Clinical trial NCT03448458
Conditions: Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma Stage IV Prostate Cancer AJCC v7
Sponsor: Emory University
Start date: 2018-02-22; Completion date: 2023-02-06
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies how well gallium Ga 68-DOTATATE positron emission tomography (PET)/computed tomography (CT) works in treating patients with castration resistant prostate cancer that has spread to other placed in the body. Gallium Ga 68-DOTATATE PET/CT may help doctors to identify those patients with early neuroendocrine transdifferentiation and who are at greater risk for poor outcomes.

Detailed description:
PRIMARY OBJECTIVE:

Establish the feasibility of using gallium Ga 68-DOTATATE (68Ga-DOTATATE) PET as a predictive imaging biomarker for neuroendocrine transdifferentiation in prostate cancer.

SECONDARY OBJECTIVE:

Correlate progression of disease with degree of uptake on 68Ga-DOTATATE PET examination.

OUTLINE:

Patients receive gallium Ga 68-DOTATATE intravenously (IV). Within 55-70 minutes, patients undergo PET/CT.

After completion of study, patients are followed up for at least 1 year.

Arms: arm 1: Patients receive gallium Ga 68-DOTATATE IV. Within 55-70 minutes, patients undergo PET (positron emission tomography)/CT (computed tomography).
Interventions: intervention 1: CT (Computed Tomography) intervention 2: Gallium Ga 68-DOTATATE intervention 3: Positron Emission Tomography
Intervention descriptions: intervention 1: Undergo PET/CT intervention 2: Given IV intervention 3: Undergo PET/CT

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Version Date:11/2/2017                                                                                                                1 
 
 
Study Title: Winship 4165-17: Molecular Imaging with Ga-68 DOTATATE PET to Investigate 
Neuroendocrine Differentiation in Prostate Cancer Patients 
 
Principal Investigator: Mehmet Asim Bilen, M.D. 
Emory University  
Department of Hematology and Medical Oncology 
Emory University School of Medicine, Atlanta, GA 
Phone:  (404) 778-3693 
email: mbilen@emory.edu 
 
Co-Investigator: Ephraim Parent, MD, PhD 
Emory University  
Department of Radiology and Imaging Science  
Emory University School of Medicine, Atlanta, GA 
Phone:  (404) 712-4843 
email: ephraim.parent@emoryhealthcare.org 
 
Supplied Agent(s):  [Ga-68 DOTATATE & NETSPOT] 
 
 
 
 
 
 
 
 


Protocol Version Date:11/2/2017                                                                                                                2 
 
  
Scheme 1: 
 
 
 
 
 
 
Patient recruitment per inclusion criteria (n=20) 
Metastatic castration resistant prostate carcinoma  
All patients to undergo baseline PSA, bone scan and other 
standard of care imaging such as CT or MR. 
 
Whole body Ga-68 
DOTATATE PET-CT 
examination  
Follow-up per clinician discretion until progression or death. 
Progression may be based on PSA, clinical, imaging, change in 
therapy and/or mortality.  


Protocol Version Date:11/2/2017                                                                                                                3 
Table of Contents 
Scheme 1: ...................................................................................................................................................... 2 
Precis/Abstract: ............................................................................................................................................. 4 
A. Introduction and Background:.................................................................................................................. 5 
B. Objectives ................................................................................................................................................. 6 
C. Study design and methods ........................................................................................................................ 8 
C.1 Ga-68 DOTATATE radiolabeling ...................................................................................................... 8 
C.2 PET-CT imaging protocol .................................................................................................................. 9 
C.3 Systemic therapy .............................................................................................................................. 10 
C.4 Routine Laboratory and Imaging Biomarkers .................................................................................. 10 
C.5 Image Analysis of Ga-68 DOTATATE PET-CT ............................................................................. 10 
C.6 Comparison to Ga-68 DOTATATE uptake with standard response criteria .................................... 11 
C.7 Follow up.......................................................................................................................................... 11 
D.  Patient selection  ................................................................................................................................... 11 
E. Statistical Analysis ................................................................................................................................. 12 
F. Adverse Events ....................................................................................................................................... 12 
G. Data and Safety Monitoring Plan (DSMP): ........................................................................................... 13 
H: Pharmaceutical, biologic, and device information ................................................................................. 14 
I. References and appendices ...................................................................................................................... 15 


Protocol Version Date:11/2/2017                                                                                                                4 
Precis/Abstract: 
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer (PCa) that is usually 
diagnosed in later stages of the disease. Some patients with PCa that continue to progress while on 
androgen deprivation (AD) therapy have been shown to have increased risk of having undergone a 
transdifferentiation process resulting in a neuroendocrine phenotype.  There is preliminary evidence that 
molecular positron emission tomography (PET) imaging with the somatostatin analog, 
68Ga-
DOTATATE, may allow for whole body, non-invasive identification of NEPC in patients with known 
prostate cancer.  This project will determine the feasibility of imaging with 68Ga-DOTATATE PET/CT in 
men with PCa that continue to progress while on AD therapy, as a means to identify those patients with 
early neuroendocrine transdifferentiation and who are at greater risk for poor outcomes.  These patients 
will be followed with standard of care blood work, imaging, and therapy to determine if there is a 
difference in clinical outcome between the patients with greater neuroendocrine differentiation as 
demonstrated with 68Ga-DOTATATE uptake on an initial scan and those without.  Results of this pilot 
study may be used to design larger and more comprehensive studies examining clinical utility.  
 
 
 


Protocol Version Date:11/2/2017                                                                                                                5 
A. Introduction and Background: 
Prostate cancer (PCa) is the most common cancer among men in the United States (1).  AD (androgen 
deprivation) therapy is the standard for advanced prostate cancer, with the expectation that most patients 
will eventually convert to an androgen refractory disease and end up dying from castration resistant 
prostate cancer (CRPC). Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate 
cancer that most frequently arises in later stages of CRPC.  Several recent studies indicate that some of 
the difficulty in treating patients with CRPC may be due to neuroendocrine differentiation (2). The 
detection of NEPC has clinical implications as androgen receptor (AR) targeted therapies have little effect 
(3).   
Diagnosis of NEPC depends on histological confirmation and results in a poor prognosis with limited 
treatment options.  As NEPC diagnosis requires tissue sampling, it is generally only detected in the later 
stages of the disease when patients continue to progress despite antiandrogen therapy (4). Almost all 
prostate cancers show focal neuroendocrine (NE) differentiation, but most demonstrate only rare or single 
NE cells in the tissue sample.  In 5-10% of patients with PCa, there are zones with a large number of 
clustered NE cells that are detected by chromogranin A (CgA) immunostaining (5). In tumors that can be 
classified as NEPC, the NE component varies usually between 5% and 30% of the tumor mass (6, 7). 
There is mixed evidence as to whether NE differentiation worsens in typical PCa with androgen 
deprivation therapy (4, 8, 9).  Some preclinical and clinical studies support increased NE differentiation in 
hormonally treated PCa (10-12).  
The mechanisms by which NE cells influence prostate carcinogenesis are not fully understood.  The 
transdifferentiation process from a typical epithelial-like to a NE-like phenotype may be a consequence of 
the selective pressure induced by treatments that result in decreased androgen levels, stimulation of NE 
and neural factors, and loss of tumor suppressors and genomic stability (13, 14). NE differentiation is 
usually determined by immunoreactivity for NE markers, such as CgA and neuron specific enolase.  
NEPC does not usually express AR and prostate specific-antigen (PSA) (15) and does not have a high 
proliferative activity (16).  Neuroendocrine differentiation can generally be classified into two categories 
in PCa: small cell carcinoma of the prostate with neuroendocrine phenotypes (SCCP) which accounts for 
approximately 1-5% of prostatic malignancies (17), and recurrent carcinoma displaying NE features.  
SCCP is a high grade tumor and may occur de novo or as a recurrent tumor in patients who received ADT 
(18).  
Due to the high prevalence of NE differentiation in patients who receive prolonged ADT, the true 
incidence of NEPC remains controversial.  Perez et al. evaluated NE differentiation in 450 patients with 
PCA and only 3 patients demonstrated NE differentiation (19). Conversely, Jimenez et al. evaluated 237 
metastases from 187 patients with PCa and 92 metastatic biopsies from 79 patients demonstrated positive 
NE differentiation (20).  Seven of these patients initially had negative biopsies that successively became 
positive. 
The diagnosis of NEPC is not straightforward and can be misdiagnosed.  CgA is considered a specific NE 
tumor marker and CgA plasma levels could reflect the NE activity present in different organs, including 
the prostate (21).  Serum CgA levels and potentially other markers such as pro-gastrin-releasing peptide 
(22) may be useful in identifying those patients with NE differentiation (23).  However, there is no 
standard blood marker that is able to accurately determine NEPC levels.  Alternatively, there are reports 


Protocol Version Date:11/2/2017                                                                                                                6 
that somatostatin specific imaging can identify those patients with NEPC.  Somatostatin is a neuropeptide 
that suppresses prostate growth and neovascularization by inducing cell-cycle arrest and apoptosis.  
Prostate NE cells produce somatostatin and express high levels of somatostatin receptors with autocrine 
and paracrine function (24, 25).  
There are a few preliminary case reports that suggest 68Ga-DOTA labeled somatostatin analogs may have 
high sensitivity in identifying NEPC (26-29).  In a recent study involving 12 patients with CRPC, all 
patients had at least 1 blastic neuroendocrine metastasis with increased radiotracer uptake (30).  Patients 
with multiple bone metastases also had significantly higher SUVmax when compared to patients with few 
metastases. However, none of the available studies have correlated 68Ga-DOTA uptake with histologic 
confirmation nor disease progression.  Additionally, to the best of our knowledge, all studies have 
focused on patients with late stage, chemotherapy resistant prostate cancer without evaluating early 
transdifferentiation to NEPC as we propose in this study.    
In vivo imaging studies using the 
111In-labeled somatostatin analog (DTPA-D-Phe)-octreotide, 
(OctreoScan) have been used clinically for the localization of primary and metastatic lesions expressing 
type 2 somatostatin receptors on the cell surface of NE tumors.  However, Octreotide has imaging 
limitations including relatively slow pharmacokinetics, high-energy-emissions, and unfavorable patient 
dosimetry limiting injectable activity.  Clinical studies evaluating OctreoScan as a means to determine 
NEPC in CRPC found a relatively low positive rate (37%) when compared to bone scintigraphy.   
Octreotide scintigraphy was also not able to identify clinical responders in patients that underwent 
Octreotide therapy (31, 32).   68Ga-DOTATATE, as compared to OctreoScan, has faster imaging 
pharmacokinetics and demonstrates higher affinity for somatostatin receptors than Octreotide (33).  In 
prostate- and non-prostate neuroendocrine carcinoma patients, 68Ga-DOTATATE demonstrated higher 
lesion detection rate than Octreotide (26, 34) and changed the clinical management in patients with non-
prostate neuroendocrine carcinoma that previously had negative Octreotide studies (35). 
 
B. Objectives 
The goal of our proposal is to determine the feasibility of identifying neuroendocrine transdifferentiation 
in NEPC patients using noninvasive imaging, and assess whether such an early imaging biomarker can 
predict eventual progression. Specifically we plan to employ the newly FDA approved PET radiotracer 
68Ga-DOTATATE as an off-label probe for somatostatin receptors that have been shown to be 
upregulated in prostate cancer when compared to somatostatin receptor expression in normal prostate 
tissue and in benign prostate hypertrophy (36, 37).  This upregulation of somatostatin receptors in early 
castration resistance may explain in part the mechanism of neuroendocrine transdifferentiation (36, 38). 
While prostate cancer may be indolent, it can also be rapidly lethal in a subset of patients. Early 
identification of this progression could potentially be utilized in the future to study adaptive therapy 
strategies. In addition, NEPC is underdiagnosed as men rarely undergo biopsy of metastatic lesions after 
spread to soft tissue and bones which is required for histologic confirmation (2). Furthermore, standard 
biopsy is subject to sampling error both within a lesion itself and on a global basis, since all lesions 
cannot ethically undergo biopsy. Therefore, we will determine if global body interrogation via a 
noninvasive imaging method to probe for somatostatin receptor upregulation is feasible, and generate 
preliminary data to investigate the relationship of the degree of PET uptake with treatment outcome with 


Protocol Version Date:11/2/2017                                                                                                                7 
our ultimate goal to determine if uptake on an initial 68Ga-DOTATATE PET can be used as an early 
predictive imaging biomarker of outcome.  
 
Primary Objective. Establish the feasibility of using 68Ga-DOTATATE PET as a predictive imaging 
biomarker for neuroendocrine transdifferentiation in prostate cancer.  
Secondary Objective. Correlate progression of disease with degree of uptake on 68Ga-DOTATATE PET 
examination.  
 
Rationale.  As has been outlined in Section A of this proposal, there is no established noninvasive 
imaging or laboratory technique to identify neuroendocrine transdifferentiation in prostate cancer 
(NEPC).  Our hypothesis is that interrogating the upregulation of the somatostatin receptor which occurs 
within a subset of prostate cancer patients, or prostate cancer metastatic lesions, is possible by utilizing 
68Ga-DOTATATE PET as a visual biomarker, which specifically binds to the somatostatin receptor 
SSTR2 (the somatostatin receptor most upregulated in NEPC) (36). To that end we will perform 68Ga-
DOTATATE PET imaging on up to 20 patients to determine the degree of uptake in patients with 
metastatic prostate cancer (mCRPC) who is about the start first line of treatment (abiraterone acetate or 
enzalutamide) for castration resistant disease. We believe that this inflection point best balances early 
detection of potential neuroendocrine transdifferentiation with imaging, as these patients typically have 
higher ECOG (Eastern Cooperative Oncology Group) performance status than those further along the 
continuum of their treatment. Patients with mCRPC will continue to receive standard of care therapy with 
no clinical decisions being made based upon the results of the 68Ga-DOTATATE PET study.  The goal of 
this study is not to compare the diagnostic performance of 68Ga-DOTATATE in neuroendocrine tumors 
with other imaging modalities, as this has already been externally verified (39-41). 
Our hypothesis is that patients with higher levels of 68Ga-DOTATATE uptake on an initial PET scan 
(presumed NEPC) will have a shorter time to progression while on oral agents (abiraterone acetate or 
enzalutamide) due to inherent resistance to antiandrogen based therapeutics (42) when compared to those 
with lower 68Ga-DOTATATE uptake.   
To investigate this secondary objective, we will correlate degree and intensity of uptake of 68Ga-
DOTATATE with subsequent progression of disease, being determined by standard of care whole body 
bone scans (43) and CT/MR imaging (44), as well as clinical parameters. We will utilize 6 and 12 month 
progression free survival outcomes within the context of our one year funding mechanism, and believe 
these parameters are realistic for this patient population. However, as it is likely that some of the patients 
will not have evidence of progression until after completion of our funding mechanism, patients will be 
consented to be followed until there is clinical evidence of progression.  To the best of our knowledge, 
there are no studies that have investigated 68Ga-DOTATATE uptake in patients who have recently 
become castration resistant nor evaluated the correlation between the level of 68Ga-DOTATATE uptake 
and treatment outcome with oral agents (abiraterone acetate or enzalutamide). This study will use 
standard of care, well-defined and accepted measures of progression free survival, to correlate with 
uptake on an initial 
68Ga-DOTATATE PET as a surrogate for degree of neuroendocrine 
transdifferentiation. This study will not be utilizing a follow-up 68Ga-DOTATATE PET for therapy 
response.  


Protocol Version Date:11/2/2017                                                                                                                8 
C. Study design and methods 
Experimental design. We will undertake a study with 20 patients who have castration resistant metastatic 
prostate carcinoma with skeletal and/or nodal and/or visceral involvement. The patients will serve as their 
own control. We will perform a Ga-68 DOTATATE PET-CT of the whole body as per the detailed 
protocol below (Objective 1). Prior to the Ga-68 DOTATATE PET-CT, all patients will undergo 
conventional staging including 99mTc MDP bone scanning and CT or MR within 90 days which are 
standard of care at our institution. This study will not interfere with standard patient evaluation or delay 
therapy. Other imaging may also be obtained clinically.  
The patients will be also followed up in the context of this study (per clinical routine) for at least one-year 
post-therapy to determine if the degree of Ga-68 DOTATATE uptake correlates with progression free 
survival of disease as evidence by imaging progression, PSA progression, clinical progression, which 
defined by investigator and mortality (Objective 2).  It is expected that higher Ga-68 DOTATATE uptake 
will lead to a shorter time to progression with discrete foci of uptake greater than liver being defined as 
positive for enhanced receptor expression, and thus indicative of malignancy.   
C.1 Ga-68 DOTATATE radiolabeling 
Radiochemistry staff will perform syntheses, conduct quality control tests and approve the final 
preparation following USP standards according to the NETSPOT prescribing information. The 
NETSPOT kit is supplied as 2 vials and an accessory cartridge which allows for direct preparation of Ga 
68 DOTATATE injection with the eluate from an Eckert & Ziegler GalliaPharm Germanium 68/Gallium 
68 (Ge 68/Ga 68) generator (Scheme 2). Ge 68 breakthrough and other gamma emitting radionuclides 
should be ≤ 0.001%. The Ga 68 chloride is sterile as eluted from the GalliaPharm generator.  Vial 1 
(reaction vial with lyophilized powder contains: 40 mcg dotatate, 5 mcg 1,10 phenanthroline; 6 mcg 
gentisic acid; 20 mg mannitol) is pierced with a sterile needle connected to a 0.22 micron sterile vented 
filter to maintain atmospheric pressure within the vial during the reconstitution process. Using a 1 mL 
sterile syringe, the required volume of the reaction buffer from Vial 2 (buffer vial contains: 60 mg formic 
acid; 56.5 mg sodium hydroxide and water for injection) is withdrawn. The generator is eluted directly 
into Vial 1 through the accessory cartridge (accessory cartridge contains: 660 mg porous silica. The 
accessory cartridge reduces the amount of Ge 68 potentially present in generator eluate) to reconstitute 
the lyophilized powder with 5 mL of eluate. The syringe and the 0.22 micron sterile air venting filter are 
removed from vial 1, and Vial 1 is moved to the heating hole of the dry bath, leaving the vial at 203 °F 
(95 °C, not to exceed 98 °C) for at least 7 minutes (not exceeding 10 minutes heating) without agitation or 
stirring.  After 7 minutes, the vial from the dry bath is placed in an appropriate lead shield and let cool 
down to room temperature for approximately 10 minutes.  After which, the appropriate quality controls 
are performed according to recommendations.  The amount of radioactivity injected into the patient’s IV 
is recorded immediately prior to injection, with residual activity in the syringe recorded immediately after 
injection. The single IV injection will contain a maximum mass dose of 68Ga-DOTATE of ≤50 µg. The 
total volume administered is typically between 2 and 20 mL with the recommended amount of 
radioactivity to be administered for PET imaging is 2 MBq/kg of body weight (0.054 mCi/kg) up to 200 
MBq (5.4 mCi). 
 


Protocol Version Date:11/2/2017                                                                                                                9 
Scheme 2: 
 
 
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.   
Patients are encouraged to drink a sufficient amount of water to ensure adequate hydration prior to 
administration of Ga-68 DOTATATE. Patients are encouraged to drink and void frequently during the 
first hours following administration to reduce radiation exposure and should void prior immediately prior 
to placement on the imaging table.  There are no dietary restrictions for or nor activity limitations prior to 
Ga-68 DOTATATE scans.  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. An intravenous catheter will be placed into an antecubital vein for a bolus infusion of Ga-68 
DOTATATE (5 mCi).  The subject will be placed in the tomograph gantry for completion of the PET/CT 
scan which will include a whole body acquisition from skull to mid-thigh with images acquired 55 to 70 
minutes after the intravenous administration of the Ga-68 DOTATATE.  
 


Protocol Version Date:11/2/2017                                                                                                                10 
Summary of PET-CT Scanning Procedure 
1) The patient will then receive a bolus of Ga-68 DOTATATE injected IV of approximately 5 mCi 
(185 MBq). 
2) 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).  Patient arms will ideally be positioned overhead to minimize beam hardening and 
field of view truncation artifacts.   
3) Images will be acquired between 55 and 70 minutes after injection. A 3 minutes per bed position 
PET acquisition will start at the proximal thighs and extend for 7 table position to the skull base 
or higher.  
4) The entire study including injection of radiotracer should take approximately 120 minutes or less. 
C.3 Systemic therapy   
Patients with metastatic prostate cancer who are failing standard androgen deprivation therapy and 
diagnosed with castration resistant disease will be the target recruitment demographic for scanning with 
Ga-68 DOTATATE.  Following scanning with Ga-68 DOTATATE, patients will be treated according to 
standard of care per the clinician`s discretion with oral agents (abiraterone acetate or enzalutamide) or 
other FDA approved agents.  The results of the Ga-68 DOTATATE PET/CT will not influence the 
clinician’s treatment decisions.  
C.4 Routine Laboratory and Imaging Biomarkers 
As per clinical routine, all patients will undergo routine imaging including CT, MR, FDG/PET/CT or 
bone scan and PSA evaluation within 90 days prior to the Ga-68 DOTATATE PET-CT study.  
Subsequent routine imaging and standard laboratory analysis (e.g. PSA level) will be performed 
according to the clinician’s discretion.  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.  
C.5 Image Analysis of Ga-68 DOTATATE PET-CT  
Methods: The methods of image analysis to be used for the Ga-68 DOTATATE 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) and total lesion activity 
as well as standard bi-dimensional size measurements of lesions. Whenever possible we will use 
3 dimensional PET-Edge conformational regions of interest (ROI) to encompass the entire 
structure under question such as a lymph node or prostatectomy bed.  
2) Visual inspection of the PET-CT images in separate sessions by a board certified nuclear 
medicine physician/nuclear radiologist.  Up to 5 representative index lesions in each category will 
be selected as markers of Ga-68 DOTATATE uptake.  If 5 lesions each are not definable in each 
patient, all demonstrable lesions up to 5 will be utilized. Lesions chosen will be independent but 
may coincide with index lesions on conventional imaging.   
3) Ga-68 DOTATATE organ and tumor uptake will be quantified using maximum standardized 
uptake values (SUVmax) and mean standardized uptake values (SUVmean). SUVmax of 
pathological findings will be compared with accumulation of the radiotracer in a liver as a 
reference organ. Definitive criteria defining high, moderate, and mild uptake have not been 


Protocol Version Date:11/2/2017                                                                                                                11 
established. However, based on literature examples (30), a diagnosis of high Ga-68 DOTATATE 
uptake will be assigned to lesions with a SUVmax ≥ 8, moderate Ga-68 DOTATATE uptake will 
be assigned to lesions with a SUVmax ≥ 5, and mild Ga-68 DOTATATE uptake will be assigned 
to lesions with uptake greater than liver and/or SUVmax ≥ 3.   
4) In addition, the measurements above will be supplemented by the following from RECIST 1.1 
Criteria (44).  
C.6 Comparison to Ga-68 DOTATATE uptake with standard response criteria 
For response criteria to oral agents, patients will serve as their own controls.  
1) Ga-68 DOTATATE PET-CT uptake will be correlated with clinical response criteria including 
time to PSA progression, which is defined as the time from initiation of treatment to the date of 
earliest objective evidence of PSA progression, which will be assessed at each clinic visit, and is 
defined as time from initiation of treatment to the date of PSA absolute increase ≥ 2 ng/mL and ≥ 
25% above nadir or baseline values confirmed by a second consecutive value obtained at least 3 
weeks later or death due to any cause.  Repeat imaging during treatment will obtain per clinician 
discretion such as when any sign of clinical progression or PSA progression. Radiological 
progression of bone lesions will be determined by using Prostate Cancer Working Group 3 
(PCWG3) recommendations for clinical trial conduct in castration resistant disease and 
radiographic progression of soft tissue lesions will be determine by using modified RECIST 1.1 
criteria.  
We will utilize 6 and 12 month progression free survival outcomes and patients will be consented to be 
followed until there is any evidence of progression.  
C.7 Follow up 
This will be done as part of routine standard of care without special visits required of the patient. Clinical 
visits will be determined by clinician`s discretion as will be ordering of laboratory tests including CBC, 
CMP, testosterone and PSA.  Within one year after Ga-68 DOTATATE PET-CT imaging (or earlier if 
progression), imaging response to therapy using standard criteria including repeat CT or MR, bone scan 
and PSA will be obtained.  Accrual goals will be 4 patients every year for a total of 20 patients in 5 years.  
D.  Patient selection  
Patients will be recruited from the Genitourinary Medical Oncology clinic at Winship Cancer Institute per 
the inclusion and exclusion criteria below. It is estimated that a minimum of 20 patients per month who 
meet inclusion criteria are seen in the Genitourinary Medical Oncology clinic at Winship Cancer Institute.   
However, if we do not enroll our target goals, patients with mCRPC from Georgia Cancer Center for 
Excellence at Grady will be referred to this study as Dr. Bilen also staffs that genitourinary oncology 
clinic.  
Inclusion Criteria:  
1) Patients must be 18 years of age or older. 
2) Patients with metastatic castration resistant prostate carcinoma with skeletal, visceral and/or nodal 
involvement. 
3) Ability to lie still for PET scanning 


Protocol Version Date:11/2/2017                                                                                                                12 
4) Patients must be able to provide written informed consent 
 
Written consent will be obtained from the patient prior to the PET scan day and documented.  
Eligibility checklist will be verified with the patient prior to the scan day once consent is obtained.     
 
Procedures: 
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.  
E. Statistical Analysis  
Patient baseline characteristics and digress of 68Ga-DOTATATE uptake will be summarized using 
descriptive statistics. The inter-rater agreement will be assessed by Kappa statistics or intra-class 
correlation coefficient. The degree of uptake will be plotted against length of time to progress, and the 
association will be described by Spearman correlation coefficient with 95% confidence interval (CI). In 
addition, we will dichotomize degree of update by median and defined it as high vs. low, and apply 
Wilcoxon rank sum test or Fisher exact test wherever appropriate.  The association with progression free 
survival will be able to describe by Kaplan-Meier method along log-rank p-value (due to the small sample 
size, this may not be feasible). This is a pilot study with main goal to evaluate the feasibility, and no 
statistical power is possible.  
F. Adverse Events 
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 10 hours post scan will 
not be considered an AE since the radiotracer has effectively decayed by 10 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 


Protocol Version Date:11/2/2017                                                                                                                13 
• 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 68Ga-
DOTATATE imaging, Drs. Bilen, Parent, and Schuster, 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 
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.   
G. Data and Safety Monitoring Plan (DSMP): 
Patients will be monitored by the technologists and study nurse before and after whole body Ga-68 
DOTATATE PET-CT examination for any adverse events/reactions per clinical routine.  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 Ga-68 
DOTATATE itself will be reported as part of this trial as the therapy itself is not considered 
experimental.  
 


Protocol Version Date:11/2/2017                                                                                                                14 
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 1 Ga-68 
DOTATATE study. 
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) 
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. 
A 5 mCi (185 MBq) injection of Ga-68 DOTATATE  results in a whole-body effective dose equivalent of 
0.48 rem (4.8 mSv) and critical organ absorbed doses of 2.3 rad (23.1 mGy) to the urinary bladder wall, 
1.7 rad (17.0 mGy) to the kidneys, and 5.2 rad (52.2 mGy) to the spleen (45). 
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 0.5 rem 
for each PET scan (1.05 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).  


Protocol Version Date:11/2/2017                                                                                                                15 
I. References and appendices 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. 
 
2. 
Parimi V, Goyal R, Poropatich K, Yang XJ. Neuroendocrine differentiation of prostate cancer: a 
review. Am J Clin Exp Urol. 2014;2:273-285. 
 
3. 
Santoni M, Scarpelli M, Mazzucchelli R, et al. Targeting prostate-specific membrane antigen for 
personalized therapies in prostate cancer: morphologic and molecular backgrounds and future 
promises. J Biol Regul Homeost Agents. 2014;28:555-563. 
 
4. 
Komiya A, Yasuda K, Watanabe A, Fujiuchi Y, Tsuzuki T, Fuse H. The prognostic significance of 
loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among 
castration-resistant prostate cancer patients. Mol Clin Oncol. 2013;1:257-262. 
 
5. 
di Sant'Agnese PA. Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, 
prognostic, and therapeutic implications. Cancer. 1992;70:254-268. 
 
6. 
di Sant'Agnese PA. Neuroendocrine differentiation in prostatic carcinoma: an update on recent 
developments. Ann Oncol. 2001;12 Suppl 2:S135-140. 
 
7. 
Volante M, Rindi G, Papotti M. The grey zone between pure (neuro)endocrine and non-
(neuro)endocrine tumours: a comment on concepts and classification of mixed exocrine-endocrine 
neoplasms. Virchows Arch. 2006;449:499-506. 
 
8. 
Bostwick DG, Qian J, Pacelli A, et al. Neuroendocrine expression in node positive prostate 
cancer: correlation with systemic progression and patient survival. J Urol. 2002;168:1204-1211. 
 
9. 
Theodorescu D, Broder SR, Boyd JC, Mills SE, Frierson HF, Jr. Cathepsin D and chromogranin A as 
predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of 
the prostate. Cancer. 1997;80:2109-2119. 
 
10. 
Jongsma J, Oomen MH, Noordzij MA, et al. Androgen deprivation of the PC-310 [correction of 
prohormone convertase-310] human prostate cancer model system induces neuroendocrine 
differentiation. Cancer Res. 2000;60:741-748. 
 
11. 
Jiborn T, Bjartell A, Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma 
during hormonal treatment. Urology. 1998;51:585-589. 
 
12. 
Li Q, Zhang CS, Zhang Y. Molecular aspects of prostate cancer with neuroendocrine 
differentiation. Chin J Cancer Res. 2016;28:122-129. 


Protocol Version Date:11/2/2017                                                                                                                16 
 
13. 
Beltran H, Tomlins S, Aparicio A, et al. Aggressive variants of castration-resistant prostate 
cancer. Clin Cancer Res. 2014;20:2846-2850. 
 
14. 
Hu CD, Choo R, Huang J. Neuroendocrine differentiation in prostate cancer: a mechanism of 
radioresistance and treatment failure. Front Oncol. 2015;5:90. 
 
15. 
Huang J, Yao JL, di Sant'Agnese PA, Yang Q, Bourne PA, Na Y. Immunohistochemical 
characterization of neuroendocrine cells in prostate cancer. Prostate. 2006;66:1399-1406. 
 
16. 
Grobholz R, Griebe M, Sauer CG, Michel MS, Trojan L, Bleyl U. Influence of neuroendocrine 
tumor cells on proliferation in prostatic carcinoma. Hum Pathol. 2005;36:562-570. 
 
17. 
Mazzucchelli R, Morichetti D, Lopez-Beltran A, et al. Neuroendocrine tumours of the urinary 
system and male genital organs: clinical significance. BJU Int. 2009;103:1464-1470. 
 
18. 
Lipianskaya J, Cohen A, Chen CJ, et al. Androgen-deprivation therapy-induced aggressive 
prostate cancer with neuroendocrine differentiation. Asian J Androl. 2014;16:541-544. 
 
19. 
Perez D, Linares E, Almagro E, et al. Neuroendocrine differentiation in carcinoma of the 
prostate: An institutional review. Journal of Clinical Oncology. 2014;32. 
 
20. 
Jimenez RE, Nandy D, Qin R, Carlson R, Tan W, Kohli M. Neuroendocrine differentiation patterns 
in metastases from advanced prostate cancer. Journal of Clinical Oncology. 2014;32. 
 
21. 
Berruti A, Dogliotti L, Mosca A, et al. Potential clinical value of circulating chromogranin A in 
patients with prostate carcinoma. Ann Oncol. 2001;12 Suppl 2:S153-157. 
 
22. 
Tarle M, Ahel MZ, Kovacic K. Acquired neuroendocrine-positivity during maximal androgen 
blockade in prostate cancer patients. Anticancer Res. 2002;22:2525-2529. 
 
23. 
Berruti A, Dogliotti L, Mosca A, et al. Effects of the somatostatin analog lanreotide on the 
circulating levels of chromogranin-A, prostate-specific antigen, and insulin-like growth factor-1 in 
advanced prostate cancer patients. Prostate. 2001;47:205-211. 
 
24. 
Nelson EC, Cambio AJ, Yang JC, Ok JH, Lara PN, Jr., Evans CP. Clinical implications of 
neuroendocrine differentiation in prostate cancer. Prostate Cancer Prostatic Dis. 2007;10:6-14. 
 
25. 
Borre M, Nerstrom B, Overgaard J. Association between immunohistochemical expression of 
vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, 


Protocol Version Date:11/2/2017                                                                                                                17 
and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res. 2000;6:1882-
1890. 
 
26. 
Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine 
tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508-518. 
 
27. 
Alonso O, Gambini JP, Lago G, Gaudiano J, Quagliata A, Engler H. In vivo visualization of 
somatostatin receptor expression with Ga-68-DOTA-TATE PET/CT in advanced metastatic prostate 
cancer. Clin Nucl Med. 2011;36:1063-1064. 
 
28. 
Chen S, Cheung SK, Wong KN, Wong KK, Ho CL. 68Ga-DOTATOC and 68Ga-PSMA PET/CT 
Unmasked a Case of Prostate Cancer With Neuroendocrine Differentiation. Clin Nucl Med. 2016;41:959-
960. 
 
29. 
Todorovic-Tirnanic MV, Gajic MM, Obradovic VB, Baum RP. Gallium-68 DOTATOC PET/CT in vivo 
characterization of somatostatin receptor expression in the prostate. Cancer Biother Radiopharm. 
2014;29:108-115. 
 
30. 
Gofrit ON, Frank S, Meirovitz A, Nechushtan H, Orevi M. PET/CT With 68Ga-DOTA-TATE for 
Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer. Clin 
Nucl Med. 2017;42:1-6. 
 
31. 
Nilsson S, Reubi JC, Kalkner KM, et al. Metastatic hormone-refractory prostatic adenocarcinoma 
expresses somatostatin receptors and is visualized in vivo by [111In]-labeled DTPA-D-[Phe1]-octreotide 
scintigraphy. Cancer Res. 1995;55:5805s-5810s. 
 
32. 
Kalkner KM, Acosta S, Thorsson O, et al. Octreotide scintigraphy and Chromogranin A do not 
predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate 
cancer. Prostate Cancer Prostatic Dis. 2006;9:92-98. 
 
33. 
Antunes P, Ginj M, Zhang H, et al. Are radiogallium-labelled DOTA-conjugated somatostatin 
analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34:982-
993. 
 
34. 
Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-
DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 
2007;34:1617-1626. 
 
35. 
Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J. The role of 68Ga-
DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-
DTPA-octreotide scintigraphy. J Nucl Med. 2010;51:875-882. 


Protocol Version Date:11/2/2017                                                                                                                18 
 
36. 
Morichetti D, Mazzucchelli R, Santinelli A, et al. Immunohistochemical expression and 
localization of somatostatin receptor subtypes in prostate cancer with neuroendocrine differentiation. 
Int J Immunopathol Pharmacol. 2010;23:511-522. 
 
37. 
Montironi R, Cheng L, Mazzucchelli R, et al. Immunohistochemical detection and localization of 
somatostatin receptor subtypes in prostate tissue from patients with bladder outlet obstruction. Cell 
Oncol. 2008;30:473-482. 
 
38. 
Volante M, Brizzi MP, Faggiano A, et al. Somatostatin receptor type 2A immunohistochemistry in 
neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor 
scintigraphy. Mod Pathol. 2007;20:1172-1182. 
 
39. 
Deppen SA, Blume J, Bobbey AJ, et al. 68Ga-DOTATATE Compared with 111In-DTPA-Octreotide 
and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A 
Systematic Review and Meta-Analysis. J Nucl Med. 2016;57:872-878. 
 
40. 
Alonso O, Rodriguez-Taroco M, Savio E, Bentancourt C, Gambini JP, Engler H. (68)Ga-DOTATATE 
PET/CT in the evaluation of patients with neuroendocrine metastatic carcinoma of unknown origin. Ann 
Nucl Med. 2014;28:638-645. 
 
41. 
Haug AR, Cindea-Drimus R, Auernhammer CJ, et al. The role of 68Ga-DOTATATE PET/CT in 
suspected neuroendocrine tumors. J Nucl Med. 2012;53:1686-1692. 
 
42. 
Hirano D, Okada Y, Minei S, Takimoto Y, Nemoto N. Neuroendocrine differentiation in hormone 
refractory prostate cancer following androgen deprivation therapy. Eur Urol. 2004;45:586-592; 
discussion 592. 
 
43. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-1159. 
 
44. 
Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph nodes with RECIST 1.1. Eur J Cancer. 
2009;45:261-267. 
 
45. 
Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of 68Ga-
DOTATATE. J Nucl Med. 2013;54:855-860. 
 


Protocol Version Date:11/2/2017                                                                                                                19 
Required Data Calendar.  (Note that this calendar does not preclude other routine or standard 
clinical labs.) 
* (or earlier if progression) 
 
 
 
  
 
Screening 
Ga-68 
DOTATATE 
PET-CT 
≤ 90 days 
Post screen 
Continue 
therapy 
 
Informed consent 
 
X 
 
Standard of care 
medical history & 
examination 
X 
 
 
Bone scan 
X 
 
 
CT or MR  
X 
 
 
Standard of care 
laboratory 
X 
 
X 
Ga-68 
DOTATATE 
PET-CT 
 
X 
 
Systemic 
Therapy 
 
 
X 

ICF_000.pdf: 
Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 1 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular Imaging with Ga-68 DOTATATE PET to Investigate Neuroendocrine Differentiation in Prostate 
Cancer Patients 
 
 
 
NCT03448458 
 
 
Informed consent date: Nov 7th, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 2 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
 
 
You Are Being Asked to Be in a Research Study 
 
What Is a Research Study? 
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.   
 
Do I Have to Do This? 
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study.  
 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.   
 
What Is This Document? 
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you. 
 
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom. 
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used. 
 
What Should I Do Next? 
1. Read this form, or have it read to you. 
2. Make sure the study doctor or study staff explains the study to you. 
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)  
4. If there will be medical treatment, know which parts are research and which are 
standard care. 
5. Take time to consider this, and talk about it with your family and friends. 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 3 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
 
 
Emory University  
Consent to be a Research Subject / HIPAA Authorization  
 
 
Title: Molecular Imaging with Ga-68 DOTATATE PET to Investigate Neuroendocrine Differentiation in 
Prostate Cancer Patients 
 
Investigator-Sponsor: Mehmet Asim Bilen, MD and Ephraim Parent, MD, PhD 
 
Study-Supporter: Emory Department of Radiology & Imaging Sciences Winship Cancer Institute of 
Emory University 
 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you everything 
you need to think about before you decide if you want to be a part of the study.  It is entirely your 
choice.  If you decide to take part, you can change your mind later on and withdraw from the 
research study. The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you decide not to take part in this study, your doctor will continue to treat you. 
 
Before making your decision: 
 Please carefully read this form or have it read to you 
 Please listen to the study doctor or study staff explain the study to you  
 Please ask questions about anything that is not clear 
 
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether 
you would like to participate. You may wish to discuss your decision with family or friends. Do not sign 
this consent form unless you have had a chance to ask questions and get answers that make sense 
to you.  By signing this form you will not give up any legal rights. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
What is the purpose of this study? 
The purpose of this study is to evaluate a new imaging test for men with prostate cancer that 
has progressed while on androgen deprivation therapy. The test might be able to identify 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 4 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
patients with early neuroendocrine transdifferentiation, which can develop into a more 
aggressive form of prostate cancer.  
 
The imaging agent that will be tested is called 68Ga-DOTATATE, which is combined with positron 
emission tomography (PET) CT scanning. Neuroendocrine tumors have high levels of proteins called 
somatostatin receptors. Some studies have suggested that agents similar to somatostatin (such as 
68Ga-DOTATATE) can bind to these receptors and enter tumors, and may therefore be useful in 
detecting neuroendocrine tumors using imaging tests such as PET-CT scans. 
 
68Ga-DOTATATE will be injected into a vein in your arm, then scans (“pictures”) are taken using 
the PET scans. These pictures will allow the doctor to see the inside of your body. 68Ga-
DOTATATE has been approved by the FDA (Food and Drug Administration) for PET/CT 
imaging of patients with somatostatin receptor positive neuroendocrine tumors.  
 
Here at Emory, we planned to enroll twenty (20) patients in this study. The treating physician will 
identify patients who are eligible for this study. These are patients whose prostate cancer has 
been treated with androgen deprivation and is not responding to the treatment (“castration-
resistant”).  
 
What will I be asked to do? 
All patients who are enrolled in this study will have a 68Ga-DOTATATE PET/CT scan followed by 
standard of care treatment and imaging.  
 
Screening: 
 Your physician will review your medical charts to see if you are eligible to take part in the 
study. If you are eligible, the physician will discuss the study with you and you will be given 
time to review this consent form and ask questions.  
 
Day 1: 
 If you are eligible to take part in the study, you will be asked to sign consent.  
 You will be asked about your medical history 
 The 68Ga-DOTATATE PET/CT scan will be performed. An intravenous tube called a catheter 
(IV) will be put in a vein in your arm to be used later for injection of the 68Ga-DOTATATE 
 
68Ga-DOTATATE PET-CT scan: 
The PET-CT scans are done in the Nuclear Medicine Department on the first floor of the Emory 
University Hospital or in the Winship Cancer Institute. The entire procedure takes about 2 hours, 
including set up and preparation time. You are not required to fast before the PET-CT scan and 
are encouraged to drink water before and after administration of 68Ga-DOTATATE with frequent 
voiding.  One hour prior to scanning, you will drink one glass (450 ml) of oral contrast to allow 
for better pictures of your abdomen and pelvic organs 
  


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 5 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
The scanner has the appearance of a large box. You will be asked to lie on a scanning bed, the bed 
will move slowly through the PET/CT scanner. The CT portion of the exam sends X-rays through the 
body that is then measured by detectors in the CT scanner. This portion usually takes about one 
minute. Following this, you will receive the FACBC by injection into the IV and the PET scan portion 
of the exam will begin. The PET scanner has cameras that detect the gamma rays emitted from the 
patient, and turns those into electrical signals. A computer processes these to generate the images. 
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. Once the 
procedure is finished, the IV needle is removed and you will be able to leave the PET Center after this 
time. 
 
Standard of care evaluation 
Note that you will undergo typical evaluation by your doctor for at least 1 year following the 68Ga-
DOTATATE. PET/CT.   These follow up includes blood tests such as PSA, and routine imaging such 
as bone scan, CT, or MRI of the body. 
 
Follow-Up 
Follow-up phone call will be made to patient one week after each PET scan to assess for any ill 
effects. 
 
All patients will be followed for at least one (1) year. We will look at your medical records to see 
your PSA results and the results of any scans. 
  
Who owns my study information and samples? 
You will not receive any compensation for your information to make a new product. If you withdraw 
from the study, data that were already collected may be still be used for this study.   
  
What are the possible risks and discomforts? 
There may be side effects from the imaging agent that are not known at this time.   
 
Everyone taking part in the study will be watched carefully for any side effects. However, 
researchers do not know all the side effects that may happen. Side effects may be mild or very 
serious. The procedures described in this study may cause all, some, or none of the side effects 
listed here. These common procedures are considered relatively safe. Previously unknown side 
effects can also occur. If new side effects are reported, you will be told. It is also important that 
you give us accurate and complete information about your past medical history.  
 
You may also find it uncomfortable to lie without moving during the approximately 45 minutes 
necessary to complete the scan. If you believe you cannot lie still for 45 minutes, you should not 
take part in this study. 
 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 6 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
Although the risk is small, it is possible to develop an allergic reaction to the Ga-68 DOTATATE. 
This can result in hives, rash, itching, and difficulty breathing which may require emergency 
medical treatment. In three single center studies that used Ga-68 DOTATATE PET to image 
neuroendocrine tumors, no adverse effects were reported; however, it is important to report to 
your doctor, any unusual side effects that you are having such as itching, flushing, pain or rash 
spreading up your arm, hives or swelling of your lips, tongue or face, fever, chills, nausea, 
dizziness, and vomiting.  
 
There is always the risk that the test result incorrectly shows that the condition exists (false positive).  
 
Intravenous Catheter: 
When the IV is placed or removed, the site of insertion may become sore or bruised. Rarely, bleeding 
or infection can occur at this site; however, this is highly unlikely. A small gauze pad or bandage is 
placed over the site after the IV catheter is removed.  
 
Radiation Safety: 
You will be exposed to radiation from nuclear medicine and CT scans. Some of these procedures are 
not necessary for your medical care and will occur because you participate in this study. The 
estimated radiation dose that you will receive is equal to or less than the annual radiation exposure 
limit allowed for persons who are occupationally exposed to radiation (for example, x-ray technologist, 
radiologist).  The principal risk associated with a radiation dose is the possibility of developing a 
radiation-induced cancer later in life.  The risk for radiation-induced cancer from this study is minimal. 
 
Will I benefit directly from the study?We do not know that the information from this study will help 
researchers learn more about how best to treat men who are receiving treatment for prostate cancer, 
but are trying to find something out in this Pilot trial which may also find nothing. 
Will I be compensated for my time and effort? 
You will not be offered compensation for being in this study.   
What are my other options? 
If you decide not to enter this study, there is care available to you outside of this research study. The 
study doctor will discuss these with you.  
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records.  Your 
name and other identifying information will not appear when we present or publish the study results. 
 
Study records can be opened by court order.  They also may be provided in response to a subpoena 
or a request for the production of documents.  
 
Storing and Sharing your Information 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 7 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
De-identified data from this study, including your de-identified genetic information, may be shared 
with the research community at large to advance science and health. Data from this study may be 
placed into public databases where, in addition to having no direct identifiers, researchers will need to 
sign data use agreements before accessing the data. We will remove or code any personal 
information that could identify you before your information is shared. This will ensure that, by current 
scientific standards and known methods, it is extremely unlikely that anyone would be able to identify 
you from the information we share. Despite these measures, we cannot guarantee anonymity of your 
personal data. 
 
Medical Record 
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare 
medical record.  If you have never been an Emory Healthcare patient, you do not have one.   An 
Emory Healthcare medical record will be made for you if an Emory provider or facility gives you any 
services or procedures for this study.   
 
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare 
medical record you have now or any time during the study.   
  
In Case of Injury 
If you get ill or injured from being in the study, Emory will help you get medical treatment.  Emory and 
the sponsor have not, however, set aside any money to pay you or to pay for this medical treatment. 
The only exception is if it is proven that your injury or illness is directly caused by the negligence of an 
Emory.  “Negligence” is the failure to follow a standard duty of care.  
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  
If you do not have insurance, or if your insurer does not pay, then you will have to pay these costs.   
If you believe you have become ill or injured from this research, you should contact Dr. Bilen at 404-
778-1900. You should also let any health care provider who treats you know that you are in a 
research study.  
If you have Medicare or Medicaid: the sponsor may need information about your identity and your 
study treatment to give to the government agencies that run these programs.  
Your insurance will be billed for any costs of medical treatment for your injury or illness that the 
sponsor does not pay.  Your insurer may be told that you are in a research study. If you do not have 
insurance, or if your insurance does not pay, then you will have to pay these costs.  
Costs 
The study sponsor will pay for certain items and services that you may receive if you take part in this 
study.   
You will not be charged for the Ga-68 DOTATATE PET scan, The Sponsors will pay for this scan. 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 8 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor 
will not pay for your regular medical care including bone scans, MRI or CT scans that will be done to 
see if you are responding to the treatment. Any other care you receive related to your prostate 
problem. 
 
If you have insurance, Emory will submit claims to your insurance for items and services that the 
sponsor does not cover.  Emory will send in only those claims for items and services that it 
reasonably believes your insurance will pay and that the sponsor has not paid.  
 
The actual amount that you have to pay depends on whether or not you have health insurance and 
whether or not that insurance will pay for any research study costs. Generally, insurance companies 
will not pay for items and services that are required just for a research study. Some insurance 
companies will not pay for regular medical treatment or treatment for complications if you are in a 
study.  How much you will have to pay for any co-payments, deductibles or co-insurance depends on 
your plan.  Emory will not pay for these costs.  
 
It is a good idea to contact your insurance provider and tell them you want to be in this research 
study.  Ask them what they will pay for and what they will not pay for.  You can also ask the study 
team for help in figuring out what you will have to pay.  
 
If you do not have insurance, Emory will review your case as part of its program for low-income 
patient care.  The standard policies of that program will apply.  The program will figure out if you have 
to pay any costs for taking part in the study and what those costs will be. 
 
Withdrawal from the Study 
You have the right to leave a study at any time without penalty.   
 
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to 
have some of the final steps done.   
 
The researchers also have the right to stop your participation in this study without your consent for any 
reason, especially if they believe it is in your best interest or if you were to object to any future changes 
that may be made in the study plan. 
 
Authorization to Use and Disclose Protected Health Information 
 
The privacy of your health information is important to us.  We call your health information that 
identifies you, your “protected health information” or “PHI.”  To protect your PHI, we will follow federal 
and state privacy laws, including the Health Insurance Portability and Accountability Act and 
regulations (HIPAA).  We refer to all of these laws as the “Privacy Rules.”  Here we let you know how 
we will use and disclose your PHI for the main in which you may choose to participate. 
 
Main Study 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 9 of 12                       Version Date: 01/26/2018                                                             
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
 
PHI that Will be Used/Disclosed:   
The PHI that we will use or share for the main research study includes: 
 Medical information about you including your medical history and present/past 
medications. 
 Results of exams, procedures and tests you have before and during the study. 
 Laboratory test results. 
 
Purposes for Which Your PHI Will be Used/Disclosed: 
We will use and share your PHI for the conduct and oversight of the research study.  We will 
use and share your PHI to provide you with study related treatment and for payment for such 
treatment.  We will also use and share your PHI to conduct normal business operations.  We 
may share your PHI with other people and places that help us conduct or carry out the study, 
such as laboratories, data management centers, data monitors, contract research 
organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
we may use your PHI to determine your health, vital status or contact information. We will use 
and disclose your PHI for the administration and payment of any costs relating to subject injury 
from the study.   
 
Use and Disclosure of Your Information That is Required by Law:   
We will use and disclose your PHI when we are required to do so by law. This includes laws 
that require us to report child abuse or abuse of elderly or disabled adults. We will also comply 
with legal requests or orders that require us to disclose your PHI. These include subpoenas or 
court orders.   
 
Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this 
document. You do not have to sign this form to authorize the use and disclosure of your PHI.  
If you do not sign this form, then you may not participate in the research study or receive 
research-related treatment.  You may still receive non-research related treatment.   
 
People Who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the 
research study: 
 
 The Principal Investigator and the research staff will use and disclose your PHI to 
conduct the study and give you study related treatment. 
 Emory l may use and disclose your PHI to get payment for study related treatment and 
to run normal business operations. The Principal Investigator and research staff will 
share your PHI with other people and groups to help conduct the study or to provide 
oversight for the study. 
  Mehmet Asim Bilen, MD and Ephraim Patent, MD, PhD is the Sponsor of the study.  
The Sponsor may use and disclose your PHI to make sure the research is done 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 10 of 12                       Version Date: 01/26/2018                                                           
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
correctly and to collect and analyze the results of the research.  The Sponsor may 
disclose your PHI to other people and groups like study monitors to help conduct the 
study or to provide oversight for the study.   
 The research team and the Sponsor may use and disclose your PHI, including 
disclosure to insurance carriers to administer payment for subject injury.  
 The following people and groups will use your PHI to make sure the research is done 
correctly and safely: 
o Emory offices that are part of the Human Research Participant Protection 
Program and those that are involved in study administration and billing.  These 
include the Emory IRB, the Emory Research and Compliance Offices, and the 
Emory Office for Clinical Research.  
o  
o Public health agencies. 
o Research monitors and reviewer. 
o Accreditation agencies. 
 
Sometimes a Principal Investigator or other researcher moves to a different institution. If 
this happens, your PHI may be shared with that new institution and their oversight 
offices. PHI will be shared securely and under a legal agreement to ensure it continues 
to be used under the terms of this consent and HIPAA authorization. 
 
Expiration of Your Authorization 
Your PHI will be used until this research study ends. 
 
Revoking Your Authorization 
If you sign this form, at any time later you may revoke (take back) your permission to use your 
information.  If you want to do this, you must contact the study team at: 
 
Dr. Mehmet Asim Bilen 
1365 Clifton Road NE 
Atlanta, GA 30322 
404-778-1900 
 
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose 
the information you already gave them so they can follow the law, protect your safety, or make sure 
that the study was done properly and the data is correct.  If you revoke your authorization you will not 
be able to stay in the main study.  
 
Other Items You Should Know about Your Privacy 
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care 
providers, health care payers, and health care clearinghouses.  If we disclose your information to 
people who are not covered by the Privacy Rules, including HIPAA, then your information won’t be 
protected by the Privacy Rules.  People who do not have to follow the Privacy rules can use or 
disclose your information with others without your permission if they are allowed to do so by the laws 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 11 of 12                       Version Date: 01/26/2018                                                           
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
that cover them.  The Sponsor, and people and companies working with the Sponsor on this study 
are not covered by the Privacy Rules.  They will only use and disclose your information as described 
in this Consent and Authorization.  
 
To maintain the integrity of this research study, you generally will not have access to your PHI related 
to this research until the study is complete.  When the study ends, and at your request, you generally 
will have access to your PHI that we maintain in a designated record set.  A designated record set is 
data that includes medical information or billing records that your health care providers use to make 
decisions about you. If it is necessary for your health care, your health information will be provided to 
your doctor.  
 
We may remove identifying information from your PHI.  Once we do this, the remaining information 
will not be subject to the Privacy Rules.  Information without identifiers may be used or disclosed with 
other people or organizations for purposes besides this study.   
 
Contact Information 
Contact Dr. Mehmet Asim Bilen, Ephraim Patent, MD, PhD and study coordinators at 404-778-1900 
 if you have any questions about this study or your part in it,   
 if you feel you have had a research-related injury or a bad reaction to the imaging agent, or 
 if you have questions, concerns or complaints about the research 
 
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or irb@emory.edu: 
 if you have questions about your rights as a research participant. 
 if you have questions, concerns or complaints about the research. 
 You may also let the IRB know about your experience as a research participant through our 
Research Participant Survey at http://www.surveymonkey.com/s/6ZDMW75. 
 
Consent and Authorization 
 
 
 
TO BE FILLED OUT BY SUBJECT ONLY 
Please print your name, sign, and date below if you agree to be in the main study. By signing this 
 
 
 
 
 
Name of Subject  
 
 
 
 
 
 
 
 
 
 
 
 
____:____ am / pm 
Signature of Subject  
 
 
       Date 
 
    Time    (please circle 


Study No.: IRB00099167 
Emory University IRB 
IRB use only 
Document Approved On: 11/7/2019 
 
 
 
PI: Mehmet Asim Bilen, MD                                          Page 12 of 12                       Version Date: 01/26/2018                                                           
Protocol # WINSHIP4165-17  
 
                                                                                                                                    
 
 
TO BE FILLED OUT BY STUDY TEAM ONLY 
 
 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
 
____:____ am / pm 
Signature of Person Conducting Informed 
 
Date 
 
Time (please circle) 
Consent Discussion