Molecular Imaging With Ga-68 DOTATATE PET to Investigate Neuroendocrine Differentiation in Prostate Cancer Patients
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v7
Sponsor: Emory University

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 
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Protocol Version Date:11/2/2017                                                                                                                16 
 
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Protocol Version Date:11/2/2017                                                                                                                17 
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Protocol Version Date:11/2/2017                                                                                                                18 
 
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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