resonance imaging/ultrasound fusion guided prostate biopsy 
improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric 
magnetic resonance imaging," The Journal of urology 186, 1281-1285, 2011). 
         
The TRUS-guided procedure uses an 18-gauge needle for prostate biopsy. This procedure does not 
intend to remove the tumor but take a tiny tissue sample for pathological processing and diagnosis of 
prostate cancer. Based on the well-known Epstein criteria on clinically significant tumors, a tumor with 
a radius of less than 5 mm is considered insignificant (Epstein,JI; Sanderson,H; Carter,HB; and 
Scharfstein,DO.  Utility of saturation biopsy to predict insignificant cancer at radical prostatectomy. 
Urology.  66:356-360. 2005). Based on the size of the 18-gauge needle and based on the Epstein 
criteria, the amount of cancer tissue that may be possibly remove by a standard TRUS-guided biopsy 
core will not affect the evaluation of the targeted biopsy for the diagnosis of clinically significant 
cancer.     
 
 
Aim 2:  To develop and optimize the workflow for performing deformable registration and 
fusion of FACBC PET/CT and 3D ultrasound of human patients for fusion targeted 
biopsy of the prostate  
 
We hypothesize that FACBC PET/CT images can be combined with 3D ultrasound to direct a biopsy 
needle to a suspicious cancer target as shown on FACBC images. We have developed deformable 
image registration and fusion software to combine FACBC PET/CT and 3D ultrasound images of 
human prostate. We have developed a workflow for fusion targeted biopsy and will optimize its 
efficiency in our clinic setting.     
 
The specific aim 2 is to optimize the clinical workflow for the registration between PET/CT and 3D 
ultrasound images for the fusion targeted biopsy. We have performed the PET/TRUS fusion targeted 
biopsy in nine patients based on our currently approved IRB protocols. This new protocol is to 
combine two IRB-approved protocols into one protocol so we can streamline the recruitment of 
patients. The study is currently supported by two NIH grants. The feasibility of the specific aim 2 has 
been demonstrated in our preliminary study. This aim has mostly been achieved and the workflow will 
be continuously optimized during the whole study.  
 
Milestones for this specific aim: For the first specific aim, there are three milestones. The first 
milestone is to obtain a complete set of FACBC PET/CT and 3D ultrasound data to test the fusion 
method. This milestone was achieved after we acquired the PET/CT and 3D ultrasound data from the 
first patient. The second specific aim is to complete a fusion targeted biopsy plan in a 3D prostate 
model. This milestone was also achieved when we completed the biopsy procedure in our first 
patient. The third milestone is to complete the first half patients, i.e. 18 patients, for the NIH-funded 
early-phase study. This milestone will be achieved when we recruit more patients into the study and 
when we complete the optimization of the workflow.  
 


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4. Research Design and Methods 
 
4.1. Patient Selection: 
Thirty-six (N=36) patients will be enrolled in this study. All patients in this study may undergo routine 
conventional testing and imaging per usual clinical determination. This study will not interfere with 
routine diagnostic evaluation. All patients will have a FACBC PET-CT scan.  
The 3D ultrasound device has received the FDA 510K approval. Because the device can provide 3D 
ultrasound images as well as fused PET/MRI/ultrasound images, we believe that the clinician will be 
able to better biopsy the tissue at the right location.  
  
Inclusion Criteria:  
1) Patients must be 18 years of age or older.  
2) Patients will have been originally diagnosed with 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: Older ASTRO 
criteria of three consecutive rises of PSA or earlier if clinically appropriate, and/or nadir + 2.0 
ng/ml (ASTRO-RTOG Phoenix criteria).  
5) Patients must be able to provide written informed consent. 
 
Exclusion Criteria: 
1) Age less than 18.  
2) Less than 1 year since cryotherapy, external beam radiation therapy, or HiFU, or 2 years since 
brachytherapy. Does not meet above criteria of suspicious PSA elevation.  
3) Cannot provide written informed consent.  
4) Less than 1 month since any prior prostate biopsy (to decrease false positive from 
inflammation). 
5) Not otherwise eligible for prostate biopsy. 
 
Patients will be required to fast in preparation for PET scan. Verbal consent will be obtained 
from patient prior to the PET scan day 
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.    
PET Scan Day:  The following procedures will be performed: 
 Obtain written informed consent 
 Inclusion/exclusion criteria review 
 


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4.2. 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. The automated radiosynthesis 
of anti-[18F]FACBC will be carried out in a chemical process 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 200 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
 
 
4.3. 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 other PET-CT scanner.  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 450ml of 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 (approximately 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. 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. 
 
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). 
Synthesis of anti-
FACBC 
 


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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. 
 
 
4.4. Image Analysis of anti-[18F]FACBC PET-CT 
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 
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 a board certified nuclear medicine imager who will 
be blinded to all history and other imaging.  
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.  
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. 
 
4.5. Clinical and Histological Assessment. 
After the anti-[18F]FACBC scan has been obtained and interpreted, the following will occur: 
1) All patients with identifiable sites of disease on FACBC PET will, if clinically feasible, undergo 
targeted fusion biopsy followed by the standard TRUS-guided biopsy. The targeted biopsy will 
be performed before the standard TRUS-guided biopsy because patient motion and movement 
may affect the accuracy of the targeted biopsy and because the standard TRUS-guided biopsy 
is a random biopsy and does not have a high requirement on patient motion.  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.  


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2) 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 1. 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.  
3) As a secondary endpoint, patients with abnormal extraprostatic suspicious findings on 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. Due to the high PPV of FACBC for extraprostatic disease, at the least, the 
referring clinician will discuss the findings with the patient and offer biopsy or other diagnostic 
investigations (such as advanced bone imaging for suspected skeletal lesions) as deemed 
clinically appropriate. In the event that the PET/CT demonstrates that the prostate cancer may 
have spread to areas outside of the prostate, the referring urologist or primary care physician 
will be notified and the findings will be discussed with the patient. 
  
4.6. Statistical Analysis 
The PI consulted with Dr. Nelson Chen at the Winship Statistical Core. The following description was 
provided by Dr. Chen for the analysis plan and sample size. 
 
Analysis Plan: After we obtain the pathological results for each core from the standard TRUS-guided 
biopsy and the PET/TRUS fusion targeted biopsy, we will calculate the cancer detection rate per 
core. For example, we will calculate how many cores are able to detect prostate cancer in the 
standard TRUS-guided biopsy and how cores will detect cancers in the PET/TRUS-guided biopsy. 
Based on the total numbers of cores for each biopsy approach, we can calculate the cancer detection 
rate per core for each biopsy approach. In order to compare the detection rates between the PET 
positive and negative groups, Chi-square test will be used to compare the detection rates with 
standard biopsy between the two arms with FACBC scan positive and negative, respectively. 
Logistics will be further employed to test their adjusted effect after adjusting for other factors in the 
multivariate analysis. In the first specific aim, the goal is to determine if the PET/TRUS fusion targeted 
biopsy can detect more prostate cancer than the standard TRUS-guided biopsy. Therefore, among 
the FACBC positive arm, Kappa coefficient will be calculated to measure the correlation of the paired 
diagnostic results between the standard biopsy and the fusion targeted biopsy. McNemar's test will be 
further used to test on its significance.  
 
Sample Size: We will recruit a total of 36 patients for this study. According to the inclusion criteria, 
approximately half of patients will have positive imaging scans and the other half negative.  We 
determine the sample size in order to compare the performance of standard biopsy with the fusion 
targeted biopsy. We will expect to have 18 patients with FACBC positive, therefore, with McNemar’s 
test, the sample size of 18 paired samples will achieve a power of at least 80% to detect a Kappa 
coefficient of 0.62 or higher between the two methods at the significant level of 0.05, assuming equal 
probability of positive or negative diagnosis outcome. We also like to determine the power to compare 
the detection rates of standard TRUS-guided biopsy between the PET positive and negative groups. 
With 18 FACBC positive patients and 18 FACBC negative patients, this study will have a power of at 


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least 80% to detect a difference in detection rates of 41% or higher between the two groups at the 
significant level of 0.05.   
   
5. Registration/Randomization 
Patients will be registered and consented into the study by one of the research nurses on staff 
working in the clinical Urology or Radiology setting. There will be no randomization. Patients are 
referred to the study by an Emory physician and or Co-I via email or telephone.  Patient is seen at 
next appointment or at FACBC PET scan visit.  Patient is then consented, registered into ERMS and 
eligibility criteria completed. 
 
6. Intervention  
This is not a therapeutic study. Diagnosis only.  
 
Standard transrectal ultrasound (TRUS) guided biopsy: An ultrasound probe about 2.5 cm in 
diameter is gently inserted into the rectum. This ultrasound probe allows visualization of the prostate 
on two-dimensional (2D) images and allows for the placement of a biopsy needle that collects 
samples of the prostate. Usually, a total of 12 biopsy specimens are usually collected. The procedure 
takes about 20 minutes. This TRUS-guided biopsy is considered as the standard method for prostate 
cancer diagnosis. However, this biopsy procedure randomly takes tissue specimens from the 
prostate. Because of sampling errors, this standard TRUS-guided biopsy may miss the tumor in the 
prostate. In this proposed study, we will use three-dimensional (3D) ultrasound imaging to guide the 
biopsy in order to improve the location of the biopsy needle and will also use PET imaging to direct 
the biopsy to a suspicious target. The 3D ultrasound guided biopsy procedure is outlined in the next 
paragraph.     
 
3D ultrasound-guided biopsy: In this proposed study, we will test the 3D ultrasound-guided biopsy 
with the aid of PET images. The steps of the proposed prostate biopsy are as follows.  (1) Before 
biopsy, the patient already has a PET/CT scan with FACBC. The anatomic CT images will be 
combined with PET images for improved localization of suspicious tumors.  (2) During biopsy, 3D 
ultrasound images will be acquired immediately before the procedure when the patient is on the table. 
The 3D ultrasound images will be registered with the PET/CT data for biopsy planning. Freshly 
acquired, real-time, 2D ultrasound images will also be acquired and then registered with the 3D 
ultrasound and PET/CT images for improved lesion targeting. Three-dimensional visualization tools 
will guide the biopsy needle to a suspicious lesion.  (3)  At the end of each core biopsy, the needle tip 
position will be recorded on the real-time ultrasound images. The location information of biopsy cores 
can be saved and then restored in the re-biopsy procedure. This allows the physician to either re-
biopsy the same area for a follow-up examination or not to re-biopsy the same region if the original 
biopsy was negative. Either of the two re-biopsy examinations is not possible with the current 2D 
ultrasound-guided biopsy approach. Furthermore, the FACBC PET images will direct the biopsy to 
the suspicious tumor for targeted biopsy. 
 
7. Pathology: 
All pathologic samples will undergo standard analysis to determine if prostate carcinoma cells are 
present. The majority of tissue will be analyzed from clinically interpreted fixed specimens. 
Specimens will be fixed in neutral-buffered formalin, embedded in formalin, sectioned at 5-micron 


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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.     
 
8. Data Collection: 
As noted above and per routine IRB requirements. 
 
9. 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 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. 
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. Blue Earth 
Diagnostics, Ltd,(BED).  BED is involved in the development and commercialization of FACBC for 
diagnostic purposes and will supply the FACBC cassettes for FACBC production.  BED will receive 
data on safety since they supply the FACBC cassettes.  
 
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). Pharsafer is the 
clinical research organization (CRO) that functions as the safety oversight on behalf of BED   Events 
should be reported to Pharsafer within 24 hours of the investigator becoming aware of the events 
occurrence.  
 
10. 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.  


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Version 3/29/2018 
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 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. 


16 
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