Clinical trial NCT04727736
Conditions: Prostate Cancer
Sponsor: Ashok Muthukrishnan
Start date: 2021-05-01; Completion date: 2022-12-31
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an interventional, single group assignment, prospective nonrandomized, open label Phase 2 trial designed to evaluate 18F-DCFPyL PET imaging in men diagnosed with prostate cancer with increasing prostate-specific antigen (PSA) levels.

Detailed description:
This is an trial designed to evaluate the positive predictive value of 18F-DCFPyL PET imaging in men diagnosed with prostate cancer with increasing PSA levels. Patients will receive a single dose of 18FDCFPyL PET and undergo a PET imaging study. 18F-DCFPyL Injection is an 18F-labeled small molecule that targets the extracellular domain of PSMA. One intravenous catheter will be placed for radiopharmaceutical administration. Patients will be injected with ≤ 333 MBq (≤ 9 mCi) of 18F-DCFPyL via this catheter. The dose range for 18F-DCFPyL will be 7 - 9 mCi. The PET imaging may be repeated at a later date if the biopsy of the lesion is negative and if the lesion is present on follow-up imaging.

Arms: arm 1: Participants will receive a single dose of 18F-DCFPyL and undergo a PET imaging study.

(The PET imaging may be repeated at a later date if the biopsy of the lesion is negative and if the lesion is present on follow-up imaging.)
Interventions: intervention 1: 18F-DCFPyL
Intervention descriptions: intervention 1: 18F-DCFPyL (single dose injection) - a radiolabeled prostate-specific membrane antigen (PSMA) ligand

Protocol documents:
Prot_SAP_000.pdf: 
Phase 2 Study of 18F-DCFPyL Positron Emission Tomography (PET) in Men 
with Intermediate or High Risk Biochemically Recurrent Prostate Cancer 
 
INSTITUTION: 
UPMC Hillman Cancer Center 
 
PROTOCOL NUMBER: 
HCC 20-009 
 
STUDY PHASE: 
Phase 2 
 
IND NUMBER: 
147610 
 
NCT NUMBER: 
NCT04727736 
PROTOCOL VERSION DATE: 
10/21/2021 
INVESTIGATIONAL PRODUCT: 18F-DCFPyL 
Provided by Progenies Pharmaceuticals, Inc. 
c/o Lantheus Medical Imaging, Inc. 
331 Treble Cove Road 
North Billerica, MA 01862 
 
PRINCIPAL INVESTIGATOR: 
Ashok Muthukrishnan, MD 
UPMC Hillman Cancer Center 
5150 Centre Avenue, Room 564 
Pittsburgh, PA 15232 
Phone: (412) 647-0104 
24-Hour Number: (412) 721-4816 
Email: muthukrishnana@upmc.edu 
 
BIOSTATISTICIAN: 
Hong Wang, PhD 
UPMC Hillman Cancer Center Biostatistics Facility 
Sterling Plaza, Suite 325 
201 N Craig Street 
Pittsburgh, PA 15213 
Phone: (412) 383-1588 
Email: how8@pitt.edu 


2 
 
Good Clinical Practices 
This clinical investigation will be performed in compliance with the protocol, the Declaration of 
Helsinki, Good Clinical Practices as set forth in the ICH Guidelines for Good Clinical Practice, 
and applicable local regulatory requirements. 
 
Confidentiality Statement 
This document contains confidential information of the Sponsor. This information is to be 
disclosed only to the recipient study staff and the Institutional Review Board or Institutional Ethics 
Committee reviewing this protocol. This information can be used for no other purpose than 
evaluation or conduct of this study without prior written consent from the Sponsor. 


3 
 
PRINCIPAL INVESTIGATOR SIGNATURE 
 
Title: 
 
 
Protocol Number: 
Phase 2 Study of 
18F-DCFPyL Positron Emission 
Tomography (PET) in Men with Intermediate or High 
Risk Biochemically Recurrent Prostate Cancer 
HCC 20-009 
My signature below confirms that I have read and approved this protocol and assures that 
this clinical study will be conducted according to all requirements of this protocol, 
including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and ICH guidelines. 
 
 
Electronically signed by: 
Asflok Mulhukrishnan 
Reason: I approve this 
agreement 
Date: Oct 21. 2021 13:05 
EDT 
[Signature of Principal Investigator] 
 
 
 
Ashok Muthukrishnan, MD 
[Principal Investigator Printed Name] 
Oct 27, 2021 
 
Date 


4 
 
SYNOPSIS 
 
Name of Sponsor 
Ashok Muthukrishnan, MD 
Investigational 
Product 
18F-DCFPyL 
Indication (phase) 
Phase 2 
Title of Study 
Phase 2 Study of 18F-DCFPyL Positron Emission Tomography (PET) 
in Men with Intermediate or High Risk Biochemically Recurrent 
Prostate Cancer 
Protocol Date 
I 10/21/2021 
STUDY LOCATIONS 
UPMC Hillman Cancer Center 
UPMC Magee-Women's Hospital 
UPMC Shadyside Hospital 
OBJECTIVES 
Primary Objective: 
To determine the positive predictive value (PPV) of 18F-DCFPyL Positron Emission Tomography 
(PET) on a per-patient basis in men diagnosed with prostate cancer with increasing PSA levels. 
Secondary Objective: 
To determine the PPV of 18F-DCFPyL PET on a per-region basis, specifically focusing on the 
prostate or prostate bed, pelvis, extra pelvis, and bones. 
ENDPOINTS 
Primary Endpoint: 
Positive predictive value (PPV) of 18F-DCFPyL PET (per-patient): Number of true positives (TP) 
divided by number of TP plus number of false positives (FP) as detailed in Section 3.5.1. 
Secondary Endpoint: 
Positive predictive value (PPV) of 18F-DCFPyL PET (per-region): TP/TP + FP as detailed in 
Section 3.5.1. 


5 
 
Name of Sponsor 
Ashok Muthukrishnan, MD 
Investigational 
Product 
18F-DCFPyL 
METHODOLOGY 
Study Design 
This  is  an interventional, single  group  assignment,  prospective  non- 
randomized, open label Phase 2 trial designed to evaluate the PPV of 
18F-DCFPyL PET imaging in men diagnosed with prostate cancer with 
increasing prostate-specific antigen (PSA) levels. Eligible patients will 
undergo baseline assessments as per the Schedule of Study Activities in 
Appendix A. A schematic of the study design can be found in Appendix B. 
Approximately 300 participants are planned for enrollment in this study. 
Participants will receive a single dose of 18F-DCFPyL and undergo a PET 
imaging study. The PET imaging maybe repeated at a later date if the biopsy 
of the lesion is negative and if the lesion is present on follow-up imaging. 
Intervention 
The intervention is a PET CT scan with a single dose of the radiolabeled 
prostate-specific membrane antigen (PSMA) ligand, 18F-DCFPyL. 
18F-DCFPyL PET will be acquired using a GE Discovery PET-CT scanner. 
Intervention 
Duration 
Patients meeting study eligibility criteria will receive one dose of 18F-DCFPyL 
supplied by the current Good Manufacturing Practice (cGMP)-compliant PET 
production facility and will be monitored for safety for 120 minutes following 
administration. 
Investigational 
Agent and 
Formulation 
18F-DCFPyL Injection is an 18F-labeled small molecule that targets the 
extracellular domain of PSMA. It is a sterile, clear particle-free solution 
supplied at a specific activity of at least 1000 mCi/µmol at the Time of 
Administration (TOA), and a radioactivity concentration (RAC) of 1-90 
mCi/mL at the Time of Calibration (TOC). 
Dose and Route 
of 
Administration 
One intravenous catheter will be placed for radiopharmaceutical 
administration. Patients will be injected with :'S 333 MBq (:'S 9 mCi) of 
18F-DCFPyL via this catheter. The dose range for 18F-DCFPyL will be 7 - 9 
mCi. 


6 
 
Name of Sponsor 
Ashok Muthukrishnan, MD 
Investigational 
Product 
18F-DCFPyL 
SUBJECT POPULATION 
Number of 
Patients 
Planned for 
Enrollment 
Approximately 300 participants are planned for enrollment in this study. 
Inclusion 
Criteria 
Patients must meet all inclusion criteria to be considered eligible for 
participation in the study. Male patients 2: 18 years of age. 
To be eligible to participate in this trial, subjects must meet all of the following 
criteria: 
• Histologically confirmed diagnosis of prostate cancer 
• Biochemical recurrence was defined as a PSA of 0.2 or more ng/mL 
measured more than 6 weeks after prostatectomy or a PSA of2 or more 
ng/mL rise above nadir fo11owing radiation therapy (ASTRO Phoenix 
consensus definition) 
• 
If PSA values are reported in double decimal points, it will be 
rounded to the nearest single value decimal point (e.g., 0.14 
will be rounded to 0.1 and 0.15 - 0.19 will be rounded to 0.2) 
• Age 2: 18 years of age 
• Eastern Cooperative Oncology Group (ECOG) performance status :S 2 
(Karnofsky 2: 60%) 
• Ability to understand and willingness to sign a written informed 
consent document 
• Willing to comply with clinical trial instructions and requirements 


7 
 
Name of Sponsor 
Ashok Muthukrishnan, MD 
Investigational 
Product 
18F-DCFPyL 
Exclusion 
Criteria 
Patients meeting any of the exclusion criteria will not be eligible for 
participation in the study. 
• 
History of another active malignancy within 3 years, other than basal 
cell and squamous cell carcinoma of the skin 
• 
Presence of prostate brachytherapy implants unless approved by the PI 
• 
Administration of another radioisotope within five physical half-lives 
of trial enrollment 
• 
Radiation or chemotherapy within 2 weeks prior to trial enrollment 
• 
Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 
• 
Serum total bilirubin > 3 times the upper limit of normal 
• 
Aspartate transaminase (AST) or alanine aminotransferase (ALT)> 5 
times the upper limit of normal 
• 
Inadequate venous access 
• 
 Claustrophobia or any other condition that would preclude PET 
1magmg 
• 
Patients must not be receiving ADT except per criteria directly 
below. Patients who received ADT in the past must have a serum 
testosterone that is recovered to at least 100 ng/dL. 
• 
Patients who have been on ADT +/- novel hormonal agent 
(NHA) and developed MO CRPC. 
I ASSESSMENTS 
Efficacy 
PET imaging evaluated qualitatively and semi-quantitatively. 
Safety 
Patient safety will be evaluated based on incidence and nature of adverse 
events (AEs) and severe AEs (SAEs) or findings on physical examination. 


8 
 
Name of Sponsor 
Ashok Muthukrishnan, MD 
Investigational 
Product 
18F-DCFPyL 
STATISTICAL METHODS AND ANALYSIS 
Efficacy 
PPV will be estimated by the number of true positives (TP) divided by 
number of patients who are tested positive (i.e., TP + FP) based on the PET 
imaging, with the corresponding exact 95% confidence intervals (Cis) being 
reported. The determination of TP and positive testing is detailed in Section 
3.5.1. 
All patients will be followed up for histopathologic analysis, conventional 
imaging (CT, MRI and/or bone scan) and/or serum PSA after focal salvage 
therapy acquired during clinical routine. Combination of (in descending 
priority) histopathologic analysis, imaging, and PSA follow-up after 
local/focal therapy will be taken as composite reference standard. 
Validation will be performed by the unblinded local investigators after 
reviewing images and reports, following prespecified criteria of the study 
protocol. In patients with follow-up, positive 18F-DCFPyL PET findings 
will be validated as true or false-positive results. Region negative on 
18F-DCFPyL PET, but with subsequently confirmed prostate cancer by 
histopathologic analysis, will be considered false-negative results. True 
negative will not be defined. 
Safety 
The safety and tolerability of 18F-DCFPyL Injection will be assessed using 
the incidence, nature, and severity of adverse events up to 1 day following 
infusion. The maximum grade for each type of toxicity will be recorded for 
each patient, and frequency tables will be reviewed to determine toxicity 
patterns. 


9 
 
TABLE OF CONTENTS 
Page 
SYNOPSIS ....................................................................................................................................... 4 
ABBREVIATIONS AND DEFINITIONS .................................................................................... 12 
1. 
BACKGROUND AND RATIONALE .............................................................................. 13 
1.1 
INTRODUCTION.................................................................................................. 13 
1.2 
Rationale for Developing Prostate Cancer Imaging Agents .................................. 15 
1.3 
Targeting PSMA for Prostate Cancer Detection .................................................... 17 
1.4 
Name and Description of Investigational Product ................................................. 19 
1.5 
Results of Nonclinical Studies ............................................................................... 20 
1.5.1 Summary of Pharmacology Studies ........................................................... 21 
l.5.2 Summary of Pharmacokinetics Studies ...................................................... 21 
1.5.3 Determination of Radiation Dose Estimates in Humans ........................... 23 
1.5.4 Toxicology ................................................................................................. 24 
1.5.4.1 Single-dose Toxicity Studies ....................................................... 24 
1.6 
Results of Clinical Studies ..................................................................................... 24 
1.6.1 Previous Human Experience ...................................................................... 25 
1.6.1.1  Study J1418: Study 18F-DCFPyL a Second Generation Low- 
molecular Weight PSMA based PET Radiotracer, in Patients 
with Prostate Cancer .................................................................... 25 
1.6.1.2 Study J1545: Pilot Study of 18F-DCFPyL PET/CT in the 
Evaluation of Men with an Elevated PSA Following Radical 
Prostatectomy .............................................................................. 30 
1.6.1.3 Case Report from Study J1545 - Detecting Metastatic Lesions 
Compared to Bone Scan .............................................................. 31 
1.6.1.4 PyL2301: A Prospective Phase 2/3 Multi-center study of 18F- 
DCFPyL PET/CT imaging in Patients with Prostate Cancer: 
Examination of Diagnostic Accuracy (OSPREY) ....................... 32 
1.6.1.5 Efficacy Results ........................................................................... 32 
1.6.1.6 Safety Results .............................................................................. 33 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 34 
2.1 
Primary Objective .................................................................................................. 34 
2.1.1 Primary Endpoint ....................................................................................... 34 
2.2 
Secondary Objective .............................................................................................. 34 
2.2.1 
Secondary Endpoint .................................................................................. 34 
3. 
INVESTIGATIONAL PLAN ............................................................................................ 35 
3.1 
Overall Study Design and Plan .............................................................................. 35 
3.1.1 Description ................................................................................................. 35 
3.2 
Selection of Study Population ................................................................................ 35 


10
 
3.2.1 Inclusion Criteria ....................................................................................... 35 
3.2.2 Exclusion Criteria ...................................................................................... 35 
3.2.3 Removal of Patients from Study ................................................................ 36 
3.2.3.1 Patient Withdrawal or Early Termination .................................... 36 
3.2.3.2 Planned Follow-up for Discontinued Patients ............................. 36 
3.3 
Investigational product. .......................................................................................... 37 
3.3.1 Identity of Investigational Product: 18F-DCFPyL Injection ....................... 37 
3.3.2 Packaging and Labeling ............................................................................. 37 
3.3.3 Receiving, Storage, Dispensing, and Return ............................................. 37 
3.3.3.1 Receipt of Drug Supplies ............................................................. 37 
3.3.3.2 Storage and Handling .................................................................. 37 
3.3.3.3 Dispensing of Study Drug ........................................................... 38 
3.3.4 Administered Intervention ......................................................................... 38 
3.3.5 Selection of Dose in the Study ................................................................... 38 
3.3.6 Selection and Timing of Dose for Each Subject. ....................................... 39 
3.3.7 Procedures for Ensuring Subject Compliance ............................................ 39 
3.3.8 Method of Assigning Subjects to Treatment Groups ................................. 39 
3.3.9 Investigational Product Accountability ...................................................... 39 
3.3.9.1 Investigational Product Inventory Records ................................. 39 
3.3.9.2 Return or Destruction oflnvestigational Product ........................ 39 
3.3.10 Blinding ...................................................................................................... 40 
3.4 
Schedule of Study Activities .................................................................................. 40 
3.5 
Assessment of INTERVENtION ........................................................................... 40 
3.5.1 Imaging Protocol and Follow up ................................................................ 40 
3.5.2 Screening Assessments .............................................................................. 44 
3.5.3 Procedure for Registration of Subjects ...................................................... 45 
3.6 
Assessments during INTERVENTION ................................................................. 45 
3.6.1 Demographic and Medical Record Review ............................................... 45 
3.6.1.1 Patient Demographics .................................................................. 45 
3.6.1.2 Medical History ........................................................................... 45 
3.6.1.3 Physical Examination .................................................................. 46 
3.6.2 Interventional Examination ........................................................................ 46 
3.7 
FOLLOW UP ASSESSMENTS ............................................................................ 47 
3.7.1 Post-Study Follow Up ................................................................................ 47 
3.7.2 Long Term Follow Up ............................................................................... 47 
3.8 
Assessment of Safety ............................................................................................. 47 
3.8.1 Safety evaluation ........................................................................................ 47 
3.8.2 Radiation exposure from PSMA PET imaging .......................................... 47 
3.8.3 Adverse Events .......................................................................................... 48 
3.8.3.1 Definition of Adverse Events ...................................................... 48 
3.8.3.2 Definition of Serious Adverse Events ......................................... 48 
3.8.3.3 Evaluation of Adverse Events ..................................................... 49 


11
 
3.8.3.4 Relationship to Study Intervention .............................................. 49 
3.8.3.5 Expectedness ............................................................................... 50 
3.8.3.6 Assessment and Documentation of Adverse Events ................... 51 
3.8.4 Review of Safety Information: Sponsor Responsibilities ............................. 52 
3.8.5 IND Safety Reports ....................................................................................... 52 
3.8.5.1 Serious and unexpected suspected adverse reaction .................................. 52 
3.8.5.2 Findings from other studies ........................................................................ 53 
3.8.5.3 Findings from animal or in vitro testing .................................................... 53 
3.8.5.4 Increased rate of occurrence of serious suspected adverse reactions ......... 53 
3.8.6 Submission of IND safety reports .......................................................................... 53 
3.8.6.1 Unexpected fatal or life-threatening suspected adverse reaction reports ... 54 
3.8.6.2 Reporting format or frequency ................................................................... 54 
3.8.6.3 Investigations of marketed drugs ............................................................... 54 
3.8.6.4 Reporting study endpoints ......................................................................... 54 
3.8.7 Follow-up ............................................................................................................... 54 
3.8.8 Disclaimer .............................................................................................................. 55 
3.8.9 Reporting adverse events to the responsible IRB ..................................................... 55 
3.9 
Data Quality Assurance ......................................................................................... 55 
3.9.1 Data Collection, Monitoring, and Transfer ................................................ 56 
3.9.2 Quality Control and Quality Assurance ..................................................... 56 
3.9.3 Data and Safety Monitoring Plan ............................................................... 56 
3.10 
Statistical Methods Planned in the Protocol and Determination of Sample Size ... 57 
3.10.1 Study Design .............................................................................................. 57 
3.10.2 Sample Size ................................................................................................ 58 
3.10.3 Analysis of Primary and Secondary Endpoints .......................................... 58 
3.10.4 Missing Data .............................................................................................. 59 
3.10.5 Interim Analyses ........................................................................................ 59 
4. 
ETHICS .............................................................................................................................. 59 
4.1 
Compliance Statement ........................................................................................... 59 
4.2 
Subject Information and Consent. .......................................................................... 59 
5. 
PUBLICATION POLICY .................................................................................................. 59 
6. 
REFERENCE LIST ........................................................................................................... 60 
7. 
APPENDICES.................................................................................................................... 64 
7.1 
Appendix A: Schedule of Study Activities .......................................................... 64 
7.2 
Appendix B: Study Schematic ............................................................................. 66 


12 
 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
AE 
ALT 
AST 
BP 
BUN 
CBC 
CFR 
CT 
eCRF 
FDA 
GCP 
1B 
ICH 
IND 
IRB 
IV 
MBq 
MRI 
PC 
PET 
PSA 
PSMA 
SAE 
SRT 
Tmax 
 
t112 
WBC 
Term 
Adverse event 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood pressure 
Blood urea nitrogen 
Complete blood count 
Code of Federal Regulations 
Computerized tomography 
Electronic Case Report Form 
Food and Drug Administration 
Good Clinical Practice 
Investigator Brochure 
International Conference on Harmonisation 
Investigational New Drug 
Institutional Review Board 
Intravenous(ly) 
Megabecquerel 
Magnetic resonance imaging 
Prostate cancer 
Positron emission tomography 
Prostate-specific antigen 
Prostate-specific membrane antigen 
Serious adverse event 
Salvage radiation therapy 
Time to maximum plasma concentration 
Half-life 
White blood cell 
 
 


13 
 
1. 
BACKGROUND AND RATIONALE 
1.1 
INTRODUCTION 
Prostate cancer is the most common cancer among men in the US with an estimated 174,650 
new cases diagnosed yearly, and it is the second leading cause of cancer- related death in men 
[1]. Most men who die of prostate cancer succumb to metastatic, recurrent disease. Thus, 
imaging modalities that can detect, monitor, and restage residual, recurrent locoregional disease, 
and metastatic disease are highly desirable. Conventional anatomic and functional imaging 
including contrast-enhanced computed tomography (CT), [99mTc] methylene diphosphonate 
(MDP) bone scan, ultrasound, or magnetic resonance imaging (MRI) may not be sufficiently 
sensitive and specific for detection of prostate cancer lesions [2-5]. 
Tumors typically exhibit abnormally high metabolism and this mechanism has been exploited 
for imaging cancers. Positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D- 
glucose (FDG PET), the clinical standard for a number of cancers, has demonstrated diverse 
results in prostate cancer imaging [6-9]. Other tumor metabolism-based approaches tested in 
prostate and other cancers are the use of labeled choline, taking advantage of the increased 
expression of choline kinase (ChKa) in tumor cells [10], or increased uptake of amino acids such 
as methionine or leucine.11C Choline was approved by the US Food and Drug Administration 
(FDA) in 2012 for imaging prostate cancer; however, the sensitivity of 11C choline PET imaging 
is limited in extraprostatic lesions [11-15]. Recently, the synthetic L-leucine analog trans-l- 
amino-3-18F-fluoro-cyclobutane carboxylic acid (18F-FACBC), or 18F-fluciclovine (Axumin®), 
was approved by the FDA as a PET imaging agent for use in men with suspected recurrence of 
prostate cancer based on elevated blood prostate specific antigen (PSA) levels following prior 
treatment [16]. However, both 11C-choline and 18F-fluciclovine uptake are not specific for 
prostate cancer, and their imaging performance are not as reliable in patients with blood PSA 
levels < 2 ng/mL. 
The high unmet need to accurately detect known or suspected recurrent or metastatic prostate 
cancer as early as possible has prompted the introduction of novel, prostate-specific membrane 
antigen (PSMA)-targeted PET tracers have for imaging prostate cancer with superior accuracy 
to facilitate appropriate disease management decisions [17-22]. Low-molecular-weight agents 
that bind to the PSMA, which is highly expressed in both primary and metastatic prostate cancer, 
have proven to be particularly effective [23-25]. A novel highly selective, low-molecular weight 
PSMA-targeted PET radiotracer with high specific activity, 18F-DCFPyL, was discovered at 
Johns Hopkins University School of Medicine (JHU) and in-licensed to Progenies in 2015. 
Progenies has completed the clinical development of 18F-DCFPyL and has recently submitted 
an NDA to support regulatory approval of 18F-DCFPyL. 
In the recent CONDOR trial, Morris et al studied 208 men with biochemically recurrent prostate 
cancer with a median PSA of 0.8 who underwent imaging with this tracer. The study included 
patients  with  PSA  2:  0.2  ng/mL  in  the  post-radical  prostatectomy  patient  and 
2: 2.0 ng/mL in the post-RT or cryotherapy patient. The primary endpoint of the study was the 
correct localization rate (CLR), which is defined as the percentage of patients who had at least 


14 
 
one lesion on PET which correlated with either pathology, correlative imaging, or PSA response. 
Their study design in depicted in the image below: 
 
 
 
 
 
The median age was 68, with a median of 5.9 years from the time of original prostate cancer 
diagnosis. About half the patients had received radical prostatectomy only, 35% received RP 
and RT, and 15% received only RT. Most (73%) had a Gleason< 8 and 34% of patients had a 
PSA < 0.5. In terms of detecting disease with 18F-DCFPyL-PET/CT, 59-65% of patients had 
positive imaging findings by PET. Of note, all of these patients had no evidence of disease with 
standard of care imaging. Of the positive findings, the majority of patients had clinical 
localization. 
The CLR rate was 85 - 87% amongst the three PyL PET/CT readers. CLR was highest amongst 
patients with a PSA > 5 (96%) but remained high even in patients with a PSA < 0.5 (73%). For 
patients with a PSA > 5, PyL PET detected disease in 96% of patients and up to 36% of patients 
with a PSA < 0.5. 
63.9% of the subjects had a change in the intended management after the PSMA PET scan, 
78.6% were attributable to positive and 21.4% to negative PSMA PyL scans. 131/205 (64%) of 
patients had a change in intended management after PyL PET/CT. 21% of patients had a change 
in goal of treatment from non-curative intent to curative intent. The most common change was 
changing from salvage local therapy to systemic therapy (58/131). Other changes included 


15 
 
changing from systemic therapy to salvage therapy (43/131), changing from treatment to 
observation (9/131). PyL was well tolerated and the most common AE was headache (n=4, 
1.9%). 
 
 
 
 
 
The CONDOR study met its primary endpoint, demonstrating excellent diagnostic performance 
of DCFPyL PET/CT imaging in men with biochemically recurrent prostate cancer even at low 
PSA values. The CONDOR data has demonstrated DCFPyL-PET can detect disease in the 
majority of patients with a PSA>5 and even in a third of patients with a PSA < 0.5 More 
importantly, this detection leads to a change in management for the majority of patients, some 
even changing treatment intent from palliative to curative [60]. 
 
 
1.2 
 RATIONALE 
FOR 
DEVELOPING 
PROSTATE 
CANCER 
IMAGING 
AGENTS 
Prostate cancer is a significant public health problem affecting more than 2.3 million men in the 
US and another 4 million in Europe. Annually, nearly 174,650 and approximately 450,000 new 
cases of prostate cancer are diagnosed in the US and Europe, respectively [1, 26]. It was estimated 
that there were 359,000 prostate cancer associated deaths worldwide in 2018 [27]. The mortality 
from the disease is second only to lung cancer in men [1, 26]. An estimated $8 billion is currently 


16 
 
spent annually in the US on surgery, radiation, drug therapy, and minimally invasive treatments 
of prostate cancer [28]. 
Several conventional imaging modalities are currently used for the diagnosis, staging and 
prognosis of prostate cancer metastases. Conventional cross-sectional imaging with computed 
tomography (CT) and magnetic resonance imaging (MRI) rely on anatomical changes (lesions> 
1 cm), often resulting in missed lymph node metastases and has low sensitivity. Approximately 
one quarter of high risk prostate cancer patients have regional lymph node metastases based on 
postoperative histological evaluation, and half of these patients may already have bone metastases 
based on conventional bone scans [29, 30]. More accurate preoperative staging, better surgical 
planning, in combination with salvage dissection or radiation of extraprostatic lesions, may 
improve surgical planning and increase cure rates, especially in patients with pre- operatively 
diagnosed oligometastases. Similarly, in patients with recurrent or metastatic disease, early and 
accurate localization of recurrent or metastatic disease may afford benefits ranging from timely 
initiation of curative interventions, such as salvage lymph node dissection or radiation, to timely 
onset of systemic therapy. Nodal enlargement of metastases occurs relatively late in the 
progression of prostate cancer and neither CT nor MRI are effective at detecting the often 
microscopic lymph node metastases at the earliest stages of disease progression. Additionally, 
nodal enlargement can also be caused by infection or inflammation, thereby reducing the 
specificity. 
Meta-analyses of 24 published studies reveal that CT and MRI perform equally poorly in the 
detection of lymph node metastases from prostate cancer [31]. Results of pooled sensitivity and 
specificity are 42% and 82%, respectively, for CT and 39% and 82%, respectively, for MRI. 
Thus, the reliance on either CT or MRI may misrepresent the patient's true status regarding nodal 
metastases, and misdirect the therapeutic strategies offered to the patient [31]. Radionuclide bone 
scans are commonly used for monitoring bone metastases. However, as bone scans detect tissue 
remodeling, as opposed to tumor burden, false positives can be caused by inflammation, previous 
bone injuries, and arthritis, especially in older men [32]. 
One of the most challenging aspects of clinically managing prostate cancer is the development of 
suspected or known disease recurrence after initial definitive therapy. Rising PSA after initial 
definitive therapy is known as biochemical recurrence (BCR) of prostate cancer and may occur 
in 20-30% of prostate cancer patients before a more definitive diagnosis of metastatic disease can 
be established by conventional imaging modalities [33-36]. 
Therefore, new agents that will detect and localize the primary tumor, as well as small metastatic 
lesions, with high sensitivity and specificity are essential to more accurately diagnose and stage 
the disease and monitor therapy. 
This particular study aims to focus on the detection of metastatic disease or local recurrence early 
on in prostate cancer patients with biochemical recurrence. This group of prostate cancer patients 
after definitive local therapy currently have limited imaging options in the United States. The 
current standard-of-care imaging tests detect local recurrence or metastatic lesions long after 
when the serum PSA levels become detectable. Also, these imaging tools are not sensitive or 


17 
 
specific enough to detect tumor recurrence. In addition, the therapeutic options for such of group 
of patients are not clearly delineated in current clinical practice as the evidence of disease and its 
location are not easily documented by imaging early on when a definitive therapy could make a 
difference in patient outcomes. This DCFPyl PSMA PET imaging tool holds a great deal of 
promise as evidenced from multiple studies from similar PSMA molecular imaging tracers, 
notably the recently published data from CONDOR trial. PSMA PET imaging has also become 
standard-of-care elsewhere in several countries in biochemically recurrent prostate cancer 
patients. 
The recent CONDOR trial data has shown PSMA PET imaging in extremely valuable imaging 
tool in most patients with a PSA > 5 and even in one-third of patients with a PSA < 0.5. Their 
primary endpoint was novel in that they were interested in the correct localization rate (CLR), 
which is defined as the percentage of patients who had at least one lesion on PET which 
correlated with either pathology, correlative imaging, or PSA response, which was found to be 
85 - 87%. The CLR was highest in PSA > 5, but even for those with< 0.5 it was as high as 73%. 
Our study intends to determine the positive predictive value of 18F-DCFPyL Positron Emission 
Tomography (PET) as the primary endpoint on a per-patient basis in men diagnosed with prostate 
cancer with increasing PSA levels, and to evaluate the PPV of 18F-DCFPyL PET on a per-region 
basis, specifically focusing on the prostate or prostate bed, pelvis, extra pelvis, and bones, as a 
secondary endpoint. This information we believe will help understand the PSMA tracer from 
another perspective and provide a more useful insight and serve as complementary statistics to 
the CONDOR trial [60]. 
 
 
1.3 
TARGETING PSMA FOR PROSTATE CANCER DETECTION 
PSMA, also known as folate hydrolase I (FOLHI) or glutamate carboxypeptidase II (GCPII), is 
a trans-membrane, 750-amino acid type II glycoprotein primarily expressed in normal human 
prostate epithelium at very low levels, if at all, but is highly upregulated in prostate cancer, 
including metastatic disease. 
PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates that is 
capable of sequentially removing the poly-gamma-glutamyl termini [37, 38]. Since PSMA is 
expressed by virtually all prostate cancers and its expression is further increased in poorly 
differentiated, metastatic and hormone-refractory prostate carcinomas, it is a very attractive target 
for developing agents for the diagnosis and staging of this disease [39-41]. In addition to high 
expression in malignant prostatic tissue and being directly related to tumor aggressiveness [42], 
lower levels of PSMA have also been detected in renal proximal tubules, cells of the intestinal 
brush border membrane, rare cells in the colonic crypts, the brain, salivary glands [25, 39, 43, 
44], and in the neovasculature of nonprostatic solid carcinomas (e.g., renal cells, breast, colon, 
pancreas, melanoma, and lung carcinoma) [23]. A radiolabeled anti-PSMA monoclonal antibody 
(mAb) 7El l, marketed as Indium 111 ProstaScint® (capromab pendetide), is currently used to 
detect prostate cancer nodal metastasis and recurrence. ProstaScint was first approved for 


18 
 
marketing by the FDA in 1996, and while still available today, it is rarely used in practice due to 
a number of logistical and clinical limitations [45]. Furthermore, ProstaScint targets the 
intracellular domain of PSMA and is therefore thought to bind to mostly necrotic portions of the 
prostate tumor [40]. 
To overcome ProstaScint's limitations, radiolabeled monoclonal antibodies that bind to the 
extracellular domain of PSMA have been developed, and have been shown to accumulate in 
PSMA-positive prostate tumors in animals [38]. Initial promising results in man from various 
phase 1 and 2 trials have utilized PSMA as a therapeutic target [46, 47]. 
While monoclonal antibodies hold promise for tumor detection and therapy, there has been 
relatively limited clinical success outside of hematological cancers due to their low permeability 
in solid tumors and slow clearance from the circulating blood pool. Smaller molecular weight 
compounds with higher permeability into solid tumors are more likely to provide a distinct and 
definitive advantage in achieving higher percent uptake per gram of tumor tissue and a high 
percentage of specific binding. Small molecules are also expected to have improved blood 
clearance and tissue distribution in normal tissues compared with antibodies, thus enhancing the 
target-to-background ratio and thereby making lesion detection more conspicuous. 
In the past few years, a number of investigational PSMA-targeted small molecules have been 
synthesized and labeled with various radioisotopes to be tested for use as imaging agents for 
prostate cancer: 
• 
 A single photon emission computed tomography (SPECT) agent, 99mTc-MIP-l 404, has 
completed phase 3 testing for the detection of clinically significant prostate cancer in 
patients with low grade (per biopsy) disease [48, 49]. 
• 
PET imaging agents, such as 124I-MIP-1095, 18F-DCFCBC, 18F-DCFPyL, and 68Ga- 
HBED-CC, have also generated much interest for their potential use in detecting 
localized and metastatic prostate cancer. 
68Ga-HBED-CC (68Ga-PSMA) has been broadly studied in the clinical setting at academic centers. 
In a retrospective analysis of patients with high-risk localized disease prior to radical 
prostatectomy, 68Ga-PSMA PET/CT imaging showed a sensitivity of approximately 93% for 
intraprostatic lesions and 33% for regional lymph node metastases. Specificity and positive 
predictive value (PPV) for lymph nodes were 100%, 100% and 69%, respectively [50]. A 
retrospective evaluation of data from 68Ga-PSMA PET/CT imaging in patients with biochemical 
recurrence of prostate cancer showed high detection rates, even in patients with low (0.2 to 0.5 
ng/mL) PSA (58%) [51]. 
 
Studies have also been conducted to compare 68Ga-PSMA PET/CT and 18F-choline PET/CT 
(which targets the choline transporter, not PSMA) imaging in prostate cancer: In patients with 
recurrent prostate cancer scheduled to undergo salvage lymphadenectomy (thus providing 
histopathology as the truth standard), 68Ga-PSMA PET/CT showed better performance than 18F- 
choline PET/CT with a significantly higher negative predictive value (NPV) and accuracy for the 


19 
 
detection of locoregional recurrent and/or metastatic lesions prior to salvage lymphadenectomy, 
with sensitivity of 71% vs 87%, specificity of 87% vs. 93%, and accuracy of 83% vs 92%, 
respectively [52]. In patients with biochemical recurrence of prostate cancer with a negative [18F]- 
choline PET/CT, 68Ga-PSMA-PET/CT identified sites ofrecurrent disease in 43.8% of the patients 
with negative F-choline PET/CT scans [53]. 
Another study was conducted to compare the detection rates of two PSMA-targeted PET agents, 
18F-DCFPyL and 68Ga-PSMA, side-by-side in patients with recurrent prostate cancer [54]. The 
results showed that 18F-DCFPyL PET/CT provided high image quality and visualized small 
prostate lesions with excellent sensitivity, similar to 68Ga-PSMA. 
 
F-18 tracers in general offer important advantages over Ga-68 tracers, including higher production 
capacity from the use of a cyclotron as opposed to depending on the supply from Gallium 
generators, and higher image resolution due to the intrinsic physical properties of F-18 (lower 
positron emission energy compared to Ga-68). Thus, 18F-DCFPyL PET/CT may represent a 
promising alternative to 68Ga-PSMA PET/CT for imaging prostate cancer. 
 
Progenies is completing the clinical development of PyL with the intention of seeking regulatory 
approval of PyL for the detection of prostate cancer. 
 
1.4 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT 
18F-DCFPyL Injection is a radiolabeled small molecule that binds to the extracellular domain of 
prostate-specific membrane antigen (PSMA) with high affinity. PSMA is a transmembrane 
glycoprotein expressed by virtually all prostate cancers, and its expression is further increased in 
metastatic and hormone-refractory prostate carcinomas, which makes it a useful target for 
developing agents for the diagnosis and staging of prostate cancer. The nonclinical studies 
conducted with DCFPyL and 18F-DCFPyL included biochemical activity, biodistribution in 
xenograft mice, small animal PET imaging, and a single dose IV toxicology study in rats. Data 
from enzyme inhibition assay showed that DCFPyL binds competitively to PSMA expressing 
LNCaP cells with a Ki of I. I nM. Studies in PSMA positive tumor bearing nude mice 
demonstrated significant tumor uptake and retention, coupled with a rapid clearance from non- 
target organs to provide support for the further development of 
18F-DCFPyL as a 
radiopharmaceutical for detection and localization prostate cancer in man. 
Results of a I4-day single dose rat toxicology study with DCFPyL showed a NOAEL of 0.5 mg/kg, 
the highest dose tested. The maximum human mass dose of DCFPyL is 4 µg; which indicates a 
safety margin of> 1200-fold the human equivalent dose. Several investigator-initiated clinical 
studies with 18F-DCFPyL Injection have been conducted at JHU under IND 12I,064. Safety and 
efficacy data are available from two of these studies (JI 418: a first in human, phase 1/2 study in 
men with clinically localized high to very high-risk prostate cancer, and 11545: a phase 2 study in 
men with an elevated PSA > 0.2 ng/mL following radical prostatectomy with pelvic 


20 
 
lymphadenectomy). These data demonstrate that PET imaging with 18F-DCFPyL Injection at doses 
averaging 9 ± 1 mCi per injection is overall feasible and safe. Biodistribution following 
administration of I8FDCFPyL Injection and optimal imaging time point were determined and 
radiation dose used was within limit for diagnostic radiotracers for PET. 
Physiologic accumulation of I8F-DCFPyL was found to correspond to the distribution of PSMA 
expressing organs. Accumulation in primary tumor and metastatic lesions was very high, 
suggesting that I8F-DCFPyL Injection can be used to detect residual tumor as well as regional or 
distant metastases with high sensitivity and specificity. Sensitivity and specificity with 18F- 
DCFPyL PET/CT in patients with at least localized intermediate risk prostate cancer who have 
undergone RP with lymphadenectomy was comparable to published 68Ga-PSMA imaging data 
[50].50,57 Thus, results further suggest that 18FDCFPyL PET/CT demonstrates efficacy in 
preoperative staging of patients with high-risk prostate cancer. Safety results from all JHU studies 
have shown that 18F-DCFPyL Injection is well tolerated, with no reported serious adverse events 
in any of the studies. Progenies initiated the "OSPREY" phase 2/3 study (PyL2301) under a new, 
separate IND to investigate the safety and efficacy of PyL imaging in patients with prostate cancer 
in November 2016. 
PyL2301 is a multi-center, open-label study entitled, PrOspective Phase 2/3 Multi-Center Study 
of 18F-DCFPyL PET/CT Imaging in Patients with PRostate Cancer: Examination of Diagnostic 
AccuracY (OSPREY; NCT02981368). The study completed in September 2018; a total of 385 
subjects with prostate cancer received a dose of 18F-DCFPyL Injection in PyL2301. A total of 81 
treatment-emergent adverse events (TEAEs) were reported in 51 (13.2%) subjects. A total of 5 
subjects (1.3%) experienced TEAE(s) that were National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) 2: Grade 3 in severity; all were Grade 3 and none were 
more severe. Fatigue, dysgeusia, and headache were the only TEAEs that occurred in 1% or more 
of dosed subjects. 
Seven treatment emergent serious adverse events (SAEs) were reported within the protocol- 
specified period. All seven SAEs were assessed as unrelated to study drug. There were no deaths 
or AEs that led to study discontinuation. A phase 3 study, PyL3301, entitled, "A Phase 3, Multi- 
center, Open-label Study to Assess the Diagnostic Performance and Clinical Impact of 18F- 
DCFPyL PET/CT Imaging Results in Men with Suspected Recurrence of Prostate Cancer" 
(CONDOR; NCT03739684) was initiated in November 2018. Suspected recurrence is based on 
rising PSA after definitive therapy despite negative or equivocal findings for prostate cancer on 
standard of care baseline imaging. The study is planned to be conducted in 15 sites in the US and 
Canada. 
 
1.5 
RESULTS OF NONCLINICAL STUDIES 
A description of the use ofDCFPyL in non-clinical studies can also be found in the Investigator's 
Brochure. 


21 
 
The nonclinical studies conducted with DCFPyL and 18F-DCFPyL included biochemical 
activity, biodistribution in xenograft mice, small animal PET imaging, and a single dose IV 
toxicology study in rats. All of these studies were submitted by JHU to FDA under IND 121,064. 
1.5.1 
Summary of Pharmacology Studies 
The biochemical activity ofDCFPyL was determined in an enzyme-inhibition assay using lysates 
of LNCaP cells in the presence of 4 µmol/L NAAG and DCFPyL (0.01-100 mmol/L) at 37°C 
for two hours. The amount of released glutamate was measured by incubating with a working 
solution of the Amplex Red glutamic acid kit at 37°C for 30 minutes. Enzyme inhibitory 
constants (Ki values) were generated using the Cheng-Prusoff conversion. DCFPyL potently 
inhibited PSMA's NAAGase activity with a Ki of 1.1 ± 0.1 nM. 
A PET imaging study was conducted in a single NOD-SCID mouse implanted with PSMA- 
positive PC3 PIP and PSMA-negative PC3 flu xenografts. The animal was anesthetized and 
placed in the prone position on the gantry of a small animal PET scanner and injected 
intravenously with 0.38 mCi 18F-DCFPyL in 200 mL of PBS. The images were then acquired as 
a sequence of successive whole-body images in 2 bed positions. 
As shown in Figure 1, PSMA-positive PC3 PIP (arrow) and PSMA-negative PC3 flu (dotted 
oval) tumors were present in subcutaneous tissues posterior to opposite forearms, as indicated 
(kid = kidneys, bl= bladder). Intense radiochemical uptake was seen only in the kidneys and 
PSMA-positive PC3 PIP tumor, while no uptake was noted in PSMA-negative PC3 flu tumors. 
The renal uptake was partly due to specific binding of the radiotracer to proximal renal tubules 
and partly to excretion of this hydrophilic compound. By 3.5 h after injection, only the PSMA- 
positive tumor was visible with no radiochemical background in liver gastrointestinal tract. 
 
 
Figure 1: Time Course of Radiochemical Uptake Following 18FDCFPyL Injection in 
Xenograft Mouse 
 
kid= kidneys, bl= urinary bladder [55]. 
 
1.5.2 
Summary of Pharmacokinetics Studies 
PSMA-positive PC3 PIP and PSMA-negative PC3 flu xenograft-bearing SCID mice were injected 
via the tail vein with 100 mCi of 18F-DCFPyL. Mice (4 per group) were sacrificed at 30, 60, 120, 


22 
 
 
o min 
min 
 
 min 
and 240 minutes post injection, organ and tissues were harvested, weighed and the tissue 
radioactivity was measured with an automated y-counter. The ¾ID/g was calculated by 
comparison with samples of a standard dilution of the initial dose. All measurements were 
corrected for decay. The resulting ¾ID/g values are listed in Table 2. 18F-DCFPyL showed clear 
PSMA-dependent uptake within a PSMA-positive PC3 PIP xenograft mouse model, reaching a 
value of 46.7 ± 5.8%ID/g at 30 minutes post injection, which decreased by only about 10% over 
the ensuing 4 hours. At 60 minutes post injection the kidney, liver, and spleen displayed the highest 
uptake. 
 
Rapid clearance from the kidneys was shown, decreasing from 74.1 ± 6.6%ID/g at 30 minutes to 
7.4 ± 0.9%ID/g at 4 hours. The relatively high values noted in the kidney are partially due to 
previously reported high expression of PSMA within proximal renal tubules. The ratio of uptake 
within PSMA-positive to PSMA-negative tumors ranged from 40:1 to more than 1000: 1 over the 
four-hour time period of the study. A possible explanation for the increased tumor uptake of 18F- 
DCFPyL over time could be due to ligand-mediated PSMA internalization within tumor cells. Less 
retention in kidney relative to tumor over time could be due to a lower degree of internalization in 
this tissue. Relatively low bone uptake of radioactivity(< 1% ID/g at all time points) suggests little 
metabolic de-fluorination of 18F-DCFPyL in mice. 
 
Table 2: Biodistribution of 18F-DCFPyL in Tumor-bearing Mice (mean± SD %1D/g [n = 4]) 
 
 
Blood 
1.53 ± 0.19 
.24 ± 0.05 
.43 ± 0.37 
 .03 ± 0.01 
art 
0.68 ± 0.07 
0.20 ± 0.11 
0.06 ± 0.01 
0.02 ± 0.00 
Lung 
1.91±0.47 
0.55±0.17 
.18 ± 0.02 
 .06 ± 0.00 
1 er 
3.88 ± 0.74 
2.87 ± 0.92 
2.14 ± 0.11 
1.80 ± 0.39 
Stomach 
1.50± 1.12 
0.35 ± 0.34 
.08 ± 0.03 
 .02 ± 0.00 
Pancreas 
1.02 ± 0.53 
0.26 ± 0.13 
0.08 ± 0.00 
0.03 ± 0.01 
Spleen 
7.59 ± 3.56 
2.70 ± 1.28 
.69 ± 0.11 
0.23 ± 0.09 
Kidney 
.1 ± 6.6 
42.3 ± 19.0 
15.7 ± 3.3 
7.42 ± 0.89 
 
0.39 ± 0.05 
.67 ± 0.92 
.04 ± 0.00 
0.05 ± 0.05 
Bone 
.82±0.16 
0.42 ± 0.15 
0.33 ± 0.08 
 .43 ± 0.06 
 Intest. 
0.79 ± 0.11 
.31 ± 0.12 
.11 ± 0.07 
0.05 ± 0.01 
Lrg. Intest. 
.73 ± 0.04 
0.40 ± 0.17 
0.12 ± 0.05 
0.06 ± 0.01 
dder (empty) 
18.6± 18.1 
.88 ± 4.92 
.44 ± 4.42 
1.54 ± 1.79 
PSMA+PIP 
46.7 ± 5.8 
44.2 ± 9.7 
39.4 ± 5.4 
36.6 ± 4.3 
SMA-flu 
11.17 ± 0.41 
.36 ± 0.14 
.11 ± 0.02 
 .03 ± 0.01 


23 
 
1.5.3 
Determination of Radiation Dose Estimates in Humans 
Prior to first in-human exposure, the human dosimetry values were obtained using the mouse 
biodistribution data (Table 2 above). The mouse organ activity concentrations in %ID/g were 
converted to the human %ID/organ by setting the ratio of organ %ID/g to whole-body %ID/gin 
the mouse equal to that in humans and then solving for the human %ID/organ; the adult male 
phantom organ masses listed in the OLINDA/EXM 1.0 were used for the conversion. The time- 
activity curves were fitted using a monoexponential function. Table 3 below lists target human 
organ absorbed doses. The organ with the highest mean absorbed dose per unit administered 
activity was the urinary bladder wall, 0.15 mGy/MBq, followed by the kidneys at 0.05 mGy/MBq. 
Based on the dosimetry results, 9 mCi (331 MBq) could be administered without exceeding the 50 
mGy critical organ dose limit (urinary bladder wall in this case), as specified in CFR 21, part 361 
for a single administration of radioactive material for research use. 
Table 3: Estimated Human Organ Absorbed Dose 
 
Target organ 
Absorbed dose 
(mGy/MBq) 
Adrenals 
6.46 E-03 
Brain 
.84 E-03 
Breasts 
3.97 E-03 
Gallbladder wall 
6.48 E-03 
Lower large intestine wall 
9.40 E-03 
Small intestine 
7.53 E-03 
Stomach wall 
5.27 E-03 
Upper large intestine wall 
6.67 E-03 
Heart wall 
3.26 E-03 
Kidneys 
.81 E-02 
Liver 
7.38 E-03 
Lungs 
3.01 E-03 
Muscle 
3.95 E-03 
Ovaries 
9.06 E-03 
Pancreas 
.38 E-03 
Red marrow 
5.35 E-03 
Osteogenic cells 
7.59 E-03 
Skin 
3.84 E-03 
Spleen 
6.57 E-03 
Testes 
7.06 E-03 


24 
 
Thymus 
.43 E-03 
Thyroid 
.45 E-03 
Urinary bladder wall 
1.51 E-01 
Uterus 
1.45 E-02 
Total body 
5.71 E-03 
Effective dose equivalent (mSv/MBq) 
1.80 E-02 
Effective dose (mSv/MBq) 
1.36 E-02 
 
1.5.4 
Toxicology 
1.5.4.1 
Single-dose Toxicity Studies 
A 14-day study was conducted to determine toxicity of DCFPyL from a single intravenous (IV) 
dose in Sprague Dawley Rats. The purpose of this OLP-compliant study was to evaluate the 
toxicity of DCFPyL on days 3 and 15 following a single intravenous dose in rats. Male and female 
Sprague Dawley rats were assigned to six groups (N=5/gender/group) and dosed intravenously on 
day 1 with 0.1 or 0.5 mg/kg DCFPyL or the vehicle control. Assessment of toxicity was based on 
mortality, clinical signs, body weight, body weight changes, and clinical and anatomic pathology. 
All rats generally gained weight and no test article-related alterations in body weight or body 
weight change were noted during the study. AU rats survived to the scheduled termination and 
remained bright, alert and responsive during the course of this study. 
For clinical chemistry, hematology and coagulation samples, there were no treatment-related 
differences noted and there were no statistical differences between the groups at Study Day 3 or 
15. No statistically significant or treatment-related differences were noted in organ weight data at 
Study Day 3 or 15. Microscopic findings in the Study Day 3 and Day 15 rats were considered 
incidental and not directly related to the test article. The test article, DCFPyL, at 0.5 mg/kg had no 
adverse effects in any of the tissues examined. 
In conclusion, under the conditions of this study, there were no treatment related findings in 
Sprague Dawley rats three or fifteen days after a single intravenous dose ofDCFPyL at 0.1 mg/kg 
and 0.5 mg/kg. The maximum human mass dose of DCFPyL is 4 micrograms. Using the 
appropriate scaling factor for conversion of rat doses to human equivalent doses (HED) based on 
body surface area (x 0.16), the safety margins in humans is> 1200-fold HED. 
 
 
1.6 
RESULTS OF CLINICAL STUDIES 
A description of the use of 18F-DCFPyL in clinical studies can also be found in the Investigator's 
Brochure. 


25 
 
1.6.1 
Previous Human Experience 
Several investigator-initiated clinical studies with 18F-DCFPyL Injection in prostate cancer, as well 
as non-prostate cancer, have been conducted at JHU under IND 121,064. Two of the studies in 
prostate cancer (11418 and 11545) are completed and have been published. Progenies initiated the 
"OSPREY" (PyL2301) study under a new, separate IND to investigate the safety and efficacy of 
PyL imaging in patients with prostate cancer in November 2016. The study completed in 
September 2018. 
These studies are summarized in Table 4 below. 
Table 4: 18F-DCFPyL Studies: Progenies Sponsored and Published Studies from Johns 
Hopkins University (JHU) 
 
Study 
Title 
Patient Population 
#  Patients 
Dosed 
11418 
Study  of  18F-DCFPyL,  a 
Second 
Generation 
Low- 
molecular Weight PSMA- 
based PET radiotracer, m 
Patients   with   Advanced 
Prostate Cancer 
Metastatic 
PCa 
Localized 
PCa 
N=l0 
N=28 
11545 
Pilot study of 18F-DCFPyL 
in the Evaluation of Men 
with 
an 
Elevated 
PSA 
Following 
Radical Prostatectomy 
Recurrent PCa  and 
PSA Persistence 
N=50 
PyL2301 
(OSPRE) 
A  Prospective  Phase  2/3 
Multi- center study of 18F- 
DCFPyL PET/CT imaging in 
Patients 
with 
Prostate 
Cancer: 
Examination 
of 
Diagnostic 
Accuracy (OSPREY) 
At least high-risk 
PCa 
(Cohort A); recurrent or 
metastatic PCa (Cohort B) 
N=385 (268 
Cohort A; 117 
Cohort B) 
Safety and efficacy data from these studies (11418, 11545, and OSPREY) are discussed below. 
 
1.6.1.1 
Study J1418: Study 18F-DCFPyL a Second Generation Low-molecular Weight 
PSMA based PET Radiotracer, in Patients with Prostate Cancer 
This was a first-in-human, open-label, single-arm, single-site phase 1/2 study. 
The first part of this study (Phase 1) was designed to evaluate the radiation dosimetry, 
biodistribution, metabolism, and safety of9 mCi (331 MBq) 18F-DCFPyL Injection with PET/CT 
imaging in 10 men with clinically progressive metastatic prostate cancer post local therapy 


26 
 
(prostatectomy, external beam radiation therapy, or brachytherapy of the prostate). To assess 
pharmacokinetics, metabolism, and excretion of 18F-DCFPyL Injection, blood samples were 
obtained from the vein contralateral to the site of injection for evaluation at three time points: after 
20 minutes post-injection, after 90 minutes post-injection, and at the completion of PET scanning 
(150 minutes post-injection). Urinary excretion was calculated at approximately 110 and 160 min 
post-injection. 
Once preliminary safety and tolerability were established, the second, currently ongoing, phase 2 
part of the study commenced. The objective of phase 2 is to evaluate the utility of 18F-DCFPyL 
PET/CT imaging to detect areas oflocal, nodal and/or distant prostate cancer in up to 25 men with 
clinically-localized high to very-high risk prostate cancer as defined by the National 
Comprehensive Cancer Network (NCCN) (clinical T stage 2: T3a, Gleason sum 2: 8, PSA > 20 
ng/mL) (NCCN high-to-very-high-risk: clinical stage 2: T2/3 or Gleason sum 2: 7 or PSA 2: 10 
ng/mL) who are scheduled to undergo radical prostatectomy with pelvic lymphadenectomy. 
Histopathology will be compared to 18F-DCFPyL imaging for analysis of diagnostic accuracy. A 
single IV bolus injection of 9 mCi (333 MBq) or less of 18F-DCFPyL Injection was administered 
to all enrolled subjects. Results for the phase 1 portion of the study are summarized below for 9 of 
the 10 patients imaged for whom dosimetry data are available. 
No SAEs were reported. There were three adverse events reported in two subjects, all of which 
were considered not related to study drug. One subject reported two Grade 1 adverse events 
(CTCAE v4.0) of headache and epistaxis. Another subject experienced Grade 1 thrombocytopenia 
upon clinical lab safety assessment during the post-imaging follow-up visit, which was attributed 
to the start of prostate cancer therapy. 
The time course of blood radioactivity is presented in Table 5 for seven evaluable subjects and 
demonstrates a rapid decline oflevels to approximately 50% of the initial exposure by 150 minutes. 
 
 
Table 5: 
Blood Radioactivity Concentrations (nCi/mL) in Study J1418, Phase 1 
 
Time point 
(min) 
3 
 
Patient 
Number 
5 
 
7 
8 
 
Mean 
SD 
120 
33.13 
5.02 
12.08 
23.19 
27.14 
28.73 
26.54 22.26 
110.03 
190 
22.28 
2.65 
10.21 
16.95 
16.68 
18.10 
17.71 14.94 
16.48 
1150 
16.31 
2.21 
5.69 
13.88 
12.64 
13.94 
14.70 11.34 
 6 


27 
 
The urinary excretion expressed as % injected dose per subject is listed in Table 6 below: 
 
Table 6: 
Urinary Excretion(% Injected Dose per Subject) in Study J1418, Phase 1 
 
Time point 
(min) 
3 
 
Patient 
Number 
Mean 
5 
6 
7 
 
9 
SD 
0-110 
5.86 
1.62 
5.70 
10.63 
16.54 
25.26 
14.09 111.39 
8.01 
110-160 
3.72 
0.87 
1.36 
5.12 
5.49 
9.56 
6.14 
.61 
2.98 
0-160 
9.58 
2.50 
7.06 
15.75 
22.03 
34.82 
20.22 115.99 
10.89 
The metabolic profiles in plasma were determined in three patients at 20, 90 and 150 minutes post- 
injection. Analysis of plasma samples by high-performance liquid chromatography (HPLC) up to 
173 minutes post-injection demonstrated that all plasma activities were in the form of non- 
metabolized parent compound (Example provided in Figure 2). 
 
 
Figure 2: HPLC Curves of Plasma 18F-DCFPyL (Radioactivity) in One Subject at 173 min 
Post-injection Compared with the "Cold" Reference Standard DCFPyL (UV) 
 
 
In summary, following intravenous administration, a rapid washout of 18F-DCFPyL-associated 
activity from the blood pool and significant renal excretion with radiotracer accumulation in the 
bladder were observed. The only radioactive component detected in plasma samples was 
unchanged 18F-DCFPyL. Based on PET imaging, the radioactivity detected in the small intestine 
was associated solely with the intestinal wall, suggesting a lack of fecal excretion. 


28 
 
Physiologic accumulation and excretion of 18F-DCFPyL Injection was measured using serial 
PET/CT image data from nine patients and subsequently used to derive dosimetry calculations. 
Physiologic accumulation of 18F-DCFPyL Injection corresponded to the distribution of PSMA- 
expressing organs and excretion. Outside of the tumor, the longest residence time in normal organs 
was observed in kidneys, liver, muscle and bladder (Table 7). 
Table 7: Mean Tissue/Organ Residence Times of 18F-DCFPyL in Nine Patients (Study 
J1418) 
Organ/Tissue 
Res. Time (Bq-h)/Bq 
Adrenals 
2.55E-04 
Brain 
5.26E-03 
Gallbladder Wall 
9.36E-04 
Lower large intestine wall 
3.48E-03 
Stomach Wall 
1.03E-02 
Upper large intestine wall 
2.52E-02 
Heart Wall 
4.32E-03 
Kidneys 
2.06E-01 
Liver 
2.59E-01 
Lungs 
3.92E-02 
Muscle 
2.88E-01 
Pancreas 
2.90E-03 
Red Marrow 
5.l0E-02 
Spleen 
1.95E-02 
Testes 
1.30E-03 
Thyroid 
2.24E-04 
Lens 
2.24E-04 
Lacrimal Glands 
2.60E-04 
Parotid Glands 
1.94E-02 
Submandibular Glands 
6.63E-03 
Total Body 
1.91E+00 
Remainder of Body 
9.61E-01 
Heart content 
2.12E-02 
The radiation absorbed doses (Table 8) to radiosensitive organs such as red marrow and gonads 
were low (0.01 mGy/MBq or less). Highest radiation exposure was observed in kidneys (0.0896 
mGy/MBq), followed by the urinary bladder wall (0.0873 mGy/MBq), parotid glands (0.0495 
mGy/MBq), and liver (0.0420 mGy/MBq). PSMA-expressing tissues, including the lacrimal, 
salivary and parotid glands, exhibited moderate radiation absorbed doses (between 0.042 
mGy/MBq and 0.027 mGy/MBq). The effective dose from 18F-DCFPyL was calculated to be 
0.0169 mSv/MBq or 5.5 mGy (0.55 rem) for an injected dose of 9 mCi (333 MBq), which is less 
than other commonly used tracers for oncologic imaging such as 18F-FDG. 


29 
 
Table 8: Mean Absorbed Dose of 18F-DCFPyL in Nine Patients (Study Jl418) 
 
Organ 
Mean  Absorbed 
Dose 
(mGy/MBq) 
SD 
Adrenals 
3.l 7E-02 
8.04E-03 
Brain 
2.33E-03 
4.58E-04 
Breasts 
4.87E-03 
l.05E-03 
Gallbladder Wall 
1.46E-02 
2.19E-03 
LLIWall 
1.07E-02 
2.23E-03 
Small Intestine 
9.43E-03 
1.82E-03 
Stomach Wall 
1.30E-02 
6.75E-03 
ULI Wall 
1.77E-02 
5.40E-03 
Heart Wall 
1.47E-02 
2.98E-03 
Kidneys 
8.96E-02 
3.09E-02 
Liver 
4.20E-02 
1.02E-02 
Lungs 
1.13E-02 
2.47E-03 
Muscle 
6.52E-03 
9.18E-04 
Ovaries 
9.26E-03 
1.77E-03 
Pancreas 
2.65E-02 
9.31E-03 
Red Marrow 
9.94E-03 
1.68E-03 
Osteogenic Cells 
9.70E-03 
1.83E-03 
Skin 
4.27E-03 
9.24E-04 
Spleen 
2.15E-02 
3.85E-03 
Testes 
9.25E-03 
2.39E-03 
Thymus 
5.97E-03 
l.23E-03 
Thyroid 
1.00E-02 
2.51E-03 
Urinary Bladder Wall 
8.73E-02 
3.20E-02 
Uterus 
1.19E-02 
2.44E-03 
Lens 
1.16E-03 
3.23E-04 
Lacrimal Glands 
2.74E-02 
1.45E-02 
Parotid Glands 
4.95E-02 
2.90E-02 
Submandibular Glands 
4.18E-02 
2.99E-02 
Total Body 
7.65E-03 
1.13E-03 
Effective Dose (mSv/MBq) 
1.69E-02 
l.82E-03 
Quantitative uptake of 18F-DCFPyL in abnormal foci, demonstrating the greatest uptake in terms 
of maximum standardized uptake value (SUVmax), were measured across all available PET/CT 
time points and used to determine the optimal imaging time point following injection. Two 
experienced nuclear medicine readers identified sites of abnormal uptake in a consensus read. 


30 
 
Most lesions were visually evident at the earliest time points and uptake was observed to increase 
with time while blood pool activity decreased. At approximately 1 and 2 hours, respectively, the 
highest uptake and lowest background activity were observed suggesting that PET/CT imaging of 
18F-DCFPyL as early as one hour post-injection will allow for the full extent of lesions to be 
evaluated in most patients. 
In summary, the results from the Phase 1 portion of the study showed that PET imaging with 18F- 
DCFPyL in patients with prostate cancer is feasible and safe at a radiation dose that is within 
acceptable limits for diagnostic PET radiotracers [56]. 
In the Phase 2 portion of the Jl418 study, the diagnostic performance of 18F-DCFPyL Injection 
PET/CT imaging to detect areas oflocal, nodal and/or distant prostate cancer spread was assessed 
in 25 patients with clinically localized intermediate or higher risk prostate cancer (clinical stage 2: 
T2b or GS 2: 7 or PSA 2: 10 ng/mL) prior to undergoing radical prostatectomy with pelvic lymph 
node dissection (PLND). Areas of intra- and extraprostatic tumor spread identified with I8F- 
DCFPyL Injection were compared with postop histopathology as the truth standard. 
All 25 subjects included in the analysis had at least high-risk PCa based on pre-surgery clinical, 
laboratory assessments and biopsy-based histology. 18F-DCFPyL PET/CT imaging was done 1-7 
days before surgery. The analysis was performed at the subject level as well as at the individual 
right, left side lymph node packet levels (n = 50). Eighteen (72%) subjects had Gleason score 4 + 
5 = 9 or 5 + 4 = 9, and 13 (52%) subjects were pT3a and 7 (28%) were pT3b based on whole gland 
histopathology, and seven (28%) subjects were found to have harbored one or more PCa- positive 
lymph nodes. A median of 13 (range 4-45) lymph nodes was removed at the time of surgery. 
Notably, two subjects had bilateral lymph node involvement, resulting in a total of 9 positive 
lymph packets for the entire study cohort. Positive lymph nodes were typically small, with a 
median diameter of 3 mm (range 1-12). 
Following independent image reads and adjudications, 7 (28%) subjects were confirmed to have 
2: 1 site of focal radiotracer within the pelvis consistent with N1 disease. This resulted in a 
sensitivity and specificity of 71.4% (95% CI 29.0-96.3) and 88.9% (65.3-98.6), respectively, for 
the presence or absence of metastatic prostate cancer. Similar results were found in the packet- 
level analysis with a sensitivity of 66.7% (29.9-92.5) and a specificity of 92.7% (80.1-98.5), in 
good agreement with published 68Ga PSMA imaging data [50]. Additionally, the readers 
determined that 3 (12%) subjects had PET/CT findings consistent with Mla disease (none had 
Mlb or Mlc). All 3 of these patients had a detectable PSA level within 6 months of surgery. 
In summary, results from the phase 2 portion of the study suggest that 18F-DCFPyL PET/CT may 
improve preoperative staging in patients with high risk prostate cancer [57]. 
1.6.1.2 
Study J1545: Pilot Study of 18F-DCFPyL PET/CT in the Evaluation of Men with 
an Elevated PSA Following Radical Prostatectomy 
This was an open-label, single-arm, single-site phase 2 study in up to 50 subjects with an elevated 
PSA (2: 0.2 ng/mL) following radical prostatectomy. This study broadly includes men with PSA 


31 
 
persistence and recurrent prostate cancer after surgery and aims to: 1) evaluate the safety of 18F- 
DCFPyL Injection; 2) describe the number and location of putative sites of metastatic disease as 
determined by 18F-DCFPyL PET/CT; and 3) correlate findings on 18F-DCFPyL PET/CT with 
conventional imaging (bone scan and cross-sectional imaging). 
Treatment response by 18F-DCFPyL PET/CT following six months of standard of care therapy was 
also explored in select patients. A single intravenous bolus injection of 9 mCi (333 MBq) or less 
of 18F-DCFPyL was administered. Approximately 1-2 hours after the administration of 18F- 
DCFPyL, patients voided and whole-body CT and PET scans were acquired from the mid-thigh to 
the vertex of the skull. Recruitment for this study has ended, but the patients remain in follow-up 
and final analysis of the data has not been completed. No SAEs were reported. 
1.6.1.3 
Case Report from Study J1545 - Detecting Metastatic Lesions Compared to 
Bone Scan 
Rowe et al. [58] published the case of a 45-year-old patient who had first presented approximately 
two years before the time of PET imaging with an elevated PSA level of 39 ng/mL and suspected 
clinically localized prostate cancer (biopsy GS 5+4). After radical prostatectomy and pelvic lymph 
node resection, his PSA remained high (10.5 ng/mL), and he received treatment with leuprolide 
and docetaxel, resulting in a PSA of 1.0 ng/mL. The patient was then enrolled into a series of 
clinical trials and received, in succession, sipuleucel-T, anti-PD-LI therapy, and enzalutamide, 
with persistent PSA elevations as high as 15.6 ng/mL but decreased to 1.0 ng/mL while receiving 
enzalutamide. At this point in his treatment course, the patient was imaged with 99mTc-MDP bone 
scan, Na 18F PET/CT, and 18F-DCFPyL PET/CT. All three imaging modalities revealed extensive 
skeletal metastases, with the highest number of bone lesions detected with 18F-DCFPyL PET/CT 
imaging. In addition to bone metastasis, 18F-DCFPyL PET/CT also revealed numerous soft tissue 
lesions (Figure 3). 


32 
 
Figure 3: Anterior Projection Whole-body Planar 99mTc-MDP Bone Scan, Anterior 
View of Maximum Intensity Projection (MIP) Using Na 18F PET and 18F-DCFPyL PET 
with Abnormal Lymph Node Uptake Masked in Red 
 
 
 
Lesions seen: 
12 
39 
87 
87 
1.6.1.4 
 PyL2301: A Prospective Phase 2/3 Multi-center study of 18F-DCFPyL PET/CT 
imaging in Patients with Prostate Cancer: Examination of Diagnostic Accuracy 
(OSPREY) 
PyL2301 was an open-label, non-randomized, phase 2/3, multicenter study designed to evaluate 
the safety and diagnostic performance of 18F-DCFPyL PET/CT imaging to determine the presence 
or absence of metastatic prostate cancer in subjects with at least high-risk prostate cancer who are 
planned for radical prostatectomy [RP] with pelvic lymph node dissection [PLND], cohort A), and 
subjects with radiologic evidence of local recurrence or new or progressive metastatic disease 
(cohort B). 18F-DCFPyL PET/CT scans were centrally reviewed by three, independent readers 
blinded to all clinical and other imaging information. 18F-DCFPyL PET/CT results were compared 
to histopathology (from surgery or biopsy) as the reference standard. This study was conducted in 
10 sites in the United States and Canada. The study was completed in September 2018. 
1.6.1.5 
Efficacy Results 
Three central, blinded, and independent readers evaluated the 18F-DCFPyL PET/CT scans and 
histopathology served as the reference standard to which imaging findings were compared. In 
patients with at least high-risk PCa planned for RP+PLND (Cohort A), the sensitivity of 18F- 
DCFPyL PET/CT ranged among the three central readers from 30.6-41.9% (lower bound of 95% 
CI: 19.2-29.7%), with specificities ranging from 96.3-98.9% (lower bound of 95% CI: 93.6- 


33 
 
96.0%). Additionally, the PPV and NPV ranged from 78.1-90.5% and 81.4-83.8%, respectively. 
In patients with recurrent or metastatic PCa (Cohort B), sensitivity and PPV ranged from 92.9- 
98.6% (lower bound of95% CI: 84.0-91.6%) and 81.2-87.8%, respectively. 
1.6.1.6 
Safety Results 
A total of 385 subjects received a median dose of 9.14 (6.4-10.5) mCi of 18F-DCFPyL Injection in 
PyL2301. Overall, I8F-DCFPyL was safe and well-tolerated by all dosed subjects. A total of 81 
treatment-emergent adverse events (TEAEs) were reported in 51 (13.2%) subjects. A total of 5 
subjects (1.3%) experienced TEAE(s) that were 2: Grade 3 in severity; all were Grade 3 and no 
subjects experienced Grade 4 or 5 adverse events. The incidence ofTEAEs that occurred in 1% or 
more of subjects are presented in Table 9. 
 
Table 9: Incidence of Treatment-Emergent Adverse Events that occurred in 1% or more of 
subjects (N = 385)* 
I 
 
 
*Data as ofNovember 17, 2018 
Seven serious adverse events (SAEs) have been reported within the protocol-specified period in 
subjects who received any amount of I8F-DCFPyL. All of the SAEs were assessed as unrelated to 
study drug. A tabular summary is provided in Table 10. There were no deaths or AEs that led to 
study discontinuation. 
 
 
Table 10: Cumulative Tabulation of Serious Adverse Events (SAEs) in Subjects Who 
Received Any Amount of 18F-DCFPyL* 
 
Subject 
Number 
Age Preferred Term 
Verbatim Term 
Outcome 
Causality 
102-404 
76 
Hyperkalemia 
Hyperkalemia 
Resolved 
Not 
related 
104-412 
76 
Atrial fibrillation 
Atrial fibrillation 
withRVR 
Resolved 
with 
sequelae 
Not 
related 
Adverse Event by Preferred Term 
Subjects (N=385), n (%) 
Events, n 
Fatigue 
5 (1.3) 
5 
Dysgeusia 
10 (2.6) 
Headache 
9 (2.3) 
11 


34 
 
104-482 
62 
Spinal cord 
compression 
Pain secondary to 
spinal 
cord 
compress10n 
Resolved 
Not 
related 
104-485 
76 
Lower 
gastrointestinal 
hemorrhage 
Lower 
gastrointestinal 
hemorrhage 
Resolved 
with 
sequelae 
Not 
related 
200-406 
69 
Pyelonephritis acute 
Acute pyelonephritis 
Resolved 
Not 
related 
200-409 
59 
Coronary artery 
disease 
Cardiac ischemia 
Resolved 
with 
sequelae 
Not 
related 
102-112 
66 
Coronary artery 
disease 
CAD 
Resolved 
Not 
related 
*Data as of November 17, 2018 
 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE 
To determine the positive predictive value (PPV) of 18F-DCFPyL Positron Emission Tomography 
(PET) on a per-patient basis in men diagnosed with prostate cancer with increasing PSA levels. 
 
2.1.1 
Primary Endpoint 
Positive predictive value (PPV) of 18F-DCFPyL PET (per-patient): Number of true positives (TP) 
divided by number of TP plus number of false positives (FP) as detailed in Section 3.5.1. 
2.2 
SECONDARY OBJECTIVE 
To determine the PPV of 18F-DCFPyL PET on a per-region basis, specifically focusing on the 
prostate or prostate bed, pelvis, extra pelvis, and bones. 
2.2.1 
Secondary Endpoint 
Positive predictive value (PPV) of 18F-DCFPyL PET on a per-region basis as detailed in Section 
3.5.1. 


35 
 
3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN 
3.1.1 
Description 
This is an interventional, single group assignment, prospective non-randomized, open label Phase 
2 trial designed to evaluate the positive predictive value of 18F-DCFPyL PET imaging in men 
diagnosed with prostate cancer with increasing PSA levels. Eligible patients will undergo baseline 
assessments according to the Schedule of Study Activities in Appendix A. Approximately 300 
participants are planned for enrollment in this study. Patients will receive a single dose of 18F- 
DCFPyL PET and undergo a PET imaging study. 
 
The PET imaging maybe repeated at a later date if the biopsy of the lesion is negative and if the 
lesion is present on follow-up imaging. This is outlined in the Study Schematic in Appendix B. 
 
3.2 
SELECTION OF STUDY POPULATION 
3.2.1 
Inclusion Criteria 
To be eligible to participate in this trial, subjects must meet all of the following criteria: 
• Histologically confirmed diagnosis of prostate cancer 
• Biochemical recurrence was defined as a PSA of 0.2 or more ng/mL measured more than 
6 weeks after prostatectomy or a PSA of 2 or more ng/mL rise above nadir following 
radiation therapy (ASTRO Phoenix consensus definition) [59] 
• 
If PSA values are reported in double decimal points, it will be rounded to the nearest 
single value decimal point (e.g., 0.14 will be rounded to 0.1 and 0.15 -0.19 will be 
rounded to 0.2) 
• Age 2: 18 years of age 
• Eastern Cooperative Oncology Group (ECOG) performance status::; 2 (Kamofsky 2: 60%) 
• Ability to understand and willingness to sign a written informed consent document 
• Willing to comply with clinical trial instructions and requirements 
 
3.2.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
• 
History of another active malignancy within 3 years, other than basal cell and squamous 
cell carcinoma of the skin 
• 
Presence of prostate brachytherapy implants unless approved by the PI 
• 
Administration of another radioisotope within five physical half-lives of trial enrollment 
• 
Radiation or chemotherapy within 2 weeks prior to trial enrollment 
• 
Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 
• 
Serum total bilirubin > 3 times the upper limit of normal 


36 
 
• 
 Aspartate transaminase (AST) or alanine aminotransferase (ALT)> 5 times the upper limit 
of normal 
• 
Inadequate venous access 
• 
Claustrophobia or any other condition that would preclude PET imaging 
• 
Patients must not be receiving ADT except per criteria directly below. Patients who 
received in the past must have a serum testosterone that is recovered to at least 100 
ng/dL. 
• 
Patients who have been on ADT +/- novel hormonal agent (NHA) and developed 
M0CRPC. 
 
3.2.3 
Removal of Patients from Study 
3.2.3.1 Patient Withdrawal or Early Termination 
Patients could choose to discontinue from the study at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
Patients could be discontinued from the study for any of the following reasons: 
• 
Patient decides to withdraw from the study 
• 
Intercurrent illness that prevents imaging test 
• 
Unacceptable adverse event that may be directly related to the protocol intervention 
• 
General or specific changes in the patient's condition that render the patient unacceptable 
for an imaging test, in the judgment of the investigator 
• 
Does not meet inclusion/exclusion criteria 
• 
At the discretion of the Sponsor, if deemed appropriate, for any reason 
3.2.3.2 Planned Follow-up for Discontinued Patients 
Participants have the right to withdraw from the study at any time for any reason. A participant's 
withdrawal from the study will not jeopardize the relationship with their healthcare providers or 
affect their future care. This decision must be recorded in writing at the study site. 
Should a participant decide to withdraw, all efforts will be made to complete and report the 
protocol defined study observations as completely as possible and to determine the reason for 
withdrawal. 


37 
 
3.3 
INVESTIGATIONAL PRODUCT 
3.3.1 
Identity of Investigational Product: 18F-DCFPyL Injection 
 
 
18F-DCFPyL Injection is an 18-Fluorine-labeled small molecule that targets the extracellular 
domain ofPSMA. 18F-DCFPyL Injection is labeled with ['8F] fluorine that decays by positron (P+) 
emission to ['80] oxygen and has a half-life of 109.77 minutes. The appearance of the 18F-DCFPyL 
Injection drug product is clear and free of visible particulate matters with a pH of 4.5-7.5. 18F- 
DCFPyL Injection is a sterile, clear particle-free solution supplied at a specific activity of at least 
1000 mCi/µmol at the Time of Administration (TOA), and a radioactivity concentration (RAC) of 
1-90 mCi/mL at the Time of Calibration (TOC). The TOC is at the end of synthesis (EOS). The 
recommended dose of 18F-DCFPyL is 9 mCi in a volume of :S 10 mL administered intravenously 
in a single injection. The chemical mass dose of carrier DCFPyL is less than 4 µg. The dosage 
range will be between 7 - 9 mCi . 
 
3.3.2 
Packaging and Labeling 
Detailed information on the formulation, appearance preparation and labeling procedures can be 
found in the attached Investigator's Brochure and in the Package Insert provided by the 
manufacturer for the 18F-DCFPyL Injection. 
 
3.3.3 
Receiving, Storage, Dispensing, and Return 
3.3.3.1 
Receipt of Drug Supplies 
The 18F-DCFPyL Injection product contains radioactive material and should only be handled by 
personnel trained and experienced in the use of radioactive isotopes with proper shielding and 
monitoring. Receipt and use are limited to a facility licensed by the Federal or State office for 
Radioactive Substances. Therefore, following release of the final drug product by the cGMP- 
compliant PET production facility, each unit-dose of 18F-DCFPyL Injection for intravenous 
injection will be delivered to the PET nuclear medicine laboratory at the respective investigational 
site. 
3.3.3.2 
Storage and Handling 
Following receipt of the 18F-DCFPyL Injection product, qualified personnel will ensure that the 
study drug is delivered in good condition, inventoried, labeled, stored at room temperature, and 
administered by the labeled expiration time (10 hours from the EOS). 18F-DCFPyL Injection must 
not be diluted. The drug product contains radioactive material and should only be handled by 
personnel trained and experienced in the use of radioactive isotopes with proper shielding and 
monitoring. 


38 
 
3.3.3.3 
Dispensing of Study Drug 
The drug should be labeled and dispensed in compliance with the pharmacy manual, all regulatory 
agencies, and the investigator physician's prescription order. The 18F-DCFPyL dose will be 
measured by the qualified personnel in a dose calibrator prior to dispensing. Then, the syringe will 
be placed in a shielded carrier and administered as an intravenous injection. After the dose 
administration, the qualified personnel (nuclear medicine technologist) will re-assay the syringe 
for residual tracer activity. Measured radioactivity values and times of measurement will be 
documented, as well as the total injected volume. Regulatory agencies require the disposition of 
all investigational drugs received by each clinical site to be accurately accounted for. Information 
on drug disposition required by law consists of the date received, date dispensed, quantity 
dispensed, and the patient identification number to whom the drug was dispensed. 
3.3.4 
Administered Intervention 
The dispensed dose will be injected slowly by a qualified nuclear medicine technologist as an IV 
injection. A dose of 9 mCi (333 MBq) or less 18F-DCFPyL injection will be administered via an 
in-dwelling catheter placed in an antecubital vein or an equivalent venous access. The drug product 
contains radioactive material and should only be handled by personnel trained and experienced in 
the   use  of   radioactive   isotopes   with   proper   shielding   and   monitoring. 
 
3.3.5 
Selection of Dose in the Study 
The intervention is a PET scan with the radiolabeled PSMA ligand 18F-DCFPyL. Prior to the 
first-in-human study with PyL (Study Jl418) at JHU, human dosimetry was extrapolated 
from a preclinical biodistribution study in xenograft mice.[55] The mouse organ activity 
concentrations in ¾ID/g were converted to the human %ID/organ by setting the ratio of organ 
¾ID/g to whole-body ¾ID/gin the mouse equal to that in humans and then solving for the 
human %ID/organ. The adult male phantom organ masses listed in the OLINDA/EXM 1.0 
were used for the conversion. The human source organ time-activity curves were fitted using 
a monoexponential function. 
Because the biodistribution data were radioactive decay-corrected, only the biological 
removal constants were obtained from the curve fits, and the physical decay constant for F- 
18 was added in obtaining the time-integrated activity coefficients (TIAC). The source organ 
TIACs in MBq-h/MBq were entered in the OLINDA/EXM 1.0 for the dose calculations. The 
dynamic voiding bladder model was used to obtain the TIAC for the urinary bladder contents. 
The whole-body clearance half-life (obtained as the sum of sampled tissues, excluding the 
tumors) was used as the half-life to describe urinary bladder filling. All radioactivity was 
assumed to be eliminated via the urine. A one-hour voiding interval was assumed. 
The estimated human organ exposure values are presented in Table 3. The urinary bladder 
wall was projected to be the organ with the highest absorbed dose. To limit the radiation- 
absorbed dose to the urinary bladder in accordance with 21 Code of Federal Regulations 
(CFR) § 361.1 (:S 50 mGy), the highest human dose is estimated to be 8.95 mCi. As a result, 


39 
 
the first-in-human dose used at JHU for obtaining basic information regarding the 
metabolism (including kinetics, distribution, and localization) was determined to be :S 9 mCi. 
The 9 mCi administered dose of 18F-DCFPyL Injection is comparable to the radiation dose 
of other radiotracers used in oncology such as [18F]-FDG. 
 
3.3.6 
Selection and Timing of Dose for Each Subject 
This is an open-label study. All eligible patients will receive a single dose of the investigational 
agent. All patients will receive a single intravenous dose, 9 mCi (333 MBq) or less (range 
between 7 - 9 mCi) of 18F-DCFPyL Injection. 
 
3.3.7 
Procedures for Ensuring Subject Compliance 
This is an open-label study. All eligible patients will receive a single dose of the investigational 
agent; therefore, no compliance measures are required. 
 
3.3.8 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. All eligible patients will receive the investigational agent. 
 
3.3.9 
Investigational Product Accountability 
3.3.9.1 
Investigational Product Inventory Records 
The Investigator or designee will verify the contents of each shipment against the shipping 
documents. Verification of receipt of investigational product will be documented according to the 
PI's requirements. An investigational product accountability log will be provided to the site for 
use by the Investigator to maintain current and accurate inventory records (batch, expiry, and 
quantity) covering the receipt, dispensing and the destruction of all investigational product. 
3.3.9.2 
Return or Destruction of Investigational Product 
The Investigator is responsible for accounting for all unused study product and destroying all used 
study product containers in compliance with. At the conclusion of the study, or other situations as 
applicable (ex. site closure, IP expiry, etc.) the Investigator must agree to return or destroy all study 
materials as instructed by the package insert. Unused or residual waste should be disposed of as 
radioactive waste following the institution's standard operating procedures (SOPs) and/or 
applicable regulations or guidance. 


40 
 
3.3.10 
Blinding 
This study is a single-dose, open-label study. No blinding procedures will be used. No subjects 
will be blinded. 
 
 
3.4 
SCHEDULE OF STUDY ACTIVITIES 
The time the imaging test will be performed relative to dosing is shown in the Schedule of Study 
Activities (Appendix A). 
3.5 
ASSESSMENT OF INTERVENTION 
3.5.1 
Imaging Protocol and Follow up 
Patients will be intravenously injected with::::; 333 MBq (::::; 9 mCi) of radiotracer approximately 60 
minutes prior to image acquisition and will be imaged using the GE Discovery PET-CT scanner 
at UPMC Hillman Cancer Center, UPMC Magee-Women's Hospital, or UPMC Shadyside 
Hospital. The scanner will be operated in three-dimensional (3D) emission mode on CT 
attenuation correction as the case may be and images will be reconstructed with manufacturer- 
supplied ordered subset expectation maximization iterative methods without point-spread 
function. The field of view for 18F-DCFPyL PET scans will be vertex to mid-thigh. 
 
The PET images will be evaluated qualitatively by UPMC Hillman Cancer Center (HCC) 
nuclear medicine physicians. PET scans will be randomly assigned between five PET readers. 
Interpreters will have at least more than 5 years of PET interpretation and will interpret images. 
Double reading will be performed for all the PET scans. The readers will be provided with the 
recent PSA levels and the type of primary therapy (prostatectomy vs radiation therapy) but will 
be blinded to all other information. The report will indicate the localization of detected lesions 
either in the prostate bed, locoregional lymph nodes, distant lymph nodes, bones, and/or visceral 
organs. A scan will be deemed 'positive' if at least one lesion suggestive of disease recurrence is 
noted. Prostate lesions and lymph nodes will be considered positive if the uptake in those lesions 
exceeds blood pool activity. Bone lesions will be recorded as positive if the activity is higher 
than normal bone marrow uptake. 
The UPMC HCC nuclear medicine physicians have extensive experience in interpreting FDG- 
PET/CT scans including those performed with a variety of agents currently used in the research 
setting. Scans will be interpreted using HE AW 3.2 Volume Viewer software package. 
 
Visual interpretation: 
 
1. 
Lymph nodes will be deemed positive if the PET scan uptake is focal and greater than blood 
pool (adjacent or mediastinal blood pool). Pelvic lymph nodes will be subclassified 


41 
 
according to their localization as follows: R/L obturator, R/L external iliac, R/L internal iliac 
and other (total of 7 subgroups). 
2. 
Visceral lesions will be considered positive if the uptake is focal and greater than physiologic 
background activity of the involvement organ or the anatomic location. 
3. 
Bone lesions will be considered positive if the uptake is focal and greater than normal marrow 
uptake. 
4. 
Prostate bed and prostate lesions will be considered positive if uptake is focal and greater 
than background activity of the prostate. 
 
 
Follow-up imaging: 
 
A chart review will be performed at 3, 6, 9 and 12 months with a plan to communicate with the 
referring oncologist team regarding the plan for follow-up imaging with a CT, MRI and/or bone 
scan. If a follow-up imaging is not obtained by 12 months, then imaging will be requested. 
Interpretation of follow-up imaging will be performed by local read. The follow-up conventional 
imaging should be the same modality/modalities as the initial staging work-up to allow for 
reproducible and accurate comparisons. 
PET positive findings will be validated as true or false positive as outlined in more detail below. 
False negative 18F-DCFPyL PET findings cannot be determined as this would require biopsies of 
all PET negative lesions that are present on conventional imaging. 
18F-DCFPyL PET validation will be based on follow-up imaging: 
 
1. 
Lymph nodes will be assessed by change in size. PET positive lymph nodes will be 
considered: 
a. True positive: 
• 
If on follow-up imaging within 3-12 months, lymph nodes seen on CT or MRI 
scan decrease by more than 30% (for patients undergoing systemic treatment of 
focal therapy at this site) or increase by more than 20% in short axis diameter 
(with a minimum of 3 mm in change in size). 
• 
If patients with solitary lymph node regions show a decrease of PSA by greater 
than 50% after targeted treatment (i.e. external beam radiation) and the lymph 
nodes do not change in size (less than 30% decrease or less than 20% increase 
in short axis diameter). 
b. False positive: 
• 
If on follow-up imaging within 3-12 months, sites of initial 18F-DCFPyL PET 
positive lymph node lesions seen on CT or MRI scan decrease by more than 
30% without systemic therapy or focal therapy at this site. 


42 
 
• 
If PET positive lymph node lesions do not meet the criteria for above false 
positive or true positive findings. 
 
2. 
Visceral lesions (non-lymph node soft tissue or organ) will be assessed by change in size. 
PET positive visceral lesions will be considered: 
a. True positive: 
• 
If on follow-up imaging within 3-12 months, visceral lesions seen on CT or 
MRI scan decrease by 30% (for patients undergoing systemic treatment of focal 
therapy at this site) or increase by 20% in largest diameter. 
• 
If patients with solitary visceral metastasis show a decrease of PSA by greater 
than 50% after targeted treatment (i.e. external beam radiation) and lesions do 
not change in size (less than 30% decrease or 20% increase in largest diameter). 
 
b. False positive: 
• 
If on follow-up imaging within 3-12 months, sites of initial PET positive lesions 
seen on CT or MRI scan decrease by more than 30% without systemic therapy 
or focal therapy at this site. 
• 
If 18F-DCFPyL PET positive lesions do not meet the criteria for above false 
positive or true positive findings. 
 
3. 
18F-DCFPyL PET positive bone lesions will be considered: 
a. True positive: 
• 
If there was a corresponding positive sclerotic lesion on the CT portion of the 
18F-DCFPyL PET in the same location as the focal uptake. 
• 
If there is focal uptake seen on the baseline bone scan performed within one 
month of 18F-DCFPyL PET. 
• 
If there is a lesion noted on the initial MRI imaging scan performed within one 
month of 18F-DCFPyL PET. 
• 
If within 12 months follow-up CT scan demonstrates development of sclerosis. 
• 
If within 12 months follow-up MRI scan demonstrates a new bone lesion. 
• 
If within 12 months follow-up bone scan demonstrates new focal uptake. 
 
b. False positive: 
• 
If 18F-DCFPyL PET positive bone lesions do not meet the criteria for true 
positive findings. 
 
4. 
18F-DCFPyL PET positive prostate bed and prostate lesions will be considered: 
a. True positive: 
• 
If on follow-up imaging within 12 months, lesions seen on CT or MRI scan 
decrease by 30% (for patients undergoing systemic treatment of focal therapy 
at this site) or increase by 20% in largest diameter. 


43 
 
• 
If patients with prostate bed lesions show a decrease of PSA by greater than 
50% after targeted treatment (i.e. external beam radiation) and lesions do not 
change in size (less than 30% decrease or 20% increase in largest diameter). 
 
b. False positive: 
• 
If on follow-up imaging within 3-12 months, sites of initial 18F-DCFPyL PET 
positive lesions seen on CT or MRI scan decrease by more than 30% without 
systemic therapy or focal therapy at this site. 
• 
If 18F-DCFPyL PET positive lesions do not meet the criteria for above false 
positive or true positive findings. 
 
Histopathology/Biopsy: 
1. 
Localization of lesions for histopathology/biopsy will be classified according to the regions 
in table (Definition ofregions) below. 
2. 
The 
18F-DCFPyL PET positive findings will be targeted to be confirmed by 
histopathology/biopsy if and whenever clinically feasible. 
3. 
Histopathological procedures, biopsies and follow-up imaging will be performed as 
clinically indicated and as per the standard of care/institutional protocol. The following 
elective procedures may guide the investigator: 
A.  Positive HP/Biopsy: Confirmed sites of metastatic or tumor involvement by 
histopathology/biopsy 
will 
be 
discussed 
with 
the 
responsible 
physician/surgeon. 
B. Negative Biopsy: Patients with suspected tumor recurrence on the PET with 
negative histopathology/biopsy will be handled as outlined below: 
 
1.  Lymph nodes: 
• For patients undergoing nodal dissection: Patients will be rescanned 
with dedicated CT or MRI scan, if clinically feasible, to determine if the 
suspicious 18F-DCFPyL PET positive node was removed. 
o If PET positive lymph node is still present, a repeat biopsy can 
be pursued if clinically feasible and applicable, or follow-up 
using imaging as described above will be performed. 
o If the corresponding node was removed, then this will be 
considered a False Positive. 
• For patients undergoing needle biopsy: Images of the procedure will be 
reviewed to determine if the correct node was biopsied. 
o If the correct node was biopsied, then a negative biopsy will be 
considered a False Positive. 
o If the incorrect node was biopsied, then follow-up imaging as 
described above will be performed if clinically feasible. 


44 
 
11. Bone lesions: Given the high rate of false negative biopsies for osseous 
metastases in patients with prostate cancer, patients with negative bone 
biopsies of PET positive lesions will be further evaluated: 
• 
If pathology demonstrates alternative diagnoses that is known to be PET 
positive (e.g. Renal Cell Carcinoma metastases, Paget's disease), then 
this will be considered a False Positive. 
• 
If pathology is indeterminate, then follow-up imaging as described 
above will be performed to determine if the lesion is a True Positive or 
False Positive. 
 
111. Additionally, a repeat 18F-DCFPyL PET may also be obtained as per 
treating physician discretion in addition to repeat conventional imaging (CT 
and/or MRI) in cases of negative biopsy to determine if the biopsy was true 
negative or false negative. 
C. Although not routinely performed during standard practice, 
immunohistochemical or specimens (primary and lymph node metastases) 
may be performed, although not required. 
 
 
 
Table: Definition of regions 
 
Region 
Description 
1 
Prostate bed 
2 
Pelvis outside of prostate bed (including LNs) 
3 
Extra-pelvic soft tissue lesions, LNs, visceral metastases 
4 
Osseous metastases 
 
 
3.5.2 
Screening Assessments 
Patients determined to meet the eligibility criteria to participate in the study will undergo Screening 
assessments as per the Study Schedule of Activities in Appendix A. The following screening 
procedures will be performed: 
 
• 
Informed Consent will be obtained prior to any study-related procedures 
• 
Eligibility assessment per the inclusion and exclusion criteria and diagnosis confirmation 
• 
Subject demographics 
• 
Prostate cancer history 
• 
Vital Signs 


45 
 
• 
Physical examination, including height, weight, body mass index (BMI) and ECOG 
performance status assessment 
• 
List of concomitant medications (hormonal agents only) 
• 
Lab assessments 
 
3.5.3 
Procedure for Registration of Subjects 
Patients must not start study activities prior to registration. Subjects can be enrolled after eligibility 
criteria are met. Registration will require the following information: 
• 
Date of consent 
• 
Participant's name 
• 
Date of birth 
• 
Primary study physician 
• 
Confirmation of eligibility 
 
 
3.6 
ASSESSMENTS DURING INTERVENTION 
3.6.1 
Demographic and Medical Record Review 
3.6.1.1 
Patient Demographics 
For this study, demographic information will be reviewed at the Screening Visit and include: 
• 
Date of birth 
• 
Sex 
• 
Self-reported race (American Indian/Alaskan Native, Asian, Black/African American, 
Native Hawaiian/Pacific Islander, Caucasian, or other) 
• 
Self-reported ethnicity (Hispanic/Latino or Not Hispanic/Latino) 
3.6.1.2 
Prostate Cancer History 
Medical history related to diagnosis to be recorded for each patient consists of: 
 
• 
Height 
• 
Weight 
• 
Clinically significant diseases 
• 
Surgeries 
• 
Cancer history (including prior cancer therapies and procedures) 
• 
Prior medications (hormonal agents only) 
 
These elements are considered as HIPAA identifiers and will be listed individually in the HIPAA 
authorization portion of the consent form. 


46 
 
3.6.1.3 
Physical Examination 
The physical examination will include routine examinations, not including rectal or genitourinary 
examinations. All clinically significant abnormalities will be recorded in subject's medical 
record and on the physical exam CRF page. Any abnormality that, in the opinion of the 
Investigator, is relevant to the safety of the subject or could impact safety or efficacy results for 
the subject will be considered as "clinically significant". After administration of the first dose of 
study treatment, each physical exam abnormality that is clinically significant will be recorded as 
an AE. A complete physical includes an evaluation of the: 
 
• 
Head, eyes, ears, nose, and throat 
• 
Dermatological 
• 
Musculoskeletal 
• 
Respiratory 
• 
Gastrointestinal 
• 
Genitourinary 
• 
Neurological systems 
Any abnormality identified at baseline should be recorded on the general medical history and 
baseline conditions eCRF. At subsequent visits (or as clinically indicated), limited, symptom- 
directed physical examinations should be performed. Changes from baseline abnormalities 
should be recorded in patient notes. New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF. 
 
3.6.2 
lnterventional Examination 
During the administration of the study drug, the following assessments will be reviewed: 
 
• 
Concomitant medications 
• 
Adverse event review (post-injection) 
 
3.7 
FOLLOW UP ASSESSMENTS 
Following the administration of the study, there will be a post-study follow period and a long 
term follow up period. 
 
3.7.1 
Post-Study Follow Up 
 
For the initial seven days after study drug administration, the following will be reviewed: 
 
• 
Concomitant medications 
• 
Adverse events 


47 
 
3.7.2 
Long Term Follow Up 
After the post-study follow up period, the participant will continue to be followed as described in 
section 3.5.1 Imaging Protocol and Follow Up. 
 
3.8 
ASSESSMENT OF SAFETY 
3.8.1 
Safety evaluation 
Patients will be monitored during infusion of 18F-DCFPyL and for 120 minutes after the infusion. 
The safety and tolerability of 18F-DCFPyL Injection will be assessed using the following primary 
safety outcome measures: 
 
• 
Incidence, nature, and severity of adverse events up to 7 days following infusion 
 
3.8.2 
Radiation exposure from PSMA PET imaging 
As part of this scan there is radiation delivered from the 18F and from the low dose CT or MRI 
scan that are performed as part of the PET imaging for attenuation correction and co-registration. 
Although any exposure to ionizing radiation has the potential to cause some harm to tissue, the 
radiation exposures in this study are comparable to the low-level exposures associated with 
common diagnostic procedures such as PET/CT scanning. There remains a low theoretical risk of 
developing a cancer at some point later in life as a result of the radiation exposure received in this 
study. This risk is much smaller than the clinical risks posed by the patient's current cancer or the 
salvage radiation therapy the patient might have received or will be receiving. The dose selection 
process described in section 3.3.5 was aimed at limiting the radiation-absorbed dose to the urinary 
bladder in accordance with 21 Code of Federal Regulations (CFR) § 361.1 ('.S 50 mGy). 
Consequently, the 9 mCi administered dose of 18F-DCFPyL Injection is comparable to the 
radiation dose of other radiotracers used in oncology such as [18F]-FDG. The dose range for 18F- 
DCFPyL will be 7 - 9 mCi. The approximate Effective Dose for a whole-body attenuation 
correction CT would be 0.05 rem. 


48 
 
3.8.3 
Adverse Events 
3.8.3.1 Definition of Adverse Events 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
imaging test. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. 
 
For this study, AEs are regarded as "intervention emergent," if they occur after study drug has 
been administered. 
 
Pre-planned or elective surgeries or therapies should be recorded in the patient's source documents 
but are not to be considered AEs unless there was any change to the patient's medical condition 
during the AE collection period. 
 
Collection of AEs will occur upon signature of consent. 
3.8.3.2 Definition of Serious Adverse Events 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
SAE reporting is required as soon as the participant signs consent. 
 
SAE reporting is required during the 30-day follow up period after the participant's investigational 
intervention. Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 


49 
 
SAE reporting will comply with UPMC HCC SOPs and with local and federal regulations. 
3.8.3.3 Evaluation of Adverse 
Events Seriousness 
The seriousness must be determined for each AE, according to the criteria given. 
Intensity/Severity 
The intensity of an AE is classified according to NCI-CTCAE version 5.0, considering the possible 
range of the intensity of the event: 
 
• 
NCI-CTCAE Grade 1 (mild) 
• 
NCI-CTCAE Grade 2 (moderate) 
• 
NCI-CTCAE Grade 3 (severe) 
• 
NCI-CTCAE Grade 4 (life-threatening) 
• 
NCI-CTCAE Grade 5 (fatal) 
Study drug action 
AEs requiring any action, i.e. medication or therapy for treatment, should be treated according to 
recognized standards of medical care to protect the health and well-being of the patient. 
3.8.3.4 Relationship to Study Intervention 
 
Causal relationship to study drug 
The possible causal relationship between the AE and the administration of the study agent is 
classified according to the following question: 
 
"Is there a reasonable likelihood that the event was caused by the study drug?" 
 
Possible answers are: 
• 
Definitely Related: Plausible time relationship to the administration of IMP/RP. There is 
no plausible explanation by underlying/concurrent disease or other drugs/events. 
• 
Probably Related: Plausible time relationship to the administration of IMP/RP, and a 
respond to dechallenge of IMP/RP. 
• 
Possibly Related: Plausible time relationship to the administration ofIMP/RP, but the AE 
can be also plausibly explained by the underlying/concurrent disease or other medicinal 
products/events. 


50 
 
• 
Unlikely Related: Minimal plausible relationship to the administration of IMP/RP. Other 
medicinal products, events, and the underlying/concurrent disease provide a plausible 
explanation. 
• 
Unrelated: No plausible relationship to the administration of IMP/RP. There is clear 
evidence that the AE is not connected to the IMP/RP administration. 
Causal relationship to study conduct 
The possible causal relationship between the AE and any study-conduct-related procedures and 
activities required by the protocol is classified according to the following question: 
 
"Is there a reasonable likelihood that the event was caused by the study conduct?" 
3.8.3.5 
Expectedness 
Expected Conduct-related AEs 
The use of an indwelling cannula for the administration of study drug may be accompanied by 
mild bruising and also, in rare cases, by transient inflammation of the vessel wall. After initial 
irritation, the presence of an indwelling cannula is usually painless and hardly noticeable. 
Patients may also experience discomfort from lying in the camera, e.g. back pain. 
 
Expected Adverse Drug Reactions 
The definition below follows ICH-GCP (see also ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting): 
 
Adverse drug reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly 
as the therapeutic dose(s) may not be established, all noxious and unintended responses to a 
medicinal product related to any dose should be considered as ADR. The phrase 'responses to a 
medicinal product' means that a causal relationship between a medicinal product and an AE is at 
least a reasonable possibility, i.e., the relationship cannot be ruled out. 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is defined as any adverse drug experience, the nature, 
specificity or severity of which is not consistent with the applicable product information (e.g. 
investigator's brochure for an unapproved investigational product or Summary of Product 
Characteristics for an approved product). "Unexpected" as used in this definition refers to an 
adverse drug experience that has not been previously observed and included in the product 
information, rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the investigational product. 


51 
 
3.8.3.6 
Assessment and Documentation of Adverse Events 
At every assessment time point during the study until end of the study, the patient will be asked a 
non-leading question such as "Have you had any health problems since you were last asked/ since 
your last visit?" 
All AEs reported in response to questioning, as well as AEs reported spontaneously and occurring 
at any other time, will be recorded on the 'adverse event' page(s) in the CRF, regardless of 
causality. 
 
If an AE fulfills any of the SAE criteria, both the AE pages of the CRF and the Serious Adverse 
Event Form must be completed. 
SAEs are recorded for the entire duration of the study. 
 
For both serious and non-serious AEs, documentation must be supported by an entry in the 
patient's hospital notes. 
REPORTING OF SERIOUS ADVERSE EVENTS 
 
All events meeting the definition of a serious adverse event should be reported according to the 
departmental SAE checklist and SAE form. SAE reporting is required from the time of the 
participant's first dose of investigational product until 30 days after the last dose of treatment or 
intervention. Any events that occur greater than 30 days after last dose that are at least possibly 
related to treatment must be reported. The initial SAE form should be sent to the following within 
24 hours/I business day of the Principal Investigator becoming aware: 
 
1. Investigator 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Sections B and C of the departmental SAE form: 
 
• 
CTCAE term(s) and grade(s) 
• 
Current status of study drug 
• 
All interventions to address the AE (testing and result, treatment and response) 
• 
Hospitalization and/or discharge dates 
• 
Event relationship to study drug 


52 
 
FOLLOW-UP REPORTS 
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original departmental SAE form. 
 
3.8.4 
Review of Safety Information: Sponsor Responsibilities 
 
The sponsor must promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from foreign or domestic sources, including information derived 
from any clinical or epidemiological investigations, animal or in vitro studies, reports in the 
scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not marketed 
in the United States. 
 
Sponsor-investigators of IND applications are subject to compliance with both the adverse 
reaction reporting requirements of the Sponsor and the adverse event reporting requirements of 
the Investigator. 
 
3.8.5 
IND Safety Reports 
 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom 
the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but 
in no case later than 15 calendar days after the sponsor determines that the information qualifies 
for reporting under Sections 3.8.5.1 to 3.8.5.4 below. In each IND safety report, the sponsor 
must identify all IND safety reports previously submitted to FDA concerning a similar suspected 
adverse reaction, and must analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information. 
3.8.5.1 
Serious and unexpected suspected adverse reaction 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture); 
• 
 An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 


53 
 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
3.8.5.2 
Findings from other studies 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under section 3.8.5.1), whether or not 
conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant 
risk in humans exposed to the drug. Ordinarily, such a finding would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates of 
these documents), or other aspects of the overall conduct of the clinical investigation. 
3.8.5.3 
Findings from animal or in vitro testing 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted 
by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near 
the expected human exposure. Ordinarily, any such findings would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates of 
these documents), or other aspects of the overall conduct of the clinical investigation. 
3.8.5.4 
Increased rate of occurrence of serious suspected adverse reactions 
The sponsor must report any clinically important increase in the rate of a serious suspected 
adverse reaction over that listed in the protocol or investigator brochure. 
3.8.6 
Submission of IND safety reports 
The sponsor must submit each IND safety report in a narrative format or on Form FDA 3500A or 
in an electronic format that FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of transmission, media, file 
formats, preparation, and organization of files). The sponsor may submit foreign suspected 
adverse reactions on a Council for International Organizations of Medical Sciences (CIOMS) I 
Form instead of a Form FDA 3500A. Reports of overall findings or pooled analyses from 
published and unpublished in vitro, animal, epidemiological, or clinical studies must be 
submitted in a narrative format. Each notification to FDA must bear prominent identification of 
its contents, i.e., "IND Safety Report," and must be transmitted to the review division in the 
Center for Drug Evaluation and Research or in the Center for Biologics Evaluation and Research 
that has responsibility for review of the IND. Upon request from FDA, the sponsor must submit 
to FDA any additional data or information that the agency deems necessary, as soon as possible, 
but in no case later than 15 calendar days after receiving the request. 


54 
 
3.8.6.1 
Unexpected fatal or life-threatening suspected adverse reaction reports 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial 
receipt of the information. 
3.8.6.2 
Reporting format or frequency 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different 
than that required under this paragraph. The sponsor may also propose and adopt a different 
reporting format or frequency if the change is agreed to in advance by the director of the FDA 
review division that has responsibility for review of the IND. 
3.8.6.3 
Investigations of marketed drugs 
A sponsor of a clinical study of a drug marketed or approved in the United States that is 
conducted under an IND is required to submit IND safety reports for suspected adverse reactions 
that are observed in the clinical study, at domestic or foreign study sites. The sponsor must also 
submit safety information from the clinical study as prescribed by the post marketing safety 
reporting requirements. 
3.8.6.4 
Reporting study endpoints 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 3.8.7 third bullet of 
this section. However, if a serious and unexpected adverse event occurs for which there is 
evidence suggesting a causal relationship between the drug and the event (e.g., death from 
anaphylaxis), the event must be reported under Serious and unexpected suspected adverse 
reaction as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (e.g., all-cause mortality). 
3.8.7 
Follow-up 
• 
The sponsor must promptly investigate all safety information it receives. 
• 
Relevant follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., "Follow-up IND Safety 
Report." 
• 
 If the results of a sponsor's investigation show that an adverse event not initially 
determined to be reportable under the IND safety reports section is so reportable, the 
sponsor must report such suspected adverse reaction in an IND safety report as soon as 
possible, but in no case later than 15 calendar days after the determination is made. 


55 
 
3.8.8 
Disclaimer 
A safety report or other information submitted by a sponsor under this part (and any release by 
FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or 
FDA that the report or information constitutes an admission that the drug caused or contributed 
to an adverse event. A sponsor need not admit, and may deny, that the report or information 
submitted by the sponsor constitutes an admission that the drug caused or contributed to an 
adverse event. 
The principal investigator must promptly review all information relevant to the safety of the drug 
obtained or otherwise received from foreign or domestic sources, including information derived 
from any clinical or epidemiological investigations, animal or in vitro studies, reports in the 
scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not 
marketed in the United States. The study sponsor must notify all participating investigators of 
potential serious risks, from clinical trials or any other source, as soon as possible. 
3.8.9 
Reporting adverse events to the responsible IRB 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board 
(IRB), the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse 
event that is determined to be 1) associated with the investigational drug or study treatment(s); 
2) serious; and 3) unexpected. Adverse event reports will be submitted to the IRB in accordance 
with the respective IRB procedures. 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the sponsor-investigator's receipt of the respective information. 
Adverse events which are 1) associated with the investigational drug or study treatment(s); 2) 
fatal or life-threatening; and 3) unexpected will be reported to the IRB within 24 hours of the 
Sponsor-Investigator's receipt of the respective information. 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the Sponsor-Investigator's follow-up 
investigation show that an adverse event that was initially determined to not require reporting to 
the IRB does, in fact, meet the requirements for reporting; the Sponsor-Investigator will report 
the adverse event to the IRB as soon as possible, but in no event later than 10 calendar days, after 
the determination was made. 
 
 
3.9 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures. These are described in the following sections. 


56 
 
3.9.1 
Data Collection, Monitoring, and Transfer 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. 
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study. Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. 
 
Clinical data including adverse events, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the Clinical Trial Management Application 
(CTMA), a 21 CFR Part 11-compliant data capture system provided by the UPMC HCC Clinical 
Research Services (CRS). The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
3.9.2 
Quality Control and Quality Assurance 
The PI will perform a clinical review to define the level of resolution required of each data field, 
with major safety fields (e.g., AE) given the highest importance. The database will be 100% 
verified against the CRFs. A clinical review will be performed by the PI to identify those minor 
issues that could remain unresolved. 
3.9.3 
Data and Safety Monitoring Plan 
Investigators, Sub-investigators and clinical research staff meet regularly to review in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
 
• 
Serious adverse events 
• 
Subject safety issues 
• 
Recruitment issues 
• 
Accrual 
• 
Protocol deviations 
• 
Unanticipated problems 
• 
Breaches of confidentiality 
Minutes from disease center DSMB meetings are available to those who are unable to attend. 


57 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI CTCAE version 5.0 and recorded prior to each course of the investigational therapy. All study 
treatment associated adverse events that are serious, at least possibly related and unexpected will 
be reported to the IRB and FDA. Any modifications necessary to ensure patient safety and 
decisions to continue or close the trial to accrual are also discussed during these meetings. If any 
literature becomes available which changes the risk/benefit ratio or suggests that conducting the 
trial is no longer ethical, the IRB will be notified in the form of an Unanticipated Problem 
submission and the study may be terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach 
in subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The disease center will forward a summary of the DSMB to the UPMC Hillman 
Cancer Center DSMC which meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB's policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, and 
approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPMC HCC DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings. 
 
All records related to this research study will be stored in a double locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research records. 
 
 
3.10 
STATISTICAL 
METHODS 
PLANNED 
IN 
THE 
PROTOCOL 
AND 
DETERMINATION OF SAMPLE SIZE 
3.10.1 
Study Design 
This is a single arm phase II clinical trial to evaluate the positive predictive value (PPV) of 
18F-DCFPyL PET imaging in men diagnosed with prostate cancer with increasing prostate-specific 
antigen (PSA) levels. PPV is the number of true positives (TP) divided by number of patients who 
are tested positive (i.e., TP + FP) based on the PET imaging. The determination ofTP and positive 
testing is detailed in Section 3.5.1. Secondary endpoints are PPV of 18F-DCFPyL PET (per-region). 
All patients who are diagnosed with prostate cancer with increasing PSA levels and who have 
received PET scans will be evaluable for the analysis. 


58 
 
All patients will be followed up for histopathologic analysis, conventional imaging (CT, MRI 
and/or bone scan) and/or serum PSA after focal salvage therapy acquired during clinical routine. 
Combination of (in descending priority) histopathologic analysis, imaging, and PSA follow-up 
after local/focal therapy will used for lesion validation. Validation will be performed by the 
unblinded local investigators after reviewing images and reports, following prespecified criteria 
of the study protocol. In patients with follow-up, positive 18F-DCFPyL PET findings will be 
validated as true or false-positive results. Region negative on 18F-DCFPyL PET, but with 
subsequently confirmed prostate cancer by histopathologic analysis, will be considered false- 
negative results. True negative will not be defined. (please see section 3.5.1. for details). 
 
3.10.2 
Sample Size 
A total of 300 evaluable participants will be enrolled into this study. We expect approximately 
85% of them, i.e., 255 patients, will have positive test results. Based on these 255 patients, the 
exact 95% confidence interval (CI) for PPV has a width ofless than 12%. The following table 
shows the exact 95% CI corresponding to different observed PPV values. 
 
Observed PPV 
95% CI of true underlying PPV 
80% 
(75%, 85%) 
84% 
(79%, 88%) 
88% 
(84%, 92%) 
92% 
(88%, 95%) 
96% 
(93%, 98%) 
100% 
(99%, 100%) 
As an example, from this table, an observed 80% PPV value indicates that we can be 95% 
confident that the true underlying PPV lies in the interval (75%, 85%). If the observed PPV is 
88%, then we can be 95% confident that the true underlying PPV lies in the interval (84%, 92%). 
 
3.10.3 
Analysis of Primary and Secondary Endpoints 
PPV will be estimated by the number of true positives (TP) divided by number of patients who are 
tested positive (i.e., TP + FP) based on the PET imaging, with the corresponding exact 95% 
confidence intervals (Cis) being reported. The determination ofTP and positive testing is detailed 
in Section 3.5.1. Secondary endpoints are the PPV of 18F-DCFPyL PET (per-region). These will 
also be estimated as the corresponding percentage and its exact 95% Cis. 
The safety profile observed to date suggests that the toxicity of the proposed study product is 
unlikely to be clinically significant. However, we will monitor toxicity closely. Any patient who 
has started the studied treatment will be evaluable for safety. The NCI CTCAE version 5.0 defines 
the term toxicity as adverse events that are classified as either possibly, probably, or definitely 
related to study treatment. The maximum grade for each type of toxicity will be recorded for each 
patient, and frequency tables will be reviewed to determine toxicity patterns. 


59 
 
3.10.4 
Missing Data 
Missing data will not be imputed except for AE and CONMED missing dates. 
 
3.10.5 
Interim Analyses 
There is no Data Safety Monitoring Committee or Interim Analysis planned for this study. 
4. 
ETHICS 
4.1 
COMPLIANCE STATEMENT 
The study will be conducted in accordance with the protocol, Good Clinical Practices, the relevant 
ICH guidelines, the applicable regulatory requirements, and the ethical principles that have their 
origins in the Declaration of Helsinki. As required by the US Food and Drug Administration (FDA) 
Code of Federal Regulations (CFR) (21 CFR 56) and the Declaration of Helsinki, the study 
protocol, amendments, and Informed Consent form will be reviewed and approved, according to 
21 CFR §50 and §56, respectively, by the study center's IEC or IRB. 
 
 
4.2 
SUBJECT INFORMATION AND CONSENT 
Before protocol-specific procedures are carried out, qualified consenting professionals will explain 
full details of the protocol and study procedures, as well as the risks involved to patients prior to 
their inclusion in the study. Patients will also be informed that they are free to withdraw from the 
study at any time. 
 
All patients must sign an !RB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the IRB of record. 
Both the patient and the qualified consenting professional will sign the consent form. The patient 
must receive a copy of the signed informed consent form. 
 
5. 
PUBLICATION POLICY 
The Investigator will refer to the Investigator agreement and clinical trial agreement for the 
publication and disclosure policy. 


60 
 
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 Castellucci, P., et al., Influence of trigger PSA and PSA kinetics on llC-Choline PET/CT detection 
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Choline C 11 [package insert], M.C.R. facility, Editor. 2012, Rochester, MN, USA. 
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Axumin® [package insert}, B.E. Diagnostics, Editor. 2016, Blue Earth Diagnostics: Burlington, MA, 
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Hricak, H., et al., Imaging prostate cancer: a multidisciplinary perspective. Radiology, 2007. 
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19. 
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worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424. 
28. 
Racioppi, M., et al., Hot topics in urological health economics. A mini review. Arch Ital Ural 
Androl, 2012. 84(2): p. 47-52. 
29. 
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undergoing radical prostatectomy: high incidence of lymph node metastasis. J Ural, 2002. 
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30. 
 Even-Sapir, E., et al., The detection of bone metastases in patients with high-risk prostate cancer: 
99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, 
and 18F-fluoride PET/CT. J Nucl Med, 2006. 47(2): p. 287-97. 
31. 
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in patients with prostate cancer: a meta-analysis. Clin Radial, 2008. 63(4): p. 387-95. 
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36. 
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37. 
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64 
 
7. 
APPENDICES 
7.1 
APPENDIX A: SCHEDULE OF STUDY ACTIVITIES 
 
Visit Type 
I Screening 
I 
I Imaging Day - 
Procedures 
I 
Imaging Day - 
Follow-up 
Post-Study 
Follow-up 
Long Term 
Follow Upg 
Day/Timing 
Within 28 
days of 
imaging 
Day 1 
(At the time of 
tracer injection) 
Day 1 
(120 min post- 
injection follow-up) 
Day7 
(+/- 2 days) 
Day 8 to 
One Year 
Procedures 
r 
r 
r 
Informed Consent 
X 
Eligibility 
X 
Medical History 
X 
Laboratory Assessmentsa 
X 
Physical Examb 
X 
Vital Signs 
X 
Administration of 18F-DCFPyL 
X 
PET Imaging Scanc 
X 
Patient Concomitant Medicationsd 
X 
X 
X 
X 
Adverse Eventse 
X 
X 
Conventional Imagingf 
IX 
a. 
Glomerular filtration rate (eGFR); serum total bilirubin; aspartate transaminase (AST); alanine aminotransferase 
b. 
Physical exam includes a review of height, weight and BMI 
c. 
PET scan will be perfonned approximately 60 minutes after administration of 18F-DCFPyL 
d. 
 Only hormonal agents are required to be collected pre-injection; concomitant medications taken for treatment-related adverse events only are required to be collected on 
Day I post-injection and Day 7 


65 
 
e. 
Adverse events information related to the injection can be collected via telephone contact 
f. 
Dedicated CT, MRI and/or bone scan; interpretation of follow-up imaging will be performed by a local read 
g. 
Long term follow-up includes chart review for imaging, biopsies, PSA levels and prostate cancer treatment at 3, 6, 9 and 12 months or until patient has responded to 
treatment 


 
66 
7.2 
APPENDIX B: STUDY SCHEMATIC 
 
 
l 
PET +ve Regions 2-4 (see 
regions table section 3.5.1) 
l 
PET -ve Regions 2-4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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