Clinical trial NCT02830880
Conditions: Prostate Cancer
Keywords: Imaging Nuclear medicine Oncology Radiology Urogenital disorders
Sponsor: Emory University
Start date: 2016-07-01; Completion date: 2019-09-30
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess if using anti-1-amino-3-\[18F\]fluorocyclobutane-1-carboxylic acid (FACBC or fluciclovine) PET scan will be useful in determining if participants are responding to chemotherapy treatment. Investigators will enroll participants whose cancer has been treated with hormone therapy and now the cancer is not responding to the treatment (castration -resistant), and so therefore will be started on chemotherapy. Investigators aim to enroll thirty participants in this study.

Detailed description:
The goal of the investigation is to examine therapeutic monitoring of chemotherapy in castrate resistant prostate carcinoma with anti-3-\[18F\]FACBC in prostate carcinoma to determine if anti-3-\[18F\]FACBC amino acid imaging can serve as an accurate and efficient imaging biomarker.

Investigators will perform a baseline anti-3-\[18F\]FACBC PET-CT of the whole body. All participants will also undergo conventional staging including 99mTc methylene diphosphonate (MDP) bone scanning and computed tomography scan (CT) or magnetic resonance imaging (MR) of the abdomen and pelvis which are standard of care at the enrolling institution. This study will not interfere with standard patient evaluation or delay therapy.

All 30 participants will receive chemotherapy every 3 weeks for 6 cycles. Participants will undergo a repeat anti-3-\[18F\]FACBC PET-CT after 1 and 6 cycles and also repeat conventional imaging including bone scanning CT or MR of the abdomen and pelvis after 6 cycles. At the end of the study, the study team will then record the response (or lack thereof) on anti-3-\[18F\]FACBC PET-CT and correlate that response with response per standard clinical criteria including bone scan uptake for skeletal lesions, CT or MR for soft tissue and skeletal lesions, prostate-specific antigen (PSA) progression or regression, and other clinical parameters such as declining performance status.

Arms: arm 1: Participants with biopsy-proven primary or recurrent castration-resistant prostate carcinoma with skeletal and/or nodal involvement will undergo an FACBC PET-CT scan.
Interventions: intervention 1: FACBC PET-CT intervention 2: MRI, CT, or Bone Scan
Intervention descriptions: intervention 1: Anti-3-\[18F\]FACBC is an investigational positron emission tomography (PET) radiotracer being studied given intravenously prior to PET scan. intervention 2: Conventional imaging such as a MRI, CT, or bone scan will be performed to correlate imaging findings.

Protocol documents:
Prot_SAP_000.pdf: 
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Investigation of Therapy Response with Amino Acid Analogue 
Transport PET Imaging  
 
Protocol dated January, 23, 2018 
 
NCT number: NCT02830880 


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Investigation of Therapy Response with Amino Acid Analogue Transport PET Imaging  
 
 
 
 
 
PI: David M Schuster, M.D. 
Emory University  
Department of Radiology and Imaging Sciences 
Emory University School of Medicine, Atlanta, GA 
Phone:  (404) 712-4859 
email: dschust@emory.edu 
 
 


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Schema: 
 
 
 
 
 
 
 
 
 
 
 
Patient recruitment per inclusion criteria (n=30) 
Castration resistant metastatic prostate carcinoma not currently 
undergoing systemic chemotherapy. (Bone involvement and/or 
nodal, both preferable.) 
All patients to undergo baseline PSA, bone scan and other 
standard of care imaging such as CT or MR. 
Initial anti-3-
[18F]FACBC PET-CT 
Scan (n=30)  
Standard of care PSA, bone scan and CT or MR. Repeat anti-3-[18F]FACBC PET-CT.  
1 cycle Docetaxel. 
Within 90 days if feasible 
6 total cycles Docetaxel (or sooner at end of chemotherapy per patient condition). 
Repeat anti-3-[18F]FACBC PET-CT 
Within 14 days if feasible 
Within 14 days if 
Within 14 days if feasible 
Follow-up per clinician discretion until progression or death. Progression may 
be based on PSA, clinical, imaging, change in therapy and/or mortality. 


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Precis/Abstract: 
Anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F]FACBC) is a synthetic amino acid 
analog which has demonstrated promise for the staging and restaging of prostate carcinoma. Yet no work 
to date has been accomplished in the ability of this radiotracer to monitor response to therapy. Yet, the 
ability to monitor response to therapy with imaging may prove to be important as a surrogate endpoint in 
treatment effectiveness and the ability to switch to other forms of therapy if the first therapy is ineffective. 
We will investigate the ability of anti-3-[18F]FACBC PET to monitor response to therapy of skeletal and 
soft tissue lesions in castration resistant metastatic prostate carcinoma after 1 and 6 cycles (or sooner at 
end of chemotherapy per patient condition) of Docetaxel/Prednisone chemotherapy, and correlate imaging 
findings with tumor and imaging biomarkers such as PSA, bone scan and other conventional imaging 
such as CT or MR. We will also correlate anti-3-[18F]FACBC PET after 1 and 6 cycles of chemotherapy 
with response to therapy at 1 year (or earlier if progression). 
 
 


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A. Introduction and Background: 
 
As more therapeutic options for the treatment of castration resistant prostate carcinoma are made 
available, monitoring response to therapy with biomarkers may play an increasingly important role (1). 
Typical median survival for this disease is 18 months with a 50% response rate by PSA criteria to 
chemotherapy. Monitoring therapeutic response has been traditionally been accomplished via serum 
biomarkers such as prostate specific antigen (PSA) and imaging biomarkers such as bone scanning for 
skeletal disease and anatomic imaging such as computed tomography (CT) for nodal disease. While bone 
scanning with Tc-99mMDP is highly sensitive for the detection of skeletal metastasis, the technique is 
prone to false positive findings. In addition, bone scanning may be subject to a “flare” phenomenon, 
whereby there is increased radiotracer uptake secondary to lesion healing despite clinical improvement, 
making the disease appear worse, when in actuality there is metabolic and clinical improvement (2, 3). 
Response on bone scan also may be subjective though there have been recent efforts to semi-quantify 
disease burden (4, 5). 
 
Modern chemotherapy regimens for castration resistant prostate cancer include docetaxel and 
cabazitaxel. Docetaxel given at a dose of 75 mg/m2 every 3 weeks is considered a standard first line 
chemotherapy regimen, while cabazitaxel is reserved for patients who are either resistant to docetaxel or 
relapse/progress after docetaxel treatment. Overall response rates in the range of 50% have been reported 
with de novo standard docetaxel therapy. The regimen is generally well tolerated with a minority of 
patients developing grade 3-4 adverse events including myelosuppression and fatigue being most 
common. 
 
While CT or magnetic resonance imaging (MR) may demonstrate exquisite anatomic detail, the 
differentiation of benign from malignant nodal disease by size criteria alone is problematic. Both CT and 
MR have demonstrated limitations in the evaluation of metastatic disease from prostate carcinoma in 
particular (6). Change in the size of a soft tissue lesion may be uncoupled from metabolic response; that 
is, a lesion can appear to be getting smaller, yet still be metabolically active and visa-versa. In addition, 
while criteria exist for the quantification of representative soft tissue lesions, bone lesions are more 
difficult to quantify in a similar manner (7). Thus, metabolic imaging biomarkers for the treatment of 
prostate carcinoma have been investigated. 
 
18F Fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proven to be very 
useful in monitoring response to therapy for a wide variety of disease processes. Yet, since FDG monitors 
only glucose metabolism it may reveal only a limited amount of information compared with the entire 
gamut of tumor metabolism (8, 9). The utility of FDG PET in therapy response assessment for prostate 
carcinoma has not been widely researched. In early work, change in FDG uptake had been correlated with 
response to hormonal therapy but not with chemotherapy (10, 11). In more recent studies, Jadvar has 
reported in preliminary work that FDG uptake decreases with successful response to both hormonal and 
chemotherapy and declines concordantly with PSA (12). Yet, in general, FDG PET has been 
demonstrated to have low utility for the staging and restaging of prostate carcinoma, especially in the 
detection of osseous metastases (13-15). In addition, other FDA approved and non-FDA approved PET 
radiotracers such as 11C-choline, 18F-fluorocholine, and 11C-acetate have been utilized mostly outside of 
the US for the staging and restaging of prostate carcinoma, yet only preliminary work has been completed 
on monitoring therapy response (16-28).  


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Figure 1: Molecular configuration of anti-3-[18F]FACBC  
Figure 3: Time activity curve of FACBC wash-
in and wash-out in benign versus malignant 
lymph nodes 
Figure 2: anti-3-[18F]FACBC PET-CT top row arrows 
demonstrates small malignant obturator lymph node
 
Amino acids are involved in many aspects of human nutrition including the synthesis of proteins. 
Amino acid metabolism has been demonstrated to be upregulated in many tumors including prostate 
carcinoma (29). A number of amino acid radiotracers have been utilized to study prostate carcinoma and 
other tumors including naturally occurring L-[11C]methionine, L-3-[123I]iodo-alpha-methyl tyrosine 
(IMT), and L-[1-11C]5-hydroxytryptophan (5-HTP). There has been little work exploring the role of 
amino acid radiotracers for evaluating response to therapy, most of which has been done with brain 
tumors (15, 30, 31). Nunez has reported on differences in uptake patterns in prostate carcinoma between 
11C-Methionine and FDG PET, and noted these could be exploited in monitoring response to therapy, but 
no formal study has been completed with amino acid imaging to monitor therapy response in prostate 
carcinoma (32). 
 
Anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F]FACBC) is a synthetic 
amino acid analog (Fig. 1) which has demonstrated promise for the 
staging and restaging of prostate carcinoma (33). In our recent papers 
anti-3-[18F]FACBC had high accuracy in differentiating prostatic 
from extraprostatic recurrent prostate carcinoma (34, 35) (Fig 2). The 
uptake of anti-3-[18F]FACBC is likely mediated through a 
combination of amino acid transport proteins and the radiotracer is not metabolized (36-39). Normal 
biodistribution of anti-3-
[18F]FACBC includes relatively 
intense uptake in the liver and 
pancreas and little renal excretion or 
brain uptake compared with 18F-FDG 
(40).  
Yet, kinetic studies have 
demonstrated rapid wash-in of the anti-
3-[18F]FACBC PET radiotracer into 
prostate malignancy with variable but generally slower 
washout (Fig 2). The explanation for this phenomenon 
is likely secondary to the complex interplay of amino 
acid transporters (AAT) involved with natural and 
synthetic amino acid transport. In addition, many of the 
AAT’s demonstrate 1:1 stoichiometry; that is, an amino 
acid is exchanged out from the cell for one to be 
brought in.  
 
In exploratory published data examining test-
retest reproducibility of anti-3-[18F]FACBC PET, 
there seems to be general reproducibility of 
background structures and selected lesions on the 
order of magnitude of 18F-FDG PET (41). 
Though a formal test retest study needs to be undertaken, we believe that it is reasonable to utilize anti-3-
[18F]FACBC to examine therapy response in a similar manner to the commonly utilized 18F-FDG 
biomarker. In addition, anti-3-[18F]FACBC has been demonstrated to be more sensitive than MR for 
evaluating early tumor response to TMZ therapy in gliomas in a rat model (42). No study to date has been 
performed on humans or for prostate carcinoma. 


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Our hypothesis is that amino acid imaging with anti-3-[18F]FACBC may be useful in monitoring 
therapy response for prostate carcinoma and will corollate with ultimate response to chemotherapy 
including PSA levels and clinical response. The overarching goal of this project is to investigate 
therapeutic monitoring of chemotherapy in castration resistant prostate carcinoma with anti-3-
[18F]FACBC in prostate carcinoma to determine if anti-3-[18F]FACBC amino acid imaging can serve as 
an accurate and efficient imaging biomarker. 
 
B. Objectives 
 
Accurate determination of imaging response to chemotherapy in castration resistant prostate carcinoma 
may be important in understanding if a particular radiotracer may be translated to the clinic and under 
what conditions it may be useful.  
 
We will explore if amino acid imaging with this radiotracer is responsive to therapy changes of 
tumors and to establish a framework to understand if anti-3-[18F]FACBC may be useful to monitor 
therapeutic effect. We will commence with a synthetic amino acid analogue radiotracer anti-3-
[18F]FACBC and prostate carcinoma – study conditions in which we have the greatest amount of 
experience. Clinical trials with anti-3-[18F]FACBC for prostate carcinoma in multiple centers has 
successfully studied over 900 patients with no untoward effects. Future studies may be directed at other 
synthetic amino acid radiotracers and other tumors to determine if these findings are generalizable to 
other amino acid imaging. 
 
The aims of this study is to determine if there is a change in radiotracer uptake in response to 
systemic chemotherapy in patients with known prostate carcinoma. We will also investigate if anti-3-
[18F]FACBC uptake after 1 cycle will predict clinical and imaging response after 6 cycles of 
chemotherapy, if anti-3-[18F]FACBC uptake after 6 cycles correlates with clinical and imaging response 
after 6 cycles of chemotherapy, and if anti-3-[18F]FACBC uptake at 1 and/or 6 cycles of chemotherapy 
will predict clinical and imaging response at one year (or earlier if progression).  
 
 
Specific Aims 
 
Specific Aim 1. To determine if uptake on anti-3-[18F]FACBC PET-CT in metastatic lesions with 
castration resistant prostate carcinoma is affected by chemotherapy. 
 
 
Specific Aim 2. To determine if response on anti-3-[18F]FACBC PET scan after 1 and 6 cycles of 
chemotherapy (or sooner at end of chemotherapy per patient condition) correlates with clinical and 
imaging response after these cycles of chemotherapy as measured by standard parameters including PSA 
and routine objective measurements.  
 
Specific Aim 3. To determine if response on anti-3-[18F]FACBC after 1 and 6 cycles of chemotherapy (or 
sooner at end of chemotherapy per patient condition) correlates with clinical and imaging response to 
therapy at one-year or earlier if progression as measured by standard parameters including routine 
objective measurements, PSA progression, clinical progression, and/or mortality. 
 
 
 


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Sub-aim 1. To determine if uptake on the baseline anti-3-[18F]FACBC PET-CT correlates with response 
to chemotherapy after 6 cycles and at one year or earlier if progression as measured by standard 
parameters.  
 
Rationale. As has been outlined in Section A of the proposal, response of amino-acid imaging PET with 
the synthetic amino acid analogue radiotracer anti-3-[18F]FACBC has not been established, yet has 
profound implications in translating a promising radiotracer from experimental conditions to the clinic. 
The specific hypothesis in this proposal is that there may be a better correlation of response with amino 
acid PET utilizing anti-3-[18F]FACBC than MDP bone scanning and with anatomic imaging modalities 
such as CT or MR. The most comprehensive manner to assess our hypothesis is to undertake a 
prospective trial examining treatment response with each patient serving as his own control.  
 
We propose assembling a dedicated multidisciplinary team of experts in amino acid radiotracer 
synthesis and imaging as well as medical and radiation oncology, urology, and biostatistics. Outcomes 
will be validated by direct comparison of patient serving as their own respective controls. We will 
examine the data for comparisons between groups with multivariate analysis among other statistical tools. 
 
C. Study design and methods 
 
Experimental design. We will undertake a study with 30 patients who have castration resistant metastatic 
primary or recurrent prostate carcinoma with skeletal metastases and/or nodal involvement. The patients 
will serve as their own control. We will perform a baseline anti-3-[18F]FACBC PET-CT of the whole 
body as per the detailed protocol below. All patients will also undergo conventional staging including 
99mTc MDP bone scanning and CT or MR within 90 days if feasible which are standard of care at our 
institution. Note that on a case by case basis, an individual scan may be accepted outside this window 
based on the best clinical and scientific judgement of the PI. This study will not interfere with standard 
patient evaluation or delay therapy. Other imaging may also be obtained clinically.  
 
Subsequently, all 30 patients will undergo a standard chemotherapeutic regime 
Docetaxel/Prednisone for 6 cycles or more as tolerated. Patients will then undergo a repeat anti-3-
[18F]FACBC PET-CT after 1 and 6 cycles (or sooner at end of chemotherapy per patient condition) and 
also repeat conventional imaging including 99mTc MDP bone scanning and CT or MR after 6 cycles (or 
sooner at end of chemotherapy per patient condition). By the termination of the study, we will then record 
the response (or lack thereof) on anti-3-[18F]FACBC PET-CT (Specific Aim 1) and correlate that 
response with response per standard clinical criteria including bone scan uptake for skeletal lesions, CT or 
MR for soft tissue and skeletal lesions, PSA progression or regression, and other clinical parameters 
(Specific Aim 2) such as declining performance status and  time to change to another therapy.  
 
 
The patients will be also followed up in the context of this study (per clinical routine) for up to 
one year post-therapy to determine if changes on previously acquired anti-3-[18F]FACBC PET-CT 
predicted ultimate response including evaluable lesions on repeat conventional imaging including 99mTc 
MDP bone scanning and CT or MR, as well as PSA progression, clinical progression, and mortality 
(Specific Aim 3). 
 
 
 


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C.1 Anti-[18F]FACBC radiolabeling 
Methods. We will prepare anti-3-[18F]FACBC via the GE FastLab cassette system. Alternatively, 
production may also be accomplished by the automated synthesis developed by J. McConathy and M.M. 
Goodman (85) as outlined in Figure 4. The automated radiosynthesis of anti-3-[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-3-[18F]FACBC after delivery of 18[F]fluoride 
will be ~70 minutes, and the average decay-corrected yield of anti-3-[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-3-[18F]FACBC at the end of synthesis. We have prepared greater than 150 batch productions 
for tumor imaging in volunteer subjects. Either methodology will be conducted under FDA IND auspices 
(IND 72437). 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
C.2 PET-CT imaging protocol  
PET-CT images will be acquired on a GE Discovery 690 (16 Slice) or other PET-CT scanner.  All studies 
will use measured attenuation correction (routinely acquired through the initial CT portion of the scan).  
Dead time, detector efficiency and scatter corrections will be applied using the routines supplied by the 
manufacturer. The resulting images will be quantitatively calibrated and have 6 mm isotropic resolution.   
 
All subjects will initially be required to fast for at least 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. The study will 
typically take place in the afternoon. Within one hour prior to scanning, the patient will drink 450 ml of 
oral contrast as possible 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. anti-3-
[18F]FACBC (10 mCi) will be injected into an antecubital vein in a bolus infusion. At 4 minutes post-
injection), consecutive 2 minutes per frame acquisitions (z axis FOV is: 15cm with 3 cm overlap per table 
position) will be obtained starting from the proximal thighs and extending superiorly for 7 table positions 
which typically reaches at least the skull base. This will immediately be repeated to obtain dual time point 
(early and delayed) data. All efforts will be made to always study the patient on the primary and same 
scanner unless there is a technical scanner failure.  
 
Summary of PET-CT Scanning Procedure 
BocHN
CO2CH3
OSO2CF3
BocHN
CO2CH3
18F
H2N
CO2H
18F
a
b
anti-[18F]FACBC
a)K18F, K222, K2CO3; 90C b) 4 NHCl, 120 C
Figure 4. 
Synthesis of 
anti-FACBC 


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1) The patient will be placed in the tomographic gantry for a CT scan of the skull to proximal thighs (80-
120 mA) to be utilized for anatomic imaging and correction of emission data (approximately 1 minute).  
2) The patient will then receive a bolus of anti-3-[18F]FACBC injected IV  
3) The dosage will be approximately 10.0 mCi (370 MBq). 
4) At 4 minutes, a 2 minute per bed position PET acquisition will start at the proximal thighs and extend 
for 7 table positions typically to the skull base or higher.  
5) This will be repeated to achieve dual time point imaging. 
6) The entire study including injection of radiotracer should take approximately 60 minutes or less. 
7) The study will be repeated within 14 days after the first cycle and 14 days after completion of the 6th 
cycle of chemotherapy as below, allowing for patient condition (or sooner at end of chemotherapy per 
patient condition). To be clear, a cycle starts from the time of chemotherapy administration on day one, 
and lasts for 3 weeks until the next cycle (or until cessation of chemotherapy). Therefore, the ideal time to 
scan the patient in followup is within a few days before the next cycle commences. Yet, this is not always 
logistically possible. Therefore, subsequent scanning may occur within 14 days after the first cycle, and 
could therefore take place within the next cycle.  
 
C.3 Chemotherapy 
Chemotherapy will consist of docetaxel 75 mg/m2 administered intravenously every 21 days with 
appropriate pre-medications (steroids and anti-emetics) administered to prevent acute adverse effects. 
Growth factor support will be provided per clinical need. If the neutrophil and platelet counts are 
adequate, chemotherapy will be repeated for a total of 6 cycles after which the patient will be treated at 
his physician’s discretion. Prednisone 5 mg can be administered orally twice daily along with docetaxel 
chemotherapy throughout the study per physician’s discretion. In patients who experienced either febrile 
neutropenia, neutrophil count <500 cells/mm3 for more than one week, severe or cumulative adverse 
event or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel may be reduced 
from 75 to 60 mg/m2. If the subject continues to experience these reactions at 60 mg/m2, the 
docetaxel treatment may be discontinued per physician’s discretion. In addition, a cycle of therapy may 
be delayed to allow for recovery of adverse event if indicated per physician’s discretion. CBC, CMP and 
PSA are done before each dose of chemotherapy. Patients may or may not be on anti-hormonal therapies 
including but not limited to LHRH agonists, antiandrogens, Abiraterone or Enzalutamide. 
 
C.4 Routine Laboratory and Imaging Biomarkers 
As per clinical routine, all patients will undergo routine PSA and CT or MR as well as bone scanning at 
baseline (within 90 days before the beginning of therapy if feasible), after 6 cycles of chemotherapy (or 
sooner at end of chemotherapy per patient condition), and at 1 year (or earlier if progression). This is 
considered a clinical standard and will not be funded from the project budget. These studies will be 
performed with the standard Emory protocols on file. The only study-specific event is the FACBC scan. 
 
C.5 Image Analysis of anti-3-[18F]FACBC PET-CT 
Methods: The methods of image analysis to be used for the anti-3-[18F]FACBC PET-CT are as follows: 
1) Images will be reconstructed with iterative technique and hardware fused (PET to CT) on a GE AW or 
MimVista or similar workstation which enables SUV (mean, maximum) and total lesion activity as well 
as standard bidimensional size measurements of lesions. Whenever possible we will use 3 dimensional 


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PET-Edge conformational regions of interest (ROI) to encompass the entire structure under question such 
as a lymph node or prostate bed.  
2) Visual inspection of the PET-CT images in separate sessions by a board certified nuclear medicine 
physicians/nuclear radiologist will take place with calculation of SUVmax, SUVmean, total lesion 
activity of 5 representative index lesions each for bone and lymph nodes (10 total). If 5 lesions each are 
not definable, all demonstrable lesions up to 5 will be utilized. Lesions chosen will be independent but 
may coincide with index lesions on conventional imaging. In addition, we will derive similar 
measurements of background structures from key organs which we have identified from prior studies with 
this radiotracer including bladder, liver, pancreas, bone marrow (L3), and blood pool (aorta at arch). 
Tumor to background values will also be calculated. All measurements will be made at both time points 
to calculate retention indices. 
3) The same measurements of the lesions and background structures will be undertaken at baseline and 
post-therapy scan. We will utilize the following parameters to follow response to therapy: SUVmax and 
total lesion activity of most intense lesion each of bone and node, sum and mean SUVmax of up to 5 
index lesions for each of bone and node, total lesion activity of most intense lesion each of bone and 
node, and sum and mean total lesion activity of the 5 index lesions for each of bone and node. Percent 
change will be calculated before and after therapy. Comparison of data for differences will be undertaken 
using standard statistical analyses (see below).  
4) In addition, the measurements above will be supplemented by the following from RECIST 1.1 Criteria 
(43): Negative anti-3-[18F]FACBC PET at baseline, with a positive anti-3-[18F]FACBC-PET at follow-up 
is a sign of PD based on a new lesion. 
 
C.6 Image Analysis of Abdominopelvic CT or MR 
A standard clinical report will have been generated per routine. The results of this report will be recorded. 
In addition, one of the investigators will record bi-dimensional measurements of up to 5 index lymph 
nodes as applicable, identified on the study. These will be used to calculate RECIST 1.1 response criteria 
briefly excerpted below (43, 44). Note that this assumes ideal conditions which may vary in individual 
patients.  
 
Specifically, measurable lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 mm by CT or MR 
scan (assuming slice thickness no greater than 5 mm). To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. Non-measurable lesions are all other lesions, including small lesions 
(longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), as well as truly 
non-measurable lesions. Up to five target lesions as appropriate will be measured. Target lesions will be 
selected on the basis of their size (lesions with the longest diameter) and be representative of all involved 
organs, as well as their suitability for reproducible repeated measurements. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters, which will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. Since mostly lymph nodes are to 
be included in the sum, only the short axis will contribute. If 5 index nodes cannot be recorded, non-target 
lesions will be identified to increase the total index lesions to 5 and followed as ‘present’, ‘absent’ or in 


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rare cases, ‘unequivocal progression’. If the patient does not have nodal disease, lymph nodes will not be 
used as index lesions. 
 
The response criteria will be as follows: Complete Response (CR): Disappearance of all target 
lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum 
of diameters of target lesions, taking as reference the smallest sum on study (this may include the baseline 
sum). The sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither 
sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.  
 
Since lymph nodes will be the target lesions, the sum of lesions will never be zero even if CR 
criteria are met since a normal lymph node is defined as having a short axis of <10mm. If the node 
becomes too small to measure, a default value of 5mm will be assigned.  
 
If non-target lesions are utilized, a qualitative assessment with the following criteria will be 
applied. Complete Response (CR): Disappearance of all non-target lesions and normalization of tumour 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the 
normal limits. Progressive Disease (PD): Unequivocal of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression). If there is no true soft tissue 
lesion, no soft tissue index lesion is used. 
 
C.7 Image Analysis of Bone Scan 
As noted above, bone scanning will be obtained per routine with a standard clinical report. For description 
of up to 5 index lesions, we will utilize standard nomenclature of none, mild (similar to surrounding 
bone), moderate (greater than surrounding bone and similar to characteristic degenerative uptake), and 
intense (greater than characteristic degenerative uptake), supplemented or supplanted by anatomic 
measurement when appropriate. Standard of truth will be characteristic metastatic appearance on bone 
scan and/or CT.  
 
In addition, if sufficient funds are secured, we may process these planar bone scan images in 
order to obtain a quantitative index of bone involvement using the Bone Scan Index (BSI) which has been 
previously validated (4, 5, 45). This parameter will be utilized to compare response to therapy on all the 
bone scans and will be accomplished via automated measurements with EXINI-Bone software (EXINI 
Diagnostics AB; Scheelevägen, Sweden), an FDA approved clinical tool. 
   
C.8 Comparison to “Truth” 
For response criteria after 1 and 6 cycles (or sooner at end of chemotherapy per patient condition), 
patients will serve as their own controls.  
1) Change in anti-3-[18F]FACBC uptake between baseline and post cycle 1, as well as between 
baseline and post 6 cycles (or sooner at end of chemotherapy per patient condition) will be 
correlated with imaging response criteria including change in bone lesion conspicuity, and 
RECIST 1.1 nodal indices post 6 cycles (or sooner at end of chemotherapy per patient condition) 
and 1 year or earlier if progression. This will be completed both qualitatively as above and using 
standardized response criteria. 


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2) Change in anti-3-[18F]FACBC uptake will be correlated with clinical response criteria post 6 
cycles (or sooner at end of chemotherapy per patient condition) and one year or earlier including 
PSA values (progression or regression), clinical progression, and mortality.  
3) Initial uptake on anti-3-[18F]FACBC will be correlated with response post 6 cycles (or sooner at 
end of chemotherapy per patient condition) and 1 year or earlier  using standardized qualitative 
and quantitative criteria including bone scan, RECIST 1.1 nodal indices, and PSA values as well 
as clinical progression and mortality. 
4) The anti-3-[18F]FACBC quantitative indices post 1 cycle and post 6 cycles (or sooner at end of 
chemotherapy per patient condition) will be correlated to each other with linear regression and 
other analyses. 
 
C.9 Followup 
This will be done as part of routine standard of care without special visits required of the patient. At one 
year (or earlier if progression), ultimate response to therapy using standard criteria including repeat CT or 
MR, bone scan and PSA will be obtained as well as mortality. Response on anti-3-[18F]FACBC PET-CT 
will also be correlated to ultimate response at 1 year (or earlier if progression) using these parameters as 
above. Accrual goals will be 2 first year, 4 second year, and then 8 each subsequent 3 years.  
 
D. Participant Selection: 
Methods: All patients will be recruited from Emory Healthcare Urology, Radiation Oncology, or Medical 
Oncology clinics per the inclusion and exclusion criteria below. It is estimated that 2-4 patients per month 
who meet inclusion criteria are seen in the Emory Medical Oncology clinic from which most recruitment 
will occur. 
 
Inclusion Criteria:  
 
1. Patients must be 18 years of age or older. 
 
2. Primary or recurrent castration resistant prostate carcinoma with skeletal and/or nodal involvement not 
currently undergoing systemic chemotherapy who are about to commence therapy with 
docetaxel/prednisone. (Note that systemic hormonal targeted therapy including LHRH agonists (Lupron 
or Trelstar), other anti-androgens, and/or Abiraterone or Enzalutamide may be in use.) 
 
3. Ability to lie still for PET scanning 
 
4. Patients must be able to provide written informed consent 
 
 
Exclusion Criteria: 
 
1. Age less than 18. 
 
 
2. Inability to lie still for PET scanning. 
 
3. Cannot provide written informed consent. 
 


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4. Undergoing current chemotherapy for organ confined or systemic disease. This does not preclude 
patients who had previously received upfront docetaxel in the hormone sensitive setting. 
 
Patients will be required to fast in preparation for PET scan. Verbal consent will be 
obtained from patient prior to the PET scan day if written consent had not been earlier 
obtained. 
 
Procedures: 
 
Day 1: PET Scan Day 
 
Obtain written informed consent if not earlier obtained. 
 
Inclusion/exclusion criteria review if not earlier done.  
 
Medical history and medication review if not earlier done.  
 
Within 14 days after completing first cycle of chemotherapy: 
 
 
A 2nd FACBC PET/CT will be performed if feasible per patient condition. 
 
Within 14 days after completing six cycles of chemotherapy (or sooner at end of chemotherapy per 
patient condition): 
 
 
A 3rd FACBC PET/CT scan will be performed if feasible per patient condition. 
 
 
E. Statistical Analysis.  
 
In the primary analysis, a two–sided paired t-test will be used to compare difference in the maximum 
SUV between two repeat measurements at each time point during the FACBC PET. A Mixed Model will 
be used to compare the overall curve of maximum SUV during the multiple time points of FACBC PET 
between the two repeat measurements before and after the experiment. Similar analysis will be conducted 
for each of other measurement outcomes of FACBC PET, such as SUV ratio, etc. In the secondary 
analyses, Spearman’s correlation coefficient and Chi-square test will be employed to measure the 
correlation between the response on anti-3-[18F]FACBC PET scan after 1 and 6 cycles of chemotherapy 
(or sooner at end of chemotherapy per patient condition) and the clinical response after 6 cycles of 
chemotherapy (or sooner at end of chemotherapy per patient condition) as measured by standard 
parameters including PSA and routine objective measurements. Similarly, Spearman’s correlation 
coefficient and Chi-square test will be also employed to measure the correlation between the response on 
anti-3-[18F]FACBC PET scan after 1 and 6 cycles of chemotherapy (or sooner at end of chemotherapy per 
patient condition) and the response to therapy at one-year (or earlier if progression) as measured by 
standard parameters including routine objective measurements, PSA progression, clinical progression, 
and mortality. The significance levels will be set at 0.05 for all tests. The SAS statistical package V9.2 or 
similar (SAS Institute, Inc., Cary, North Carolina) will be used for all data managements and analyses. 
 


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Statistical power: A two sided paired t-test was used to calculate power and sample size. From our 
previous knowledge, the mean maximum SUV was about 6.28 with a standard deviation as of 2.42. The 
sample size of 30 patients in each arm will achieve a power of at least 80% to detect a difference of about 
20% in mean maximum SUV of anti-[18F]FACBC PET between two repeat measurements before and 
after the experiment at the significance level of 0.05.  
Interim analyses: There are 2 Interim analyses and 1 final analysis in the study. The first and second 
interim analysis will be conducted after 10 and 20 patients have been enrolled and measured, respectively. 
The final analysis will be conducted after all 30 patients have enrolled and completed their measurement. 
In order to maintain the overall significance level of 0.05 while conducting two interim analyses, the 
O’Brien & Fleming method is employed to calculate the p-value for each interim analysis and final 
analysis. According to O’Brien & Fleming boundary, the p-value to be used in first interim analysis, 
second interim analysis, and final analysis is 0.0005, 0.014, and 0.045, respectively.   
F. Adverse Event 
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 20 hours post scan will 
not be considered an AE since the radiotracer has effectively decayed by 20 hours. 
  
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 
An SAE is defined as any adverse event occurring at any dose that results in any of the following 
outcomes: 
• death 
• a life-threatening adverse experience 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed. 
Any serious adverse events (see above) will be communicated by the PI to the Emory IRB using standard 
adverse event reporting forms.in case of a serious adverse event definitively ascribed to anti-[18F]FACBC 
imaging, Drs. Kucuk, Schuster, Halkar, and Jani will meet formally or communicate via email to 
investigate the reported  adverse event. 
The Investigator will report all Serious Adverse Events (as defined above) 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 


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should be reported to Pharsafer within 24 hours of the investigator becoming aware of the events 
occurrence. The Investigator is responsible for informing the ethics committee of serious events occurring 
during the study in compliance with local regulations.  
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. Data and Safety Monitoring Plan (DSMP): 
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 oncologist 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.  
It should be kept in mind that this patient cohort typically has a median survival of 18 months and 
it is of much greater probability that an SAE may occur and be related to the patient’s natural 
disease progression and/or therapy. Only those SAE’s related to the radiotracer FACBC itself will 
be reported as part of this trial as the therapy itself is not considered experimental.  
 
H: Pharmaceutical, biologic, and device information  
Radiation Dosimetry. The study will be approved by not only the Emory IRB but also the Radiation 
Safety Committee. The maximum number of PET studies a patient will receive in one year is 3 anti-
[18F]FACBC studies.   
 
Depending on the distribution of the radionuclide in the body, the whole body dose may not be the critical 
factor in single or longitudinal studies. It is also of interest to know which organ receives the highest 
absorbed dose. This organ is referred to as the critical organ. Often the limit for an individual organ dose 
is reached before the limit established for the whole-body. The United States Food and Drug 
Administration in Title 21 CFR Part 361 limits the whole body radiation dose to adult research subjects to 
less than 3 rem (30 mSv) for a single injection and 5 rem (50 mSv) effective dose equivalent (EDE) 


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annually. A single organ cannot receive more than 5 rem (50mSv) in a single injection and 15 rem (150 
mSv) effective dose equivalent annually. These constraints on dose will limit the maximum number of 
injections for research subjects. The studies proposed in this application fall within these guidelines. 
 
Whole-body human biodistribution studies of FACBC show that it is retained in liver and pancreas. A 10 
mCi (370 MBq) injection of FACBC results in a whole-body effective dose equivalent of 0.52 rem (5.2 
mSv) and a critical organ absorbed dose of 1.9  rad (19.3 mGy) to liver (40). 
 
The level of radiation for the PET scan is the same as received in widely used diagnostic studies such as 
the currently used 18F-FDG and is equal to or less than 80 percent of the amount allowed a radiation 
worker in a year (5 rem). The calculated whole body exposure to the individual will be less than 0.6 rem 
for each PET scan (1.15 total). Radiation exposure for the transmission images on the GE690 PET-CT 
(with which this study would be conducted) is 0.55 rem (5.5 mSv). Thus, total effective dose for a single 
FACBC PET/CT scan is 1.07 rem (10.7mSv). Therefore, total exposure for the 3 FACBC PET-CT scans 
proposed in this study would be 1.8 rem (18 mSv). For the CT portion of the SPECT-CT, added radiation 
exposure would be an additional 1.65 rem (16.5 mSv).  
 
Thus maximum total body exposure would be 3.45 rem (34.5 mSv) per year in this protocol as proposed. 
 
The radiotracer used in this study is governed by FDA IND 72437 for FACBC and is subject to agreed 
upon safety monitoring by the FDA, a copy of which is on file with the IND holder, Dr. David Schuster. 
 
 


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I. References and appendices 
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Required Data Calendar.  (Note that this calendar does not preclude other routine or standard clinical labs.) 
* (or sooner at end of chemotherapy per patient condition) 
** (or earlier if progression) 
 
 
 
  
 
Screening 
Day 1 
≤ 90 days 
Post screen 
Begin 
chemotherapy 
(3 weeks/cycle) 
≤ 14 days 
Post  
cycle 1  
≤ 14 days Post 
cycle 6 * 
 
1 year follow up 
**+/- 60 days 
Informed consent 
 
X 
 
 
 
 
Standard of care 
medical history & 
examination 
X 
 
 
 
X 
X 
Bone scan 
X 
 
 
 
X 
X 
CT or MR  
X 
 
 
 
X 
X 
PSA 
X 
 
 
 
X 
X 
FACBC PET 
 
X 
 
X 
X 
 
Chemotherapy 
begins 
 
 
X