A Pilot Phase I Open Label Study of Cu-64-TP3805 PET Imaging for Detection of Prostate Cancer in Men With Persistently Elevated PSA
Phase: NA
Conditions: Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

 
 
 
 
THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
A Pilot Phase I Open Label Study of Cu-64-TP3805 PET Imaging for Detection of 
Prostate Cancer in Men Persistently Elevated PSA 
Principal Investigator: 
Mathew Thakur, PhD 
Thomas Jefferson University, Depart of Radiology 
1020 Locust Street, 359 JAH, Philadelphia PA 19107 
(215) 503-7874 
Co-Investigator(s): 
Edouard Trabulsi, MD, FACS 
Dept. of Urology 
Thomas Jefferson University 
Ph: (215) 955-6961 
 
Costas Lallas, MD 
Dept. of Urology 
Thomas Jefferson University 
Ph: (215) 955-6961 
 
Leonard Gomella, MD 
Dept. of Urology 
Thomas Jefferson University 
Ph: (215) 955-6961 
 
Charles Intenzo, MD 
Dept. of Nuclear Medicine 
Thomas Jefferson University 
Ph: (215) 955-7871 
 
Peter McCue, MD 
Dept. of Pathology 
Thomas Jefferson University 
Ph: (215) 955-5588 
 
Ethan Halpern, MD 
Dept. of Radiology 
Thomas Jefferson University 
Ph: (215) 955-5345 
 
Sung Kim MD 
Department of Nuclear Medicine 
Thomas Jefferson University 
Ph: (215) 955-7875 
 
Scott Keith, PhD 
Department of Pharmacology & Experimental Therapeutics 
Thomas Jefferson University 
Ph: 2015-503-9876 

 
 
 
 
 
2 
Funding Sponsor: 
NIH 
Regulatory Sponsor: 
FDA 
IND Number: 
EIND 101550 
Study Product: 
Cu-64-TP3805 
Protocol Number: 
15F.264 
 
 
Version: Date: 
1 
 
04/29/2015 
2 
 
03/15/2016 
3 
05/10/2016 
3.1 
11/13/2018 
3.2 
01/16/2019 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 

 
 
 
 
 
3 
Table-of Contents 
 
LIST OF ABBREVIATIONS 
5
STUDY SUMMARY 
6
1 
INTRODUCTION 
7
1.1 
Specific Aims and Hypothesis 
7
1.2 
Background 
7
1.3 
Study Therapy 
13
1.4 
Preclinical Data 
14
1.5 
Toxicity Studies 
16
1.6 
Radiation Dosimetric Calculations
23
1.7 
Chemistry Preparations and controls (CMC) 
25
1.8 
Clinical Date to Date 
26
1.9 
Dose Rationale and Risk/Benefits 
26
2 
STUDY OBJECTIVES 
26
2.1 
Primary Objective 
27
3 
STUDY DESIGN 
27
3.1 
General Design 
27
3.2 
Primary Study Endpoints 
27
3.3 
Primary Safety Endpoints 
27
4 
SUBJECT SELECTION AND WITHDRAWAL 
27
4.1 
Inclusion Criteria 
27
4.2 
Exclusion Criteria 
28
4.3 
Gender/Minority/Pediatric Inclusion for Research
28
4.4 
Subject Recruitment and Screening 
28
4.5 
Early Withdrawal of Subjects 
28
4.5.1 
When and How to Withdraw Subjects 
28
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects
28
5 
STUDY IMAGING AGENT 
28
5.1 
Description 
28
5.2 
Treatment Regimen 
29
5.3 
Risks 
29
5.4 
Method for Assigning Subjects to Treatment Groups 
29
5.5 
Preparation and Administration of Imaging Agent 
29
5.6 
Subject Compliance Monitoring 
30

 
 
 
 
 
4 
5.7 
Prior and Concomitant Therapy 
30
6 
STUDY PROCEDURES 
30
6.1 
Study Visit Schedule 
30
7 
STATISTICAL PLAN 
30
7.1 
Sample Size Determination 
30
7.2 
Statistical Methods 
31
7.3 
Subject Population(s) for Analysis 
31
8 
SAFETY AND ADVERSE EVENTS 
31
8.1 
Definitions 
31
8.2 
Recording of Adverse Events 
32
8.3 
Data and Safety Monitoring Plan 
33
8.3.1 
Medical Monitoring and AE/SAE Reporting 
33
8.3.2 
Data and Safety Monitoring Committee 
35
9 
DATA HANDLING AND RECORD KEEPING 
36
9.1 
Confidentiality 
36
9.2 
Source Documents 
36
9.3 
Case Report Forms 
37
9.4 
Records Retention 
37
10 
STUDY MONITORING, AUDITING, AND INSPECTING 
37
10.1 
Study Monitoring Plan 
37
10.2 
Auditing and Inspecting 
38
10.2.1 
Independent External and Internal Audits 
38
11 
ETHICAL CONSIDERATIONS 
39
12 
STUDY FINANCES 
39
12.1 
Funding Source 
39
12.2 
Conflict of Interest 
39
12.3 
Subject Stipends or Payments 
40
13 
PUBLICATION PLAN 
40
14 
REFERENCES 
40
 

 
 
 
 
 
5 
List of Abbreviations 
3D 
 
Three dimensional 
BC 
 
Breast cancer 
BPH  
Benign prostatic hyperplasia 
C-11  
Carbon 11 
CT 
 
Computed tomography 
Cu-64  
Copper 64  
dL 
 
deciliter 
DOTA  
1, 4, 7, 10-tetraazadocdecane –N, N”, N’”, N””, -tetra acetic acid 
F-18  
Fluoride 18 
FDG  
Fluorodeoxyglucose 
FLT 
 
Fluorothymidine 
hCtr1   
human copper transport 1 protein  
IAS 
 
Internal anal sphincter 
IC50  
half maximal inhibitory concentration 
IACUC  
institutional animal care and use committee 
ID/g 
 
Injected dose per gram of tissue 
In-111  
Indium 111 
kD 
 
Dissociation constant 
kDa 
 
KiloDalton 
MCF-7 
Michigan Cancer Foundation-7 breast cancer cell line 
mCi 
 
Millicurie 
MR 
 
Magnetic resonance 
MRI 
 
Magnetic resonance imaging 
MW 
 
Molecular weight 
ng 
 
Nanogram 
nM 
 
Nanomole 
PACAP 
Pituitary adenylate cyclase activating peptide 
PC 
 
Prostate cancer 
PC-3  
Prostate cancer cell line 
PET  
Positron emission tomography 
Phe 
 
Phenylalanine 
PSA  
Prostate specific antigen 
PSMA  
Prostate specific membrane antigen 
RTPCR 
Reverse transcriptase polymerase chain reaction 
SD 
 
Standard deviation 
Tc-99  
Technectium 99 
TRAMP 
Transgenic adenocarcinoma of the Mouse Prostate 
TRUS  
Transrectal ultrasound 
Tyr 
 
Tyrosine 
VIP 
 
Vasoactive intestinal peptide 
VPAC1 
Vasoactive intestinal polypeptide receptor 1 
DCE-MRI  
Dynamic contrast enhanced MRI  
 

 
 
 
 
 
6 
Study Summary 
Title 
VPAC1 Receptor Targeted PET Imaging of Prostate 
Cancer (PC) 
Short Title 
PET Imaging of PC 
Protocol Number 
15F.264 
Phase 
Pilot Study (Phase I, feasibility study) 
Methodology/Study 
Design 
Single Arm, Open Label Diagnostic Study 
Study Duration 
 3 years 
Study Center(s) 
Single-center. 
Objectives 
   The objective is to validate the PET imaging results of Cu‐64‐TP3805, 
with the histology of the  image guided biopsy results. Generally, 
approximately 60% of the patients with elevated PSA have prostate 
cancer  
Number of 
Subjects 
20 
Diagnosis and 
Main Inclusion 
Criteria 
We will study 20 patients with persistently elevated PSA   
whom are scheduled for biopsy.. These patients shall be 
PET imaged with our Cu-64 peptide probe first and then a 
week or so later the image guided biopsy shall be 
performed. The image guided biopsy is the standard of care 
procedure. The objective is to validate the PET imaging 
results with the histology of biopsy results. Generally, 
approximately 60% of the patients with elevated PSA have 
prostate cancer. We expect 80% accuracy in identifying 20 
subjects as having histologically determined 
cancer/absence of cancer. The 95% confidence interval of 
this level of accuracy for this sample size is + or – 17.5%. 
Thus we expect to find an accuracy level between 62.5% to 
97.5%. Please note this is a pilot study, not designed to be 
an efficacy determination trial. 
Study Therapy, 
Dose, Route, 
Regimen 
Cu-64-TP3805, a novel PET imaging molecule, given as a 
single intravenous injection dose of (4 mCi ±10%). 
Duration of 
administration and 
follow-up 
Single Intravenous administration given over 5 minutes and 
patients observed for 90 min; follow up, call 24 hrs later. 
Reference therapy 
N/A 

 
 
 
 
 
7 
Statistical 
Methodology 
We expect 80% accuracy in identifying 20 subjects as 
having histologically determined cancer/absence of cancer. 
The 95% confidence interval of this level of accuracy for 
this sample size is + or – 17.5%. Thus we expect to find an 
accuracy level between 62.5% to 97.5%. Please note this is 
a pilot study, not designed to be an efficacy determination 
trial. 
Schema 
Subjects will undergo Cu-64-TP3805 PET Imaging at least 
one week prior to biopsy. Investigational PET imaging will 
be analyzed and compared to biopsy pathology to 
determine efficacy in detection and localization of PC foci. 
Urine sample will be collected prior to Cu-64 injection and 
90 minutes post injection prior to imaging 
1.0 
INTRODUCTION 
This document is a protocol for a human research study. This study is to 
be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies 
and procedures. 
1.1 Specific Aims and Hypothesis 
We hypothesize that targeting VPAC1 receptors overexpressed on PC cell 
surfaces with a Cu-64 imaging agent, TP3805 will provide a specific and 
sensitive means for molecular diagnosis of PC at an early stage, to determine its 
recurrence, and to image metastases. 
Our specific aim is to assess the ability of Cu-64-TP3805 to detect PC 
within the prostate gland. 
1.2 Background and Rationale 
Cancer is complex yet commonplace, and the most terrifying disease of 
mankind. Among men in the USA, PC is particularly lethal, second only to 
cancers of the lung and bronchus combined [1]. In 2010, more than 30,000 men 
succumbed to PC and more than 240,000 new PC cases were identified in the 
USA [1]. PC affects one in every 6 men who are 60 years or older and affects 
African-Americans at a rate 2.4 times greater than European-Americans [1]. 
Great strides have been made both in diagnosis and treatment of PC. However, 
the PC-related death rate has not yet declined, and the quality of life of survivors 
has not yet improved [1]. Three prominent screening tests, the digital rectal 
examination, MRI, and a blood test for prostate specific antigen (PSA) 
determination play a significant role in detecting pathologically advanced PC. 
However, they are not considered reliable tools for early warning of PC [2], [3], 
[4] nor can they be used reliably to detect recurrent cancer or to determine 

 
 
 
 
 
8 
metastatic status of the disease. The lack of reliable diagnosis, results in 
undertreatment or overtreatment of patients with minimal benefit, enormous 
morbidity, incontinence, and/or impotence. Therefore, histology remains the 
mainstay of PC confirmation. However, out of >750,000 biopsies performed each 
year in the USA, >65% show benign pathology, and cost hundreds of millions of 
health care dollars. Various imaging techniques have been evaluated, but their 
utility to image suspected PC or its metastatic lesions is not fully dependable [3]. 
Furthermore, monitoring the effectiveness of PC therapy continues to be a 
challenge. 
Our proposed approach to image PC, its metastases, and recurrence is 
driven by targeting an endogenous genetic product overexpressed when cells 
suffer 
genetic 
damage 
that 
ignites 
cancerous 
transformation. 
These 
characteristic fingerprints, the VPAC1 cell surface receptors, express themselves 
at the onset of the malignancy, and may be prior to elevation of PSA, and well 
before cell morphology is altered [5]. Thus VPAC1 receptors provide a specific 
target that has not yet been exploited for imaging suspected PC and its 
metastases [5]. VPAC1 mediates VIP (vasoactive intestinal peptide) and PACAP 
(pituitary adenylate cyclase activating peptide) growth hormone function in all 
types of PC [6-8]. During the past 10 years we have successfully initiated the use 
of Cu-64 labeled VPAC1 receptor-specific peptide constructs to image disease 
specific oncogene products in experimental animal models of pancreatic, 
prostate and breast cancer (BC), and in humans with BC [9-13]. 
We hypothesize that targeting VPAC1 receptors overexpressed on PC cell 
surfaces [6-8] with a pair of Cu-64 imaging agents, TP3939 (a VIP analog) or 
TP3805 (a PACAP analog), will provide a specific and sensitive means for 
molecular diagnosis of PC at an early stage, to determine its recurrence, and to 
image metastases. This molecular approach for diagnosis is both novel and 
feasible for deployment in the clinic. Furthermore, it promises to reduce the need 
for invasive biopsies, and meet the compelling need to reduce overtreatment, 
and surgery yielding minimal benefit, incontinence, or impotence. Importantly, 
PET imaging costs much less than biopsy combined with histology [14-16]. 
The need for developing oncogene receptor specific agents, such as 
those proposed here, is compelling. The primary tools for PC screening, the 
serum PSA and the digital rectal examination are neither specific nor sensitive, 
as many men with elevated PSA have been found not to have PC [2]. Transrectal 
ultrasonography (TRUS) provides an axial and sagital examination of the 
prostate gland, and allows physicians to estimate its volume. However, in 60-
70% of PC cases are hypoechoic and thus invisible by TRUS [3]. Histologic 
examination, therefore, remains the gold standard for PC but requires an 
invasive procedure for tissue sampling. By this time, the PC is usually advanced. 
However, the question still remains as to where to direct the needle for biopsy. 
As a result, out of the approximately 750,000 prostate biopsies that will be 
performed in the USA in 2010, more than 2/3 will find benign pathology [17]. 

 
 
 
 
 
9 
The use of contrast enhanced spiral computerized x-ray tomography (CT) 
is limited to advanced, high-grade tumors [18]. Using 3D MR spectroscopic 
imaging, PC was diagnosed as possible if the ratio of choline to citrate exceeded 
2SD above the normal population and definite if the ratio exceeded 3SD above 
the normal population [19]. However, sensitivity and specificity were only 80% 
and 46%, respectively [20]. Dynamic contrast enhanced MRI (DCE-MRI) is 
known to be a powerful tool for localization of vascular solid tumors [21]. 
DCE-MRI however has low sensitivity (50%) [22] and has not been able to  
distinguish between PC and benign prostatic hyperplasia (BPH) [23]. T2 
weighted endorectal MRI also has low accuracy of PC detection [24]. Much more 
work therefore, is needed to be done [25]. 
Agents for scintigraphic molecular imaging of PC are F-18-FDG, In-111-
ProstaScint 
[26], 
C-11-choline, 
C-11-acetate 
[18], 
F-18-FLT 
(F-18-
Fluorothymidine) and F-18-Fluorocholine. Cu-64 Bombesin [27], 2-F-18 
fluoropropianic acid [28] and those target PSMA [18]. Although C-11-acetate and 
C-11-choline may have improved scintigraphic advantage over F-18-FDG 
imaging, their efficacy in use centers is lacking. The F-18-FDG uptake is high in 
bladder, low in PC and overlaps with uptake in the normal gland, postoperative 
scar or local recurrence. These complicate the visualization for PC imaging even 
further [29]. Similarly the low tumor/blood ratios and high bladder uptake, of 2-F-
18-fluoropropianic acid, may question its utility in humans [28]. In-111-
ProstaScint or Tc-99m and PSMA antibody have not been considered to be a 
useful agent [18]. Despite these weaknesses, there have been 195 investigations 
in which F-18-FDG was employed and additional 109 in which In-111-ProstaScint 
was utilized (PubMed, 2012). Generally, these agents were used for imaging 
primary and recurrent disease, metastatic disease and to determine the influence 
of therapy of the PC. In none of the cases did the agents work with reliability, 
high sensitivity, or specificity. These investigations demonstrate a compelling 
need for imaging agent that can help physicians in the management of desperate 
PC patients. Genetic imaging can provide unique opportunities not only for 
imaging PC in suspected PC patients, but also for evaluating treatment response 
[13, 30]. 
With Cu-64-Bombesin tumor uptake was only 1.32±0.49% ID/g at 4 hr and 
0.28±0.21% ID/g at 24 hrs, which is significantly lower than the 7.5±3.6% ID/g at 
4 hr uptake with one of our Cu-64 labeled VPAC1 specific peptide analogues, 
TP3939, that did not significantly decline as a function of time [27, 30]. We used 
the same animal model and the same cell line as those in the Cu-64 Bombesin 
protocol. Additionally, the steady uptake of Cu-64-TP-3939 makes sense as 
more of the probe continued to bind to the VPAC receptors (see later). In 
contrast, the declining and low uptake of Cu-64-Bombesin uptake was puzzling. 
Ionic Cu-64-Cl2 has been shown to be taken up by PC (3.0±0.7% ID/g) 
[31], via human copper transport 1 protein (hCtr1). As can be seen in Table-2, 
the tumor uptake of Cu-64-TP3939 in the same PC-3 human PC tumors, in 
athymic nude mice, was 7.48±3.63 %ID/g. The Cu-64-Cl2 tumor uptake in the 

 
 
 
 
 
10 
same model in our laboratory was 4.79±0.34 %ID/g, consistent with data 
reported by the investigators referenced above. Assuming that the hCtr1 gene 
will carry Cu-64-Cl2 to MCF-7 human BC, which overexpresses VPAC1 receptors 
in nude mice, we repeated the study in MCF-7 model and found that the tumor 
uptake was <2% ID/g. This suggested that the uptake of Cu-64-Cl2 may be 
dependent upon the tumor vascularity. In order to further elucidate the nature of 
Cu-64-Cl2 tumor uptake, we performed cell binding assays using ionic Cu-64-Cl2 
with PC-3 cells. The data were analyzed as per Scatchard, strongly indicate that 
the binding was not related 
to any specific mechanism 
(Preliminary Results). These 
findings suggest that Cu-64-
Cl2 for PC imaging cannot 
be reliable. The need for 
better agents still persists. 
Rapidly 
evolving 
advances in genomics and 
proteomics shed new light 
on the genesis of many 
diseases every day and 
provide 
us 
with 
new 
approaches 
in 
molecular 
imaging, to diagnose and 
treat them. Fig. 1 is the 
schematic presentation that 
illustrates 
cell 
signaling 
pathways that overexpress 
specific fingerprints at the onset of a malignant disease within the cell nucleus or 
cytoplasm and on the cell surface. Little or no attempts have yet been made to 
utilize these databases to image PC. In this investigation, we chose to target the 
well characterized, overexpressed VPAC1 surface receptor in human PC. 
Our early data in xenografts, transgenic mice that spontaneously grow PC, 
and mimic pathogenesis of human PC are promising, and so are the early results 
in PET imaging of human BC in which we have also targeted VPAC1 receptors in 
nineteen patients. 
Background 
VPAC1 and VPAC2 Overexpression: 
Reubi and colleagues [6-8] examined more than 600 tumors and their 
metastases using histochemistry and conclusively reported that VPAC1 and 
VPAC2 receptors are overexpressed on a variety of frequently occurring human 
tumors including those of the breast, prostate. On 100% of the human prostate 
tumors examined (n=35), VPAC1 receptors were predominantly overexpressed 
Fig. 1. VPAC1 receptor activates prostate cancer cell proliferation

 
 
 
 
 
11 
on PC tissues and VPAC2 on stroma, to a lesser extent. Although VPAC1 
receptors exist on normal cells, their expression is lower on normal than on 
malignant cells [32, 33] on which the receptor density is high (104/cell) [34, 35]. A 
28 amino acid peptide VIP has high affinity for VIP receptors and the 27 amino 
acid peptide PACAP have high affinity for VIP and PACAP1 combined oncogene 
receptors expressed on malignant cell surface. Therefore, we hypothesize that 
radiolabeled VIP and PACAP1 or their analogues will provide us with excellent 
compounds for accurate and sensitive detection of human PC, once PC is 
suspected. The probe can also detect metastases, and determine therapeutic 
effectiveness. This will bridge the large void that exists today. 
Why Investigate VPAC1 Biomarker? Why Cu-64? And Why PET? 
The implications of diagnosis 
by receptor-specific imaging in the 
management of PC, and cancer in 
general, cannot be overemphasized 
[5]. If successful, the VPAC1-targeted 
peptides are will provide a specific 
and sensitive means for a true, early 
diagnosis in all patients suspected of 
having PC, and a guide to the most 
appropriate therapy. It can detect 
metastatic lesions and distinguish PC 
from 
benign 
masses. 
We 
have 
targeted VPAC1 receptors which are 
expressed also on human (BC). and 
have achieved success in PET 
imaging of BC in nineteen humans 
(Fig. 2a, Fig. 2b). Our studies in a 
transgenic (MMTVneu) mouse model 
that spontaneously 
grow 
BC, 
and 
overexpress 
VPAC1 
receptors, 
demonstrated that 
Cu-64-TP3805 
correctly imaged all 
eight unknown BC 
and its metastases. 
All 
eight 
tumors 
expressed VPAC1 
receptors 
(RTPCR).  Cu-64-
TP3805 
did 
not 
image two benign 

 
 
 
 
 
12 
lesions which did not express VPAC1 receptors and demonstrated superb 
specificity [36]. Our Preliminary results in imaging PC also show reasonable, 
hypothesis-driven, success both in experimental human PC grown in 
immunocompramised mice as well as spontaneously arising PC in TRAMP mice. 
VPAC1 surface biomarkers are a straightforward target [27, 37]. 
These data attest three important parameters as they pertain to this 
proposal: i) That the BC imaging data generated in mice by targeting VPAC1 are 
reliable and provide a firm foundation for translation into humans to image BC. ii) 
The PI and his team have the appropriate expertise and ability to drive basic 
research into clinical applications and iii) These data strongly support our 
hypothesis that the proposed investigation will enable us to initiate studies in 
patients suspected to have PC or are suffering from PC. BC PET imaging either 
with F-18 VIP analogues or Tc-99m-VIP analogues was less successful than that 
with Cu-64 VIP/PACAP analogues [37-39]. Copper chemistry is well known and 
Cu-64 (t ½ 12.8 hr) half-life is long enough to obtain commercially and use in 
humans conveniently. Position emission from Cu-64 is 19%. 
The relatively low (4-6 mm) spatial resolution of current human PET  
scanners may be a problem. However, our tumor uptake/g with 4±10% mCi Cu-
64/injection will be 240 μCi (6% ID/g) for ~7 μCi in 20 mg, a 1.7 mm diameter 
tumor. This amount of radioactivity will be large enough for unequivocal 
delineation. We further anticipate that the continuous reassessment and 
refinement in PET technique will also add to its improved resolution in years to 
come [40, 41]. The Cu-64 PET images with Cu-64 TP3805 promise early,  
accurate, and specific BC images, as we have seen in humans (Fig. 2a, Fig. 2b) 
by targeting VPAC1 receptors with SUV of 9-11. Cu-64-TP3805 unequivocally 
detected twenty out of twenty malignant lesions in nineteen patients we have 
studied so far. Additionally, four involved lymph nodes were also delineated. 
(Please see attached manuscript (J Nucl Med, 54, No. 7, 2013). Because the 
prostate is anatomically distant from the liver, we expect that PC lesions will be 
distinct despite the relatively high liver uptake. Furthermore the lack of bladder 
uptake facilitates PC delineation (please see later, Fig. 9). We further anticipate 
that metastatic bone lesions in PC patients will also be readily discerned by PET 
imaging. 
Innovation: 
We have designed, synthesized and characterized specific probes to 
target VPAC1, labeled them with Tc-99m for SPECT and with Cu-64 for PET 
imaging of BC and PC (Preliminary Results, below). This molecular approach 
targets a specific biomarker, discovered through modern advances in genomics 
and proteomics. Their translation to PC patients is a natural and timely 
progression into a new clinical capability. Our earlier results, including human BC 
imaging, are highly encouraging [9, 38]. These results lead us to hypothesize that 
one or more of the VPAC1-specific peptides will provide us with a tool for 
sensitive and specific PET imaging of suspected primary and metastatic PC 

 
 
 
 
 
13 
lesions. We expect that VPAC1 receptor specificity will differentiate malignant 
lesions from benign masses noninvasively, Unequivocal identification of PC 
lesions could help physicians tailor an appropriate therapeutic intervention. The 
anticipated reduction in false positives and false negatives should reduce 
morbidity and mortality, and improve the quality of life of PC patients.  This novel 
approach to image PC by targeting a gene product is hypothesis-driven and 
based upon our own experience and the wealth of information yielded by recent 
advances in genomics and proteomics. When prostate cells undergo genomic 
modulations for whatever reason, they overexpress VPAC1 cell surface 
receptors. These changes occur well ahead of shed PSA or cell-morphologic 
alterations, the histology of which forms the basis of current PC diagnosis. The 
specificity of genomic biomarkers, should permit us to image PC in patients. 
Biological fluids, including urine, represent a promising source of biomarkers for 
detection and prediction of PC prognosis.  Because urine is available non-
invasively and readily, numerous studies targeting DNA, RNA, protein and 
metabolite based biomarkers have been performed.  However, none have yet 
reached the clinic].  Even FDA approved PCA3 test has low sensitivity and 
limitations in predicting aggressive PC . 
VPAC1 cell surface genomic receptors are over-expressed at the onset of the 
malignancy, prior to elevation of PSA, and well before cell morphology is altered . 
We hypothesized that VPAC1 receptors expressed in high density on PC can be 
targeted for detection of shed tumor cells (STC) in patient urine, using TP4303, a 
VPAC1 specific biomolecule labeled with a near infrared fluorophore. 
    The success of these goals will meet the compelling need to a) localize 
primary PC, that can guide biopsy procedures. b) detect recurrent disease and c) 
image metastatic lesions with improved reliability. Reliable detection of PC can 
reduce the need for invasive biopsies, and minimize overtreatment, including 
surgery. It is important to note that overtreatment can cause incontinence or 
impotence. Thus, VPAC1 imaging addresses serious healthcare issues that 
current approaches cannot resolve, despite the great strides made in recent 
decades. 
The results of our previous translational research and early applications in 
imaging BC in humans 
are published [11, 13, 
42, 43] [35-38, 44] 
[36]. Our studies in a 
transgenic 
(MMTV-
neu) 
mouse 
model 
that 
spontaneously 
grow 
BC, 
and 
overexpress 
VPAC1 
receptors demonstrate 
that 
Cu-64-TP3805 
correctly imaged all 
Fig. 2.c. F-18-FDG (A, 370 MBq, (10 mCi) and Cu-64-TP3805 (B, 159.1 MBq, (4.3 mCi), F-18-FDG
equivalent 860 µCi) PEM scans of the left breast of a 39 yr old female. The F-18-FDG scan was
obtained 1 hr post injection and the Cu-64-TP3805 scan was acquired 15 min post injection. The
PUV/BGV ratios for the lesion (IDC, ER+, PR+, HER2-) were 2.9 for F-18-FDG and 2.2 (lowest of
the series) for Cu-64-TP3805.

 
 
 
 
 
14 
NH -His-Ser-Asp-Ala-Val-Phe-Thr-
Asp-Asn-Tyr-Thr-Lys-Leu-Arg-Lys-
Gln-Nle-Ala-Val-Lys-Lys-3-OCH -4OH-Phe
Lue-Asn-Ser-Val-Lue-Thr-
yAba- Lys- COOH
3
2
NH -His-Ser-Asp-Ala-Val-Phe-Thr-
Asp-Asn-Tyr-Thr-Lys-Leu-Arg-Lys-
Gln-Nle-Ala-Val-Lys-Lys-3-OCH -4OH-Phe
Lue-Asn-Ser-Val-Lue-Thr-
yAba- Lys- COOH
3
2
TP3939
TP3939
eight unknown BC and its metastases. All eight tumors expressed VPAC1 
receptors (RT-PCR). It did not image two benign lesions that did not express 
VPAC1 receptors and demonstrated superb specificity [36]. Our early results in 
imaging human BC are also promising, (Fig. 2.a, 2.b and 2.c). This success is 
both assuring and stimulating and promises similar success in PC imaging. 
1.3 Study Therapy 
This is a diagnostic product developed by the PI to specifically target 
genomic biomarker VPAC1 that is expressed on breast and PC cells in high 
density.  With FDA approved eIND (101550) and all institutional approvals, the PI 
has used this radiopharmaceutical Cu-64-TP3805 in nineteen human subjects 
with BC.  The sensitivity of this agent to image BC lesions and sentinel nodes 
was 100%. 
This project for imaging PC will use the same agent, Cu-64-TP3805 for 
which the approval by FDA is obtained. 
1.4 Preclinical Data 
1.4.1 Vasoactive Intestinal Peptide (VIP) and its Analogues: 
VPAC1 receptors are overexpressed on all PC, including metastatic 
lesions (Fig. 3) [6, 8, 45]. High expression of VPAC1 receptors (>104/cell) has 
been observed by others [34, 35, 39]. 
Both VIP28 and PACAP27 have high 
affinity for VPAC (VPAC1 and VPAC2) 
receptors. VIP is a 28-amino acid peptide 
(Fig.4) initially isolated from porcine 
intestine [46]. VIP, whose structure is 
common in humans, pigs and rats, is a 
hydrophobic, basic peptide containing 
three lysine [18, 24, 25] and two arginine 
[17, 45] residues. From the essential 
histidine residue at the N-terminus to the 
amidated C-terminus, all 28 amino acids 
of VIP are required for high affinity 
binding and biological activity [47]. 
VIP gene receptors (VIP1 and 
VIP2) have been detected on the cell 
membrane of normal intestinal [48] and 
bronchial epithelial cells [48, 49] and are 
overexpressed on various cancer cells, 
including colonic adenocarcinoma [50-
53], pancreatic carcinoma [53] and 
cancers of the prostate [6, 8, 45]. VIP 
(Tyr10 and Tyr22) labeled with I-123 
successfully imaged a number of human 

 
 
 
 
 
15 
Table 1:  Amino acid sequence of TP3805 and TP3939
tumors [32]. Following PACAP homology, these gene receptors are recently 
named VPAC1 (for VIP1 and PACAP2 combined) and VPAC2 (for VIP2 and 
PACAP3 combined).  
VPAC1 receptors are internalized after binding to VIP28 [39]. Imaging 
results of F-18-VIP have not been encouraging [35, 39]. Because VPAC1 
receptor density is greater in malignant tissue than in benign tissue, tumors can 
be imaged with greater contrast relative to normal tissue [7, 39, 54]. 
Two analogues of VIP28 with several-fold greater potency have been 
identified [55]. We have developed methods to include chelators (Fig.4) to bind a 
single Tc-99m and Cu-64 cation without compromising VIP biological activity. 
Each PC cell has ~104 receptors and each cm3 tumor includes ~109 cells, 
amounting ~1013 receptors/cm3 tumor. Assuming, conservatively, that only 5% 
of these receptors were occupied with Cu-64-VIP, each cm3 tumor would contain 
5x1011 molecules of Cu-64-VIP, i.e., 200 μCi of Cu- 64. With high target to 
background ratios, a lesion containing 10 μCi Cu-64 can be unequivocally 
delineated by a human PET scanner. The tumor uptake with our Cu-64-TP3939 
7.5% ID/g [30]. For a human dose of one mCi, one calculates 75 μCi Cu-64/g 
tumors. Up to 25 mCi Cu-64 probe (ATSM) has been administered to humans 
[56]. A tumor weighing <20 mg (1.7 mm diameter) can contain 4-5 μCi and be 
easily detectable particularly when the bladder and the normal stromal activity 
are negligible and when tumor/normal prostate radioactivity ratios averaged 
nearly 4 at 4 hr post injection and 2.7 at 24 hr post injection [30]. Theoretically, 
this should be not only a specific, but also a sensitive technique to detect a 
relatively small number of malignant cells that cannot be detected non-invasively 
by any other technique available today. These facts support our hypothesis that 
Cu-64-VIP analogues may serve as useful PET molecular probes to detect 
VPAC1 expression for early imaging of PC, its recurrence, metastatic lesions, 
and in long-term should also help physicians to determine effectiveness of 
therapy. 
The fact that PACAP27 recognizes and has high affinity (kd=1.5 nM) for 
both VIP1 and PACAP (VPAC1) receptors that are overexpressed on PC cells 
suggests that PACAP may also be a suitable agent to image PC [8, 57-67]. 
Our data show that these Cu-64 probes are highly stable in vivo [30] [38]. 
Furthermore, the high VIP affinity for receptors on malignant cells and 
subsequent internalization [10, 11, 13, 30, 37, 43] [38] minimizes its proteolysis 
and allows cell detection, as we have 
demonstrated in both mice and humans 
[30, 36, 37]. We synthesized one 
analogue of VIP28 (TP3939) and one of 
PACAP27 (TP3805) that are more 
potent and biologically stable than 
VIP28. Their amino acid sequences are 
given in Table-1. These analogues have 
the high IC50 values (4.4 nM and 5.3 

 
 
 
 
 
16 
nM, respectively) among the many that have been synthesized and evaluated 
[55, 67]. 
The rationale for choosing TP3939 VIP analogues was as follows. VIP28 
is comprised of three aromatic moieties at Phe6, Tyr10, and Tyr22, a negatively 
charged site at Asp3 and a lone pair structure at His1. Although all five sites are 
required for complete binding to receptors with high affinity, substitutions at 
position 22 of 3-OCH3-4-OH-Phe and Lys12, Nle17, Val26, Thr28-VIP produced 
the best results, increasing potency by 4 times (IC50 = 4.4 nM vs. 15 nM) over 
VIP28 [55](52). Higher affinity may enhance tumor uptake and improve image 
quality. Again, our recent preliminary data in humans, obtained using Tc-99m-
TP3654, a VIP analogue are consistent with this hypothesis [43, 68]. 
PACAP, a 38-amino acid peptide, isolated from bovine hypothalamus [69], 
was named PACAP because it stimulated the accumulation of intracellular and 
extracellular cAMP in monolayer cultures of rat anterior pituitary cells [70]. 
PACAP, a neurotransmitter and member of the VIP family, is 10 times more 
potent than VIP in stimulating adenylate cyclase in pituitary cells [70]. PACAP 
has three gene receptors, PACAP1, 2, and 3. Gottschall et al [69] isolated 27-
amino acid PACAP (PACAP27) from bovine hypothalamus and concluded that 
PACAP38 and PACAP27 were equally active and derived from a single 176-
amino acid precursor. PACAP27, like VIP, has an amidated C-terminus and 
histidine at the N-terminus. Nineteen of the 27 amino acids of PACAP27 are 
identical to VIP. It is for these reasons we chose to investigate a PACAP 
analogue TP3805 which also has higher IC50 value than VIP28. 
1.4.2 Synthesis and Biological Evaluation of VIP and PACAP Analogues: 
Synthesis of N2(S-benzyl)2 Containing VIP: 
Vasoactive intestinal peptide (VIP) bound to a C-terminal diaminodithiol 
(N2S2) chelator was synthesized on a Wang resin using an ABI 341A peptide 
synthesizer (Applied Biosystems Inc.) [37] [30, 38]. The analogues were  
prepared, purified and characterized by American Peptide Company (Sunnyvale, 
CA) and named after their molecular weights as TP3805 and TP3939. A 
schematic presentation of TP3939 is given in Fig. 4. Although peptides have 
been conjugated with chelating agents such as DOTA (1, 4, 7, 10-
tetraazadocdecane –N, N”, N’”, N””, -tetra acetic acid) it requires a prepared and 
pre-purified peptide to which DOTA is to be conjugated. The conjugated product 
then needs further purification and characterization. Preparation of our analogues 
is a one step process that provides efficiency, saves time and provides a N2S2 
type of chelating moiety for strong chelation with Cu-64 or Tc-99m. 
1.4.3 Preclinical Animal Studies: 
Preclinical animal studies included i) TP3805 functional studies to assess 
its biochemical characteristics, ii) cell binding studies to examine its receptor 
specificity and (Kd) binding affinity, iii) receptor blocking studies to confirm its 

 
 
 
 
 
17 
receptor specificity, iv) tissue distribution studies in athymic nude mice bearing 
human PC tumors, v) imaging (PET/CT) spontaneously grown PC in transgenic 
TRAMP mice and vi) in vivo stability (30, 37, 38).  As per the suggestion by 
CCRRC reviewers, the details of these data are eliminated from this revised 
application. 
1.5 Toxicity Studies: 
We plan to inject no more than 20 μg of a peptide to a standard 70 kg 
patient.  We planned to inject i.v. to a group of three adult female rabbits, each 
10 times, 50 times, and 100 times excess dose, adjusted to body weight (i.e. 
2.86 μg/kg, 14.3 μg/kg, or 28.6 μg/kg).  Preparations were made using decayed 
Cu-64 solution, as described previously.  We initiated our work with three adult 
female, white New Zealand rabbits (age > 15 wks, body weight > 3 kg).  The 
fourth rabbit served as a control.  On day-1 of the experiment, each rabbit was 
weighed in a calibrated, electronic scale by placing a rabbit in a plastic box, 
which was placed on the scale and its weight tared.  Animal body weights were 
read and recorded on an individual chart.  All rabbit work described below was 
approved by the Institutional Animal Care and Use Committee and carried out 
with assistance from a trained technologist from the institutional laboratory 
animal services department.  A staff veterinarian was available for consultation.    
The animals (named A, B, and C) were then placed in a rabbit restraint 
box and two arterial blood samples, 3 mL each, were obtained from ear artery of 
each rabbit.  One anti-coagulated sample was then given to the institutional 
hematology laboratory.  The other was centrifuged and serum was collected.  
Part of the serum was retained in our laboratory for cAMP (cyclic Adenosine 
MonoPhosphate) assay, and the other portion was provided to the institutional 
clinical laboratory for determination of comprehensive metabolic panel.  This 
procedure was followed on each rabbit.  Each rabbit was then given 28.6 μg x 
body weight of peptide preparation in 500 μL 0.8% NaCl through a lateral ear 
vein and the syringe was flushed with another 500 μL of 0.9% NaCl.  Animals 
were watched for any reaction for 10 minutes and another pair of 3 mL arterial 
blood samples was obtained through ear artery.  Each rabbit was then watched 
twice daily, and on day 5, 10, and 17 they were weighed, weight recorded, and 
two venous blood samples from each rabbit were obtained for cAMP 
measurements and for blood and serum chemistry as described above.  After 
drawing blood sample, on day 17, animals were sacrificed and samples of liver, 
spleen, kidney, lungs, and heart were removed.  The tissues were then placed in 
10% formalin; the tissues (5 x 3 treated rabbits plus 5 from a normal, untreated 
rabbit) were given to institutional histology research laboratory to obtain 5 μ thick, 
H+E stained histology slides.  These slides were then examined by Dr. Peter 
McCue, Professor of Pathology at our (TJU) hospital. 
cAMP assays were performed in triplicate on a total of 15 blood samples 
from the three experimental rabbits, along with the standards provided with a 
cAMP direct immunoassay kit obtained from Biovision (Mountain View, CA).  A 
calibration curve was prepared and assays were performed in triplicate.  Optical 

 
 
 
 
 
18 
density was measured at 450 nm.  The readings were averaged for each serum 
sample and percent change in cAMP with respect to the sample obtained before 
peptide administration were calculated and tabulated. 
1.5.1. Results of toxicology studies 
i) Comprehensive metabolic panel  
Results are tabulated in Table-2, in parts I and II.  For all electrolytes, 
enzymes and protein measurements, each rabbit sample prior to injecting the 
peptide served as its own control.  Results are presented as % difference for 
each rabbit at each time point and then as % average of the difference.  The % 
difference averaged out < 25% except for bilirubin, which averaged 100%.  We 
believe this is within the normal fluctuation range of 0.1 mg/dL to 1.2 mg/dL. 
Table-2, Part I:  Comprehensive Metabolic Panel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table-2, Part II:  Comprehensive Metabolic Panel 

 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ii) 
Co
mpl
ete blood count and differential 
Complete blood and blood differential analysis was performed on each rabbit 
blood sample obtained prior to peptide injection (control) and then at 10 min, 5d, 
10d, and 17d post injection.  Data are summarized in Table-3, parts I and II.  The 
data are presented as % difference with respect to the control sample for the 
hematological parameters in each blood sample obtained after administration of 
the diagnostic agent.  In none of the data points (except last reading for WBC in 
animal A) was the difference greater than 6% (well below 10%).  These data too 
are consistent with the lack of evidence that the agent had induced any 
pharmacologic effect. 

 
 
 
 
 
20 
Table-3, Part I:  Comprehensive Blood Panel 
 
 
 
 

 
 
 
 
 
21 
Table-3, Part II:  Comprehensive Blood Panel 
ii) Body Weight 
The animal body weights are summarized in Table-4.  No animal suffered 
any body weight loss, suggesting that the peptide administration induced no 
adverse events leading to reduced dietary intake, altering animal body chemistry, 
or physiology that would adversely influence body weight.  In fact, there was only 
an increase in the body weight, which is an expected normal phenomenon 
indicating normal health in all three animals. 
Table-4:  Rabbit Body Weights.  Peptide injected: 28.5 ug/Kg.  Total 
Peptide Injected: Rabbit A: 99.47 ug      Rabbit B: 88.92 ug   Rabbit C: 
93.20 ug 
Day 
Date 
Rabbit A 
Rabbit B 
Rabbit C 
Day 0(injection day) 
 
 
 
 
Before injection 
11-08-2007 
3.49kg 
3.12kg 
3.27kg 
10 min after injection 
11-08-2007 
Same 
Same 
Same 
Day 5 
11-13-2007 
3.53kg 
3.14kg 
3.24kg 
Day 10 
11-19-2007 
3.60kg 
3.15kg 
3.30kg 
Day 17(sacrificed) 
11-26-2007 
3.66kg 
3.27kg 
3.43kg 
iii)  Cyclic Adenosine Monophosphate 

 
 
 
 
 
22 
The data on determination of serum cAMP (pmol/mL) in all three rabbits 
are given in Table-5.  Data strongly show that in none of the rabbits, at any time 
during the 17 day experimental period, was there any statistically significant 
change (p = 0.34 or greater) in cAMP.  The normal serum cAMP range in rabbits 
is 12.76-20.93 pmol/mL.  The cAMP values in rabbits B and C were well within 
this range.  In rabbit A however, the control serum cAMP value was 21.095.  At 
the 10 min time point, this value was 21.78 and at day 10 it was 22.22.  These 
values are not statistically, significantly different within themselves.  These data 
too indicate that the cAMP levels were not altered by the administration of the 
peptide. 
Table-5:  Rabbit Serum cAMP Levels 
cAMP Concentration (pmol/mL) 
Date 
Rabbit 
Rabbit 
Rabbit 
Average 
Day 0 (Injection Day) 
Before Injection 
21.095 
16.505 
12.95 
16.85±4.085 
Day 0 (Injection Day) 
10 min After 
Injection 
21.78 
16.42 
16.59 
18.26±3.05 (p = 0.66) 
Day 5 
19.36 
16.67 
15.03 
17.02±2.19 (p = 0.915) 
Day 10 
22.22 
16.67 
12.95 
17.28±4.67 (p = 0.91) 
Day 17 (sacrifice) 
12.26 
16.07 
13.82 
14.05±1.92 (p = 0.34) 
iv) Histology 
The animal histology data are presented in Table-6 (signed by Dr. McCue, 
Professor of Pathology) and in Fig. 5 as stated by Professor McCue, no specific 
pathologic changes in organs examined were induced at any time in any of the 
animals. 
Figure 5:  Pathologic Representation of Tissue from 
a Normal and Treated Rabbits (400x) 
 

 
 
 
 
 
23 
Table-6:  Pathologic Changes in Normal and Treated Rabbits 
 
 
 
(Table 6)

 
 
 
 
 
24 
v) Conclusion 
These data in all three rabbits for 17 days after the administration of the 
highest (x100) peptide concentration dose did not show any pharmacologic effect 
in any parameter studied.  We therefore concluded that the studies in lower 
concentration (x10 and x50) doses would be unnecessary, and we could not 
justify sacrificing so many otherwise normal rabbits. 
1.6 Radiation Dosimetric Calculations 
The mouse tissue distribution data obtained at 4hr and 24hr post injection 
was converted into % ID/organ and normalized for a kg body weight.  All organs 
were weighed and average weight was used.  Blood weight was estimated at 7% 
of the body weight, intestine at 40% body weight (32) and muscle at 9.3% body 
weight (33).  Dosimetric calculations were performed using OLINDA/EXM 1.0 
program obtained from Vanderbilt University.  Data, the effective dose 
equivalent, is presented in Table-7 in mSv/mBq and rem/mCi. 
Table-7:  Estimated Absorbed Radiation Dose for Cu-64-Peptide 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
25 
For whole body imaging, (Group-A, please see section 1) we shall enroll 6 
patients. In order to determine optimal image quality, we shall inject 2 patients 
with 3 mCi (±10%), 2 patients with 3.5 mCi (±10%) and 2 with 4 mCi (±10%). 
Image quality will be determined by a physician. Imaging time shall be 
approximately 45 mins. 
Patients in group B will undergo PEM imaging using only the dose as 
determined from above. However, this dose shall not be more than 4±10% mCi. 
It is estimated that the dose received by kidneys, (total) blood, gall bladder wall, 
lungs, pancreas, uterus, and osteogenic cells will be high among all organs.  
However, the overall absorbed radiation dose is less than that from the 
commonly used diagnostic dose of 5-10 mCi of Ga-67 (Table-8) (34). 
Table-8:  Radiation Dosimetry for Ga-67 

 
 
 
 
 
26 
Please note that we expect the lung absorbed dose to be much smaller.  
This is because the mice lungs from which this human absorbed dose was 
derived had micrometastases in their lungs, secondary to the primary breast 
cancer.  In normal lung mice, the uptake is only 25% of that seen here.  
Therefore, in the studies with human lungs, free of cancer or cancer metastases, 
we anticipate much less absorbed radiation dose than presented here. 
1.7 Chemistry preparations and controls (CMC) 
1.7.1 
Preparation 
The preparation will consist of 20 μg of the peptide in 4 μL of sterile 0.1M 
acetate buffer pH = 4.6, to which will be added 400 μL of 0.2 M glycine buffer, pH 
= 9, 100 μg of SnCl2·2H2O in 20 μL 0.05M HCl, and 1000 μg of glucoheptonate 
in 20 μL sterile water, and up to 10 mCi of Cu-64 in 1-2 μL 0.1M HCl.  The 
mixture will be heated for 90 min. at 50°C. (Please note: Since we have 
increased the dose to be administered, we have increased the quantity of 
radioactivity to be added to the vial. This has changed the incubation time and 
temperature. This change has no influence on the pharmacokinetics or the 
biological activity of the preparation). 
HPLC analysis will be performed.  A typical HPLC profiles given in Fig. 6 
shows 97.4% radiochemical purity. 
The mixture will then be diluted with 500 μL of 0.9% sterile NaCl solution, 
filtered through 0.22 μ filter.  4±10% mCi of this solution will be drawn into a one 
mL, sterile syringe for injection. 
Fig. 6:  Typical Cu-64-TP3805 HPLC Analysis

 
 
 
 
 
27 
1.8 Clinical Data to Date: 
PET Imaging of Human Breast Cancer Using Cu-64-TP3805: 
Human BC also overexpresses VPAC1 receptor (Fig. 3). Fig. 2.a, Fig. 2.b 
and 2.c show that Cu-64 TP3805can detects not only the primary BC (six out of 
six malignant lesions in four patients studies so far) but also the sentential lymph 
nodes. These data provide the evidence that the Cu-64-TP3805 analogue data in 
mouse model, can be successfully translated to accurately image human tumors 
and provide a confidence that this PC imaging investigation is worthwhile. 
In the USA and abroad, prostate cancer (PC) takes thousands of lives every 
year. Yet its early and accurate detection continues to be challenging. At the 
onset of PC, VPAC1, which belongs to the superfamily of G-protein coupled 
receptors, expresses in high density on PC cells, but not on benign or normal 
cells. Our extensive preclinical findings, and preliminary data in humans, have 
shown that 64Cu-TP3805 has a high affinity for VPAC1, is stable in vivo, and has 
the ability to image breast tumors in humans and spontaneously grown PC in 
TRAMP mice. The goal was to determine the ability of 64Cu-TP3805 to image PC 
in men and to evaluate the findings with pathologic examinations. 
Methods: 25 men scheduled for radical prostatectomy and who signed IRB 
approved consent form were PET imaged preoperatively. Standardized Uptake 
Values (SUVs) were determined, malignant lesions (SUV > 1.0) were counted, 
and data compared with histologic findings. In addition, de-paraffinized whole 
mount pathology slides (n=68) from 6 VPAC1 PET imaged patients, 3 benign 
prostatic hyperplasia (BPH) patients (n=9), one malignant lymph node (n=3), and 
one benign lymph node (n=3) were incubated with 64Cu-TP3805, washed with 
PBS, dried and subjected to digital autoradiography (DAR). Slides were then 
H&E stained, read by a pathologist, and DAR images were compared with foci 
delineated as PC, benign, cyst, or prostatic intraepithelial neoplasia (PIN). 
Results: In 25 patients, 212 lesions had SUVs > 1.0 as compared to 127 lesions 
identified by histology. While the status of the remaining 85 PET lesions remains 
to be determined, in 68 histological slides from 6 PET imaged patients, DAR 
identified 105/107 PC foci (missed 2 due to artifact), 19/19 high grade PIN 
(HGPIN), 2/2 ejaculatory ducts (ED) and 5/5 urethra verumontanum (UV). 
Additionally, DAR found 9 PC lesions not previously identified by histology. The 
positive and the benign lymph nodes were correctly identified by DAR, and 
for the 3/3 BPH patients without PC, and 5/5 cysts, DAR was negative. 
Conclusion: 64Cu-TP3805, a VPAC1 receptor specific biomolecule delineates 
PC lesions in vivo and ex vivo, provides normal images for benign masses, and 
is worthy of further studies in patients. 
  
 
 
In this investigation, we will use the same preparation, Cu-64-TP3805 that 
has been prepared and used in the previoius human subjects with 100% 
success. Although no preparation will either be compounded or used out of the 
Jefferson campus, we will use a “kit” that will be ready to be heated following the 

 
 
 
 
 
28 
addition of 440 μL of sterile H2O and then Cu-64 activity. These kits will contain 
all chemicals in sterile, 10 mL glass vials. Reagents will be added to the vial, 
snap frozen in dry ice, lyophilized and the vials will be sealed in N2 atmosphere. 
They will be stored at 4°C and examined for Cu-64 labeling and shelf life stability. 
 
Such preparations will be convenient and assure consistency of reagents. Such 
kits prepared previously in our laboratory were stable for more than two years. 
We expect similar stability, but will be used only after careful examination of their 
reproducible and stable preparations, as examined by HPLC. There will be only 
one patient studied at a time. The syringe containing the Cu-64-TP3805 will be 
clearly labeled with patient’s name. “Cu-64-TP3805” name, the amount of 
radioactivity, and the time at which the dose was dispensed. 
Please note that under this eIND 101550 and with all institutional 
approvals, the agent was administered to nineteen females with known BC. All 
malignant lesions including involved lymph nodes were unequivocally delineated 
(100%). There were no adverse events except three patients sensed flushing 
which resolved without any medication within a few minutes. Therefore, we will 
not change this preparation (Cu-64-TP3805). A preprint (J Nucl Med July 2013) 
of this investigation, reference [79]. 
1.9 Dose Rationale and Risk/Benefits 
During the nineteen BC patient studies as per the suggestion by the FDA, 
a dose escalation study was performed using 3 mCi±10% (n=2), 3.5 mCi±10% 
(n=2), and 4 mCi±10% (n=2).  From these studies, it was concluded that the 
image quality was much better with a 4 mCi±10% Cu-64-TP3805 dose while the 
radiation dose (liver target organ) to the liver and all other organs were well 
within the dose delivered by routine diagnostic nuclear medicine procedures.  
Based on this, FDA approved the use of 4 mCi±10% dose to the next thirteen 
patients.  In this PC PET study therefore, we will use 4 mCi±10% dose which is 
also approved by the FDA (eIND 101550) for this PC PET study.  We will strictly 
adhere to this dose. 
2.0 STUDY OBJECTIVES 
2.1 Primary Objective:  
The primary objective of this study is to assess the ability of Cu-64-
TP3805 to detect Prostate cancer in patients with persistently elevated PSA. 
3.0 STUDY DESIGN 
3.1 General Design 
This is a single institution, open-label pilot phase I feasibility diagnostic 
imaging study. 
3.2 Primary Study Endpoints  

 
 
 
 
 
29 
The primary endpoint of study will be to determine the ability of Cu-64-
TP3805 to detect PC foci within the prostate gland in patients with persistialy 
elevated PSA as compared with tumor maps derived by histology of biopsy 
specimens obtained guided biopsy. 
3.3 Primary Safety Endpoints 
As stated previously in section 1.9, we will use 4 mCi±10% Cu-64-TP3805 
dose given with FDA approval to fifteen of the nineteen BC patients.  The peptide 
quality (20 µg) will also be kept unchanged. 
There was no toxicity in this entire study of the nineteen subjects except 
three subjects sensed flushing which resolved within minutes without any 
medication.  It is reasonable therefore to anticipate that in this PC study too, 
there will be no adverse events (AE) due to dose administered.  Nevertheless, a 
physician (either Dr. Intenzo or Dr. Kim) will be available during and after the 
injection.  An up to date first aid box will be available.  The Research Coordinator 
will call each subject 24 hrs later and make note of any AE patients may have 
experienced. 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be enrolled in this study:  
1. 
Male aged 21 years or older. 
2. 
Ability to provide signed informed consent and willingness to 
comply with protocol requirements. 
3. 
Have persistently elevated PSA. 
 
4. 
Scheduled to have biopsy at least 7days post Cu-64. 
5. 
Agree to use an acceptable form of birth control for a period of 7 
days after the Cu-64-TP3805 injection. 
4.2 Exclusion Criteria 
Subjects must not meet any of the following criteria to be enrolled in this 
study:  
1. 
Participating would significantly delay the scheduled standard of 
care therapy. 
2. 
Administered a radioisotope within 10 physical half-lives prior to 
study drug injection. 
3. 
Have any medical condition or other circumstances that, in the 
opinion of the investigator, would significantly decrease obtaining reliable data, 
achieving study objectives or completing the study. 
4.3 Gender/Minority/Pediatric Inclusion for Research 

 
 
 
 
 
30 
This study will include men of any race or ethnicity who meet eligibility 
criteria.  As PC is a disease of middle aged and older men, no women or 
pediatric patients will be included. 
4.4 Subject Recruitment and Screening 
A total of 20 patients with persistently elevated PSA, presented at Urology 
Associates Office of TJU, and are scheduled  for a biopsy, will be enrolled. Drs. 
E. Trabulsi, C. Lallas, and L. Gomella shall determine the patient eligibility, and 
inform the PI, Dr. Mathew Thakur, and the research coordinator, Nancy Pedano. 
Each patient shall sign an IRB approved consent form. Each patient shall be 
administered IV with 4 mCi ± 10% Cu-64-TP3805. 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
Patients who withdraw consent or who do not complete the investigational 
imaging or who do not have radical prostatectomy will be withdrawn from study 
and will not be included in the analysis. 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be removed from the analysis and no follow up will 
be undertaken. 
5.0 STUDY IMAGING AGENT 
5.1 Description 
In this investigation, we will use the same preparation, Cu-64-TP3805 that 
has been prepared and used in nineteen previous human BC subjects with 100% 
success. Although no preparation will either be compounded or used out of the 
Jefferson campus, we will use a “kit” that will be ready to be heated following the 
addition of 440 μL of sterile H2O and then Cu-64 activity. These kits will contain 
all chemicals in sterile, 10 mL glass vials. Reagents will be added to the vial, 
snap frozen in dry ice, lyophilized and the vials will be sealed in N2 atmosphere. 
They will be stored at 4°C and examined for Cu-64 labeling and shelf life stability. 
Such preparations will be convenient and assure consistency of reagents. Such 
kits prepared previously in our laboratory were stable for more than two years. 
We expect similar stability, but will be used only after careful examination of their 
reproducible and stable preparations, as examined by HPLC. There will be only 
one patient studied at a time. The syringe containing the Cu-64-TP3805 will be 
clearly labeled with patient’s name.  All preparations were sterile.  However, 
sterility will be examined on each dose. 
5.2 Treatment Regimen 
A protocol assistant from the Urology Department will assist with accrual 
and enrollment, and a clinical coordinator from the Radiology Department will 
guide the patient through the imaging procedure. IRB approved informed consent 

 
 
 
 
 
31 
will be obtained by one of the investigators. The patients will be asked to read the 
IRB-approved consent form and encouraged to ask any questions they deem 
necessary.  Four ±10% mCi of Cu-64-TP3805, prepared as described here in will 
be injected through an indwelling intravenous line and the lines will be flushed 
with 5 ml sterile 0.9% saline. Patient vital signs (heart rate, respiratory rate, blood 
pressure) will be monitored before administration, at 15 minute post injection and 
then at the end of  the scan.  Patients will be scanned at 90 minutes with whole 
body PET/CT.  Imaging time will be approximately one hour.  Patients will be 
contacted over the phone 24 hours later and asked for any unlikely adverse 
events.  Any AE shall be recorded and notified immediately to IRB, FDA and to 
CCRRC. 
Whole body PET/CT imaging will be acquired by a trained and 
experienced technologist at Jefferson Center City Imaging facility located within 
the TJU campus. Images will be read either by Dr. Intenzo or Dr. Kim.  Data will 
be recorded. Care will be taken of patient privacy. 
5.3 Risks 
Based on the previous nineteen recipients of Cu-64-TP3805, we do not 
anticipate any adverse events after the i.v. administration of peptide analog, the 
patients will remain in the clinic for at least two hours and observed either by the 
technologist or by the research coordinator. Dr. Kim and Dr. Intenzo will be 
available should their expertise be required. A first aid box equipped 
appropriately will be at hand all the time. 
Patient vital signs (heart rate, respiratory rate, blood pressure) will be 
monitored before administration, at 15 minute post injection and then at the end 
of the scan.  Patients will be scanned at 90 minutes with whole body PET/CT The 
nursing staff will also watch for any flushing or redness. Each reading will be 
recorded. 
Twenty-four hours later, we will telephone each patient to ask for any 
adverse events the patient may experience. These will be recorded. 
5.4 Method for Assigning Subjects to Treatment Groups 
Not applicable. 
5.5 Preparation and Administration of Study Imaging Agent 
The Cu-64 peptide analog will be prepared using the methods described 
previously. Sterile reagents and glassware will be used. The dose, no more than 
five mL in volume, will be dispensed. Sterility tests will be performed and 
recorded. To maintain the procedure uniformity, we will prepare kits and use 
them for instant Cu-64 labeling. HPLC analysis will also be performed for 
determination of radiochemical purity and data recorded. 
Four ±10% mCi of Cu-64-TP3805, prepared as described here in will be 
injected through an indwelling intravenous line and the lines will be flushed with 5 
ml sterile 0.9% saline.  

 
 
 
 
 
32 
5.6 Subject Compliance Monitoring 
Not applicable. 
5.7 Prior and Concomitant Therapy 
Not applicable. 
6.0 STUDY PROCEDURES 
6.1 Study Visit Schedule (see appendix 15.1) 
Screening 
Potential subjects identified by the urologic oncologists (Drs. Trabulsi, 
Lallas and Gomella) who have persistently elevated PSA, 4 or greater and 
scheduled for MRI fusion/TRUS .  The clinical coordinator will screen the patient 
for eligibility as per the inclusion and exclusion criteria.  Eligible subjects will 
review and sign the informed consent.  The coordinator will schedule the Cu-64-
TP3805 PET imaging study at least one week but not more than 3 weeks before 
their scheduled  MRI Fusion/TURS biopsy 
Visit 1 
The clinical coordinator will meet the subject and guide them through the 
imaging process.  They will monitor the patient before, during and after the 
imaging study, as previously described. 
Follow-up 
The clinical coordinator will follow up with the subjects by phone the day 
after the study imaging procedure to ensure that there were no adverse 
reactions.  The coordinators will be available as needed for the time period  until 
their scheduled  biopsy  procedure for questions or concerns. 
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
7.2 We will study 20 patients with persistently elevated PSA for a Cu-64 PET 
imaging in whom  biopsy are ordered. These patients shall be PET imaged 
with our Cu-64 peptide probe first and then a week or so later the image 
guided biopsy shall be performed. The image guided biopsy is the standard 
of care procedure. The objective is to validate the PET imaging results with 
the histology of biopsy results. Generally, approximately 60% of the patients 
with elevated PSA have prostate cancer. We expect 80% accuracy in 
identifying 20 subjects as having histologically determined cancer/absence 
of cancer. The 95% confidence interval of this level of accuracy for this 
sample size is + or – 17.5%. Thus we expect to find an accuracy level 
between 62.5% to 97.5%. Please note this is a pilot study, not designed to 
be an efficacy determination trial. Statistical Methods 
7.3 Subject Population(s) for Analysis 

 
 
 
 
 
33 
20 subjects completing the investigational imaging and undergoing  biopsy 
and PET imaged with 4 mCi ± 10% Cu-64-TP3805. 
 
7.4 
Replacement of Participants 
Participants who are consented but are not dosed will be replaced 
8.0 SAFETY AND ADVERSE EVENTS  
8.1 Definitions 
Adverse Event 
An AE is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance  
Serious Adverse Event 
Adverse events are classified as serious or non-serious. 
A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance. They may jeopardize 
the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  For example, drug overdose or abuse, a seizure that did 
not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
All adverse events that do not meet any of the criteria for serious should 
be regarded as non-serious adverse events. 
Adverse Event Reporting Period 

 
 
 
 
 
34 
The study period during which adverse events must be reported is 
normally defined as the period from the initiation of any study procedures to the 
end of the study treatment follow-up.  For this study, the study treatment follow-
up is defined as 24 hours following the study imaging procedure. 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event. 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until 
the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.  The investigator should notify the study sponsor of any death or adverse 
event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should 
also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a 
subject that has participated in this study. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on 
adverse events by specific questioning and, as appropriate, by examination.  
Information on all adverse events should be recorded immediately in the source 
document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should be recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded  
The clinical course of each event should be followed until resolution, 
stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the 
end of the study period must be followed up to determine the final outcome.  Any 
serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded 
and reported immediately. 

 
 
 
 
 
35 
8.3 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of 
the study at his/her site.  This safety monitoring will include careful assessment 
and appropriate reporting of adverse events as noted above, as well as the 
compliance and implementation of the KCC data and safety-monitoring plan.  
Medical monitoring will include a regular assessment of the number and type of 
serious adverse events by both the assigned Medical Monitor and the KCC 
DSMC. 
8.3.1 Medical Monitoring and AE/SAE Reporting 
A Medical Monitor is assigned to this study at the Thomas Jefferson 
University.  This is a physician/pharmacist who is not directly involved in the trial, 
and is not currently collaborating with the sponsor/investigator on any other trial.  
The role of the Medical Monitor is to review all reportable AEs/SAEs (in real-time) 
including grading, toxicity assignments, non-reportable AEs (quarterly), protocol 
violations/deviations, as well as all other safety data and activity data observed in 
the ongoing clinical trial occurring at Thomas Jefferson University. The Medical 
Monitor may recommend reporting of adverse events and relevant safety data, and 
may also recommend suspension or termination of the study to the DSMC and TJU 
IRB. 
Every KCC investigator initiated protocol includes requirements for 
reporting of adverse events based on CTC 4.0. All events are reported to the IRB 
and Medical Monitor using a password protected web-site. In addition all 
unexpected and serious adverse events (SAEs) are reported to the TJU IRB and 
to the Food and Drug Administration (FDA) if applicable. The investigator is 
required to submit all unexpected and serious adverse events to the TJU IRB 
and the Medical Monitor within the timeframes outlined in the below table. All 
AE/SAEs will be reported to the DSMC at the quarterly DSMC review meetings; 
however, if the Medical Monitor determines corrective action is necessary, an “ad 
hoc” DSMC meeting will be called. Fatal adverse events related to treatment 
which are unexpected must be reported within 24 hours to the TJU IRB and 
the DSMC. Fatalities not related to the study drug/device must be reported 
within 5 days. A summary of the reporting requirements for KCC investigator 
initiated Phase I and Phase II studies are presented below. 
 
 
Grade 1 
Grade 2 
Grade 2
Grade 3 
Grade 3 
 
Grades 4
and 5 
 
Unexpected 
and Expected Unexpected Expected 
Unexpected 
with 
Hospitalization
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization
Unexpected
and 
Expected 
Unrelated 
Unlikely 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
5 Working 
Days 
Reviewed at 
Quarterly DSMC 
Meeting and IRB
Annual Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 -   
48 Hours   
(Death: 24 
Hours) 
 
Phase 2 -   

 
 
 
 
 
36 
Annual 
Review 
5 Working 
Days       
Possible 
Probable 
Definite 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 working 
days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours    
(Death: 24 
Hours) 
Phase 1 -       
48 Hours 
Phase 2 -       
5 Working Days
48 Hours    
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 
and Phase 
2 -         
48 Hours   
(Death: 24 
Hours 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the 
TJU IRB Policy and Procedures. Please follow the individual protocol AE/SAE 
reporting guidelines if more stringent reporting procedures are specified. 
Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, sponsor-investigators of studies 
conducted under an IND must comply with following safety reporting 
requirements: 
Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:  
The Sponsor-Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the investigator to 
be possibly related to the use of Cu-64-TP3805.  An unexpected adverse event 
is one that is not already described in the Investigator Brochure. 
Such reports are to be telephoned or faxed to the FDA within 7 calendar 
days and insert funding sponsor within 24 hours of first learning of the event.  
Each telephone call or fax transmission (see fax number below) should be 
directed to the FDA new drug review division in the Center for Drug Evaluation 
and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever is responsible for the review of the IND 
15 Calendar-Day Written Report:   
The Sponsor-Investigator is also required to notify the FDA and all 
participating investigators, in a written IND Safety Report, of any serious, 
unexpected AE that is considered possibly related to the use of Cu-64-TP3805. 
An unexpected adverse event is one that is not already described in the 
Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports. 
Written IND safety reports with Analysis of Similar Events are to be 
submitted to the FDA, insert funding sponsor, and all participating investigators 
within 15 calendar days of first learning of the event.  The FDA prefers these 

 
 
 
 
 
37 
reports on a MedWatch 3500A Form but alternative formats are acceptable (e.g. 
summary letter). 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-
Investigator shall within 60 days of the anniversary date that the IND went into 
effect submit a brief report of the progress of the investigation.  Please refer to 
Code of Federal Regulations, 21 CFR § 312.32 for a list of the elements required 
for the annual report.  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to insert funding sponsor.  Copies of such 
reports should be mailed to:  NIH, Program Director Dr. H. Baker 
8.3.2 Data and Safety Monitoring Committee 
 Data and Safety Monitoring Committee (DSMC) is the Data and Safety 
Monitoring Board (DSMB) for the KCC. The DSMC is a multidisciplinary 
committee charged with overseeing the monitoring of safety of participants 
in clinical trials, and the conduct, progress, validity, and integrity of the 
data for all clinical trials at the Thomas Jefferson University KCC. The 
committee meets quarterly to review the progress and safety of all active 
research protocols that are not monitored by another safety and data 
monitoring committee or board. 
 The DSMC meets quarterly. Additional DSMC meetings are scheduled 
based on the nature and number of trials being monitored over a specified 
time period. The DSMC meets (by conference call) within 24 hours 
following the notification of an unexpected adverse event felt to be related 
to the study drug. 
 Prior to each DSMC meeting, each board member, is provided a printout 
of all reported AEs and SAEs occurring during the reporting period for this 
clinical trial. The principal investigator provides a detailed and 
comprehensive narrative assessment of current adverse events to date, 
indicating their possible significance and whether these toxicities have 
affected the conduct of the trial. DSMC members are provided with the 
principal investigator’s assessment, a written report summarizing adverse 
events, safety data, and activity data observed during the specified time 
period described in each protocol, as well as recommendations from the 
Medical Monitor. A review of outcome results (response, toxicity and 
adverse events) and factors external to the study (such as scientific or 
therapeutic developments) is discussed, and the Committee votes on the 
status of each study. 
 A summary of the board’s action is sent to each investigator, the CCRRC 
and Thomas Jefferson University IRBs. The DSMC actions may include 
recommendations/requirements that will lead to improved patient safety 
and/or efficacy, significant benefits or risks that have developed, or other 
changes determined to be necessary. The DSMC may also take note of 

 
 
 
 
 
38 
slow accrual or lack of scientific progress, and refer such issues to the 
CCRRC. The DSMC provides the investigator with the rationale for any 
decision made. 
9.0 DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject 
authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects 
in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of 
their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial.  Source data are contained in source documents   
Examples of these original documents, and data records include: hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument 
for the study.  All data requested on the CRF must be recorded.  All missing data 
must be explained.  If a space on the CRF is left blank because the procedure 
was not done or the question was not asked, write “N/D”.  If the item is not 
applicable to the individual case, write “N/A”.  All entries should be printed legibly 
in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  

 
 
 
 
 
39 
All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it. 
9.4 Records Retention 
This is a FDA regulated study.  It is the investigator’s responsibility to 
retain study essential documents for at least 2 years after the last approval of a 
marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period 
if required by an agreement with the sponsor.  In such an instance, it is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities.  The 
Investigator will also ensure that the medical monitor or other compliance or 
quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
KCC Investigator Initiated Phase I Studies  
Phase I studies require continuous monitoring by the PI of the study with 
quarterly safety and monitoring reports submitted to the CRMO and the DSMC. 
Each protocol is assigned to a medical monitor (a physician or other member of 
the DSMC who has expertise in the therapeutic area of the protocol and is not 
directly involved in this trial). The medical monitor reviews all adverse events (in 
addition to unexpected adverse events), safety data and activity data observed in 
the ongoing clinical trial at each new dose level, prior to dose escalation. 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity 
data, and any corrective action that occurred on a quarterly basis. The medical 
monitor also provides a summary of their review. The summary of all discussions 
of adverse events are submitted to the DSMC, and these reports are reviewed 
during the DSMC meetings that take place quarterly. Patients are only identified 
by initials, and no other personal health information (PHI) is included in the 
reports. 
The medical monitor may recommend reporting adverse events and 
relevant safety data not previously reported, and may recommend suspension or 
termination of the trial based on their review of AE/SAE data observed 
throughout the life of a clinical trial. In such circumstances, and “ad hoc” DSMC 
meeting will be called to discuss corrective action with the PI. If for any reason 
the PI of the trial disagrees with the conclusions of the Medical Monitor or DSMC, 

 
 
 
 
 
40 
the issue will be referred to the Associate Director of Clinical Investigations, who 
will be responsible for dispute resolution. 
The summary of all discussions of adverse events are included in the KCC 
investigator’s reports to the TJU IRBs as part of its annual progress report. The 
DSMC and the TJU IRBs may, based on the monitor’s recommendation suspend 
or terminate the trial. The quarterly safety and monitoring reports include a 
statement as to whether this data has invoked any stopping criteria in the clinical 
protocol. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and 
inspections by the IRB, the funding sponsor, government regulatory bodies, and 
University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
Participation as an investigator in this study implies acceptance of 
potential inspection by government regulatory authorities and applicable 
University compliance and quality assurance offices. 
10.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by KCC 
investigators are audited by an independent auditor once they have achieved 
10% of target accrual. However, a study can be audited at any time based on 
recommendations by the IRB, DSMC, CCRRC and/or the Director of Clinical 
Investigations, KCC. Studies are re-audited once they have achieved 50% of 
target accrual. Special audits may be recommended by the IRB, DSMC or 
CCRRC based on prior findings, allegations of scientific misconduct and where 
significant irregularities are found through quality control procedures. Any 
irregularities identified as part of this process would result in a full audit of that 
study. 
In addition to the audits at 10 and 50%, the CRMO randomly audits at 
least 10 percent of all patients entered into therapeutic KCC trials and other trials 
as necessary, on at least a bi-annual basis, to verify that there is a signed and 
dated patient consent form, the patient has met the eligibility criteria, and that 
SAEs are documented and reported to the TJU IRB. 
All audit reports are submitted to the DSMC for review and action (when 
appropriate). A copy of this report and recommended DSMC action is sent to the 
CCRRC and TJU IRB. The committee regards the scientific review process as 
dynamic and constructive rather than punitive. The review process is designed to 
assist Principal Investigators in ensuring the safety of study subjects and the 
adequacy and accuracy of any data generated. The TJU IRB may, based on the 
DSMC and auditor’s recommendation, suspend or terminate the trial. 

 
 
 
 
 
41 
11.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards 
of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
This protocol and any amendments will be submitted to a properly 
constituted independent Institutional Review Board (IRB), in agreement with local 
legal prescriptions, for formal approval of the study conduct.  The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator 
before commencement of this study. 
All subjects for this study will be provided a consent form that is compliant 
with local and federal regulations, describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in 
this study.  See Attachment for a copy of the Subject Informed Consent Form.  
This consent form will be submitted with the protocol for review and approval by 
the IRB for the study.  The formal consent of a subject, using the IRB-approved 
consent form, must be obtained before that subject is submitted to any study 
procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional 
obtaining the consent. 
12.0 STUDY FINANCES 
12.1 Funding Source 
This study is financed through a grant from the US National Institute of 
Health, through the National Cancer Institute. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent 
ownership, royalties, or financial gain greater than the minimum allowable by 
their institution, etc.) must have the conflict reviewed by a properly constituted 
Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All Jefferson University Investigators will follow the 
TJU Conflicts of Interest Policy for Employees (107.03). 
12.3 Subject Stipends or Payments 
To compensate for their travel, parking, meals and a partial loss of wages, 
each patient will be paid at the completion of the study, one hundred fifty dollars. 
13.0 PUBLICATION PLAN 
All data shall be published in a peered reviewed open access journal.  
Data will also be presented at national and international gatherings.  An 
appropriate acknowledgment to NIH will be made. 

 
 
 
 
 
42 
14.0 REFERENCES 
This is the bibliography section for any information cited in the protocol.  It 
should be organized as any standard bibliography. 
 

 
 
 
 
 
43 
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humans. J Nucl Med 41(1):107-10. 

 
 
 
 
 
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13. Rao, P.S., Thakur, M.L., Pallela, V., Patti, R., Reddy, K., Li, H., Sharma, S., 
Pham, H.L., Diggles, L., Minami, C., and Marcus, C.S. (2001) 99mTc 
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17. Wingo, P.A., Cardinez, C.J., Landis, S.H., Greenlee, R.T., Ries, L.A., 
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21. Alonzi R, P.A., Allen C (2007) Dynamic contrast enhanced MRI in prostate 
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22. Jackson ASN, R.S., Sobhaib SA, et al (2009) Dynamic contrast-enhanced 
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23. Fricke, S.T., Rodriguez, O., Vanmeter, J., Dettin, L.E., Casimiro, M., Chien, 
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49 
 
15.0 APPENDICES 
Include any attachments for this study (e.g. study schedule/visit chart from 
procedures section, Pill Diaries to be used, recruitment materials if applicable, 
AE Logs from section 5.2, Eligibility Checklist, Drug Reconciliation Form, etc.) 
15.1 Visit Chart: 
Subject with persistently high PSA  seeing  a Urologic Oncologist at 
Jefferson (Drs. Trabulsi, Lallas or Gomella) and is scheduled for MRI fusion/trans 
rectal ultrasound (TRUS) prostate biopsy . 
 
Screening Visit: 
 Clinical coordinator reviews chart and interviews patient 
 Clinical coordinator confirms subject eligibility 
 Subject signs informed consent 
 
 
Imaging Visit: 
 Clinical coordinator meets patient in Radiology 
 Vitals signs are monitored before and after imaging procedure 
 Intravenous catheter inserted and study agent (Cu-64-TP3805) infused 
 PET imaging procedure completed 
 Follow up call 24 hours later to ensure absence of adverse event 
 
 
 MRI fusion/TURS Date: 
 At least one week but not more than 3 weeks later 
  Biopsy complete and pathology results received  
 Subject completion of protocol 

 
 
 
 
 
50 
15.2 Case Report forms:  

 
 
 
 
 
51 
Cu-64-TP3805  
 
 
 
PET Imaging Date:_________ 
 MRI fusion/TURS Biopsy Date:_____ 
 
Study #_______ 
 
 
 
 
Surgeon: 
_________ 
 
Patient Identification: 
 
 
Patient Initials: 
________ 
 
Medical Record #: __________ 
 
 
 
Body Weight: 
________ 
 
Age:  
 
__________ 
 
 
 
Ethnicity: 
 
Caucasian  
 
African American 
 
 
 
Asian  
 
 
Latino 
 
Inclusion Criteria: 
 
 
 
 
Intermediate/High Risk Disease (must check at least one box): 
 
 
 
PSA :  
 
________ 
 
PSA  10 ng/DL 
 
 
 
 
 
 
DRE:  
 
________ 
 
T2b, T2C, T3 or T4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature: ____________________________ 

 
 
 
 
 
52 
 StudyCu-64-TP3805 PET Scan results 
 
 
 
 
Date: __________ 
 
Patient INT”L_____ 
 
Study #_________ 
 
Interpreting Radiologist:  
____________________ 
 
Prostate Sextant Visible Foci: 
 
 
  L Base 
SUV: ________ 
 
  R Base 
SUV: ________ 
 
 
 
 
Size:  ___ x ___ x ___ mm 
     Size:  ___ x ___ x ___ mm 
 
 
 
 
 
  L Mid 
SUV: ________ 
 
 R Mid 
SUV: ________ 
 
 
 
 
Size:  ___ x ___ x ___ mm 
     Size:  ___ x ___ x ___ mm 
 
 
 
 
 
  L Apex 
SUV: ________ 
 
 R Apex 
SUV: ________ 
 
 
 
 
 
Size:  ___ x ___ x ___ mm 
     Size:  ___ x ___ x ___ mm 
 
 
 
Signature: ____________________________ 

 
 
 
 
 
53 

 
 
 
 
 
54