Evaluation of a 68Ga Small Molecule PSMA Antagonist Produced by Two Different Methods
Phase: PHASE1
Conditions: Metastatic Prostate Adenocarcinoma
Sponsor: Weill Medical College of Cornell University

 
 
  
Page # i 
 
TITLE:  Evaluation of a 68Ga Small Molecule PSMA Antagonist Produced by Two Different 
Methods 
 
 
 
IRB Protocol #: 19-11021092 
IND/IDE #: (if applicable) 
Version Date: 03/01/2021 
Funding Source(s): NIH 
 
 
Principal Investigator: 
 
Joseph R Osborne 
520 East 70th ST-221E 
212-746-6797 
jro7001@med.cornell.edu 
 
 
Co-Investigators: 
 
Nikolaos A. Karakatsanis 
516 E 72nd St, New York, NY 10021 
(212) 746-5596 
nak2032@med.cornell.edu 
 
Scott Tagawa  
520 East 70th Street, Starr Pavilion, 3rd Floor New York, NY 10021 
646-962-2072 
stt2007@med.cornell.edu 
 
John Babich  
407 East 61 Street, New York, NY 10021 
(212) 821-0850 
job2060@med.cornell.edu 
 
Panagiotis Vlachostergios 
407 East 61 Street, New York, NY 10021 
(347) 694-5035 
pjv9003@nyp.org 
 
Daniel Margolis 
1305 York Avenue, 3rd Floor, New York, NY 10021 
(212) 746-6000 
djm9016@med.cornell.edu 
 
Josephine Kang 
1283 York Avenue, 4th Floor New York, NY 10065 
(212) 746-3607 
jok9106@med.cornell.edu 
 
NCT04685811

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Himanshu Nagar 
1283 York Avenue, 4th Floor New York, NY 10065 
(212) 746-3704 
hnagar@med.cornell.edu 
 
David Michael Nanus 
340 4th Avenue Brooklyn, NY 11215 
(646) 962-2084 
dnanus@med.cornell.edu 
 
Elizabeth Sweeney 
1300 York Ave. Box 65 
New York, NY 10065 
(212) 746-6565 
Ems4003@med.cornell.edu 
 
 
 
 
 
Participating Sites:  Single site study  
 
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................... VI 
CONFIDENTIALITY STATEMENT ............................................................................................. VI 
LIST OF ABBREVIATIONS ...................................................................................................... VII 
1. PROTOCOL SUMMARY ....................................................................................................... 1 
1.1 
Schema ...................................................................................................................... 3 
1.2 
Study Objectives ........................................................................................................ 4 
1.2.1  
Primary Objectives .............................................................................................. 4 
1.2.2  
Secondary Objectives .......................................................................................... 4 
1.2.3  
Exploratory Objectives ........................................................................................ 4 
2. BACKGROUND ................................................................................................................... 4 
2.1 
Prostate Cancer ......................................................................................................... 4 
2.2 
FDG Positron Emission Tomography (PET) .................................................................. 4 
2.3 
Rationale- PSMA PET imaging..................................................................................... 5 
2.4 
 Risk/Benefit Assessment ........................................................................................... 5 
2.4.1 
Known Potential Risks ......................................................................................... 5 
2.4.2 
Known Potential Benefits .................................................................................... 7 
2.4.3 
Assessment of Potential Risks and Benefits ......................................................... 7 
2.5 
Correlative Studies Background- Preliminary laboratory and small animal experience 7 
3. STUDY DESIGN ................................................................................................................... 8 
3.1 
Overall Design ............................................................................................................ 8 
3.2 
Scientific Rationale for Study Design .......................................................................... 9 
3.3 
Justification for Dose ................................................................................................. 9 
3.4 
End of Study Definition .............................................................................................. 9 
4. SUBJECT SELECTION ......................................................................................................... 10 
4.1 
Study Population ..................................................................................................... 10 
4.2 
Inclusion Criteria ...................................................................................................... 10 
4.3 
Exclusion Criteria ..................................................................................................... 10 
4.4 
Lifestyle Considerations ........................................................................................... 10 
4.5 
Screen Failures ......................................................................................................... 10 
4.6 
Strategies for Recruitment and Retention ................................................................ 11 
5. REGISTRATION PROCEDURES ........................................................................................... 11 
5.1 
Subject Registration (WCM only) .............................................................................. 11 
6. STUDY PROCEDURES ........................................................................................................ 12 
6.1 
Schedule of Assessments ......................................................................................... 12 

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6.1.1 
Screening Visit .................................................................................................. 13 
6.1.2 
Intervention Phase ............................................................................................ 13 
6.1.3 
Evaluation during intervention .......................................................................... 13 
6.1.4      Follow- up ......................................................................................................... 14 
7. STUDY INTERVENTION ..................................................................................................... 14 
7.1 
Study Intervention/Patient scans ............................................................................. 14 
7.2 
Availability ............................................................................................................... 15 
7.3 
Acquisition and Accountability ................................................................................. 15 
7.4 
Formulation, Appearance, Packaging, and Labeling .................................................. 15 
7.5 
Product Storage and Stability ................................................................................... 15 
7.6 
Preparation.............................................................................................................. 16 
7.7 
Dosing and Administration ....................................................................................... 16 
7.8 
General Concomitant Medication and Supportive Care Guidelines ........................... 16 
7.9 
Duration of Therapy and Criteria for Removal from Study ........................................ 16 
Participation in this study is entirely voluntary. Patients may be removed from the protocol 
for the following reasons: .................................................................................................. 16 
 
Patient decides to withdraw from the study. ............................................................... 16 
 
Intercurrent illness that prevents treatment and/or follow-up imaging ........................ 16 
 
Unacceptable adverse event that may be directly related to the protocol intervention 16 
 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator ............................ 16 
 
Does not meet inclusion/exclusion criteria .................................................................. 16 
7.10  Duration of Follow Up ............................................................................................... 16 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................................ 16 
7.12 Study Intervention/Follow-up Compliance .................................................................. 16 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 17 
8.1 
Discontinuation of Study Intervention ...................................................................... 17 
8.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 17 
8.3 
Lost to Follow Up ..................................................................................................... 17 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................................... 17 
10.  MEASUREMENT OF EFFECT ............................................................................................ 17 
10.1 Response Criteria ....................................................................................................... 17 
10.2 Duration of Response ................................................................................................. 17 
10.3 Progression-Free Survival ........................................................................................... 18 
10.4 Other Response Parameters ....................................................................................... 18 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ...................................................... 18 
11.1 Data Collection ........................................................................................................... 18 

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11.1.1 REDCap ................................................................................................................ 18 
11.2 Regulatory Considerations .......................................................................................... 18 
11.2.1 Institutional Review Board/Ethics Committee Approval ....................................... 18 
11.2.2 Ethical Conduct of the Study ................................................................................ 19 
11.2.3 Informed Consent ................................................................................................ 19 
11.2.4 Compliance with Trial Registration and Results Posting Requirements ................. 21 
11.2.5 Record Retention ................................................................................................. 21 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 22 
13.1 Adverse Event Definition ............................................................................................ 22 
13.1.1 
Investigational Agent or Device Risks (Expected Adverse Events) .................... 23 
13.1.2 
Adverse Event Characteristics and Related Attributions ................................. 23 
13.1.3 
Recording of Adverse Events .......................................................................... 23 
13.1.4 
Reporting of AE to WCM IRB .......................................................................... 23 
13.2 Definition of SAE ........................................................................................................ 23 
13.2.1 
Reporting of SAE to IRB .................................................................................. 24 
13.2.2 
Reporting of SAE to FDA ................................................................................. 24 
13.3 AE/SAE Follow Up ...................................................................................................... 24 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............................... 25 
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS ....................... 25 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) 25 
14.1.2 
Unanticipated Problem Reporting .................................................................. 26 
REFERENCES ........................................................................................................................ 27 
 
 
 
 
 
 
 
 
 

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Statement of Compliance 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the <specify NIH Institute or Center (IC) > Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the Investigational New Drug (IND) or Investigational Device Exemption 
(IDE) sponsor, funding agency and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form.] 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 
 
 
 
 
Joseph R. Osborne 
______________________________     ______________________________     ____________________ 
Principal Investigator’s Name                 Principal Investigator’s Signature            Date 
 
 

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List of Abbreviations 
 
AE 
CBIC 
Adverse Event 
Citigroup Biomedical Imaging Center  
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
WCINYP 
PCa 
68Ga 
PET  
ROI 
PSMA 
Ga-PSMAcyc 
Ga-PSMAgen 
Weill Cornell Medicine 
Weill Cornell Imaging NewYork Presbyterian 
Prostate Adenocarcinoma 
Gallium-68 
Positron Emission Tomography  
Regions of Interest 
Prostate Specific Membrane Antigen 
Ga-PSMA cyclotron 
Ga-PSMA generator 

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1. Protocol Summary 
 
Full Title: 
 
 
 
 
Evaluation of a 68Ga Small Molecule PSMA Antagonist Produced by two 
different Methods 
 
 
 
  
Clinical Phase:  
 
 
I/II 
Principal Investigator:  
 
Dr. Joseph R. Osborne 
Study Description:  
 
Patients with metastatic prostate cancer will undergo two protocol 
68Ga-PET scans within 24-48h with 68Ga-PSMA-cyclotron and 68Ga-PSMA-
generator radiotracers. The goal of the study is to evaluate repeatability 
and equivalence across the different 68Ga-PSMA production methods. 
Sample Size: 
 
Up to 30 patients will be enrolled in the study as defined by protocol                   
criteria.  
Enrollment: 
 
30 patients will be enrolled in this study 
Study Population: 
 
Patients with metastatic prostate adenocarcinoma 
Enrollment Period: 
 
2 years 
Study Design: 
 
Single-dose, non-randomized design. Patients with metastatic prostate 
adenocarcinoma will be administered a single intravenous dose of each 
of the study drugs 68Ga-PSMA-cyclotron and 68Ga-PSMA-generator 24- 
48 hours apart. 
Description of Sites/  
Facilities Enrolling 
Participants: 
 
This is a single site study. All study procedures will be performed in the 
NYP/WCMC facilities, CBIC, and WCINYP. 
Study Duration: 
 
2 years 
Participant Duration: 
 
3 Visits: 1 screening/consent and 2-infusions imaging. The duration of 
patient participation can be up to 4 weeks, depending on eligibility, and 
the scheduling and completion of required study visits 
Study Agent/Device Name  
Intervention Description: 
68Ga-PSMA-cyclotron and 68Ga-PSMA-generator; single dose each, 
approximately 100-300 mBq. 
Primary Objective: 
 
 
 
To evaluate equivalence of two processes to create 68Ga-HBED-PSMA 
(68GA-PSMA-cyclotron vs. 68Ga-PSMA-generator) 
Secondary Objectives:  
 
Comparative dosimetry and biodistribution (68GA-PSMA-cyclotron vs. 
68Ga-PSMA-generator), whole body excretion/ metabolism in patients 
with confirmed metastatic PCa 
Exploratory Objectives:  
 
 
Investigate repeatability of whole-body 68Ga-PSMA-generator Ki Patlak 
imaging against that of conventional whole-body 68Ga-PSMA- SUV imaging 
in patients with confirmed metastatic prostate adenocarcinoma. 

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 
Evaluate equivalence of whole-body 68Ga-PSMA Ki Patlak imaging between 
the two processes to create 68Ga-HBED-PSMA (68GA-PSMA-cyclotron vs. 
68Ga-PSMA-generator) 
Endpoints: 
The primary endpoint of this study is to prove equivalence between the 
cyclotron and generator produced radioisotope. To meet this endpoint we will 
make a direct comparison of the 68GA-PSMA-cyclotron vs. 68Ga-PSMA-
generator scans obtained within 24-48h. We will measure SUVmean and 
SUVmax of the same Regions of Interest (ROI) in both scans using the PET 
analysis software we use in our clinical practice. The two scans will be retrieved 
and the exact same ROIs will be drawn at the same time for the two scans 
(software offers a copy-paste function so that no discrepancies exist between 
the two measurements). The SUVmean and SUVmax obtained from both scans 
for each Region of Interest will then be analyzed to determine the within-
subject coefficient of variation value as measured by the Bland Altman analysis. 
 
 
 
 

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1.1 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-48h 

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1.2 Study Objectives 
 
1.2.1  Primary Objectives  
 
 To confirm 68Ga-PSMA-generator repeatability in patients with confirmed metastatic PCa. 
 To evaluate equivalence of two processes to create 68Ga-HBED-PSMA (68GA-PSMA-cyclotron vs. 
68Ga-PSMA-generator). 
1.2.2  Secondary Objectives  
 
 
Comparative dosimetry and biodistribution (68GA-PSMA-cyclotron vs. 68Ga-PSMA-generator), 
whole body excretion/metabolism in patients with confirmed metastatic PCa. 
1.2.3  Exploratory Objectives   
 
Investigate repeatability of whole-body 68Ga-PSMA-generator Ki Patlak imaging against that 
of conventional whole-body 68Ga-PSMA-generator SUV imaging in patients with confirmed 
metastatic PCa. 
 
Evaluate equivalence of whole-body 68Ga-PSMA Ki Patlak imaging between the two 
processes to create 68Ga-HBED-PSMA (68GA-PSMA-cyclotron vs. 68Ga-PSMA-generator). 
 
2. Background 
 
2.1 Prostate Cancer  
 
PCa is the second most lethal cancer among men in the U.S. with 26,120 estimated deaths in 2016 
(1). The ability to monitor the presence and progression of prostate cancer disease sites is crucial for 
the approximately 400,000 American men living with advanced disease. A widely available, 
economically-viable imaging agent with the potential to convey predictive or prognostic multi-
parametric information in the metastatic setting is a clear unmet need. 
 
 
2.2 FDG Positron Emission Tomography (PET) 
 
PET has advantages over conventional imaging methods because it quantitatively assesses biologic 
processes in vivo and can assess different processes using specific radiotracers. Processes that can 
be analyzed include glucose and amino acid metabolism and proliferation, blood flow, and receptor 
status (i.e., androgen receptor). Most studies have focused on the accumulation of FDG. FDG-PET 
imaging is often used in the management of advanced disease patients; however, prostate cancer is 
frequently not FDG-avid and the presence of avidity does not always parallel treatment efficacy. This 
is particularly problematic with respect to drugs in Phase II and Phase III trials. The standard RECIST 
criteria are difficult to apply and thus a major aim of prostate cancer research is to identify disease-
specific radiotracers as an adjunct to current imaging and histologic standards, with the ultimate 

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goal of implementing a biomarker driven or treatment modality sensitive tracer as may be the 
potential for 68GA-PSMA. 
 
 
2.3 Rationale- PSMA PET imaging  
 
PSMA has been studied for several years as a target for imaging prostate cancer. An antibody 
targeting the intracellular portion of PSMA (111In-Capromab) was FDA-approved in 1996 for prostate 
cancer imaging. Sensitivity has been found to be limited, probably due to limitations of the antibody 
and the SPECT imaging technology (2).  
Recent clinical studies have shown that the extracellular portion of PSMA can be targeted not only 
by antibodies and antibody fragments, but also by urea-based small molecule inhibitors of the 
enzymatic activity of PSMA. Successful targeting has been shown for iodine-123 labeled probes for 
SPECT imaging as well as for 68Ga- and 18F-labeled compounds for PET imaging (3-7). 
Two recent case series including 319 and 248 patients, respectively, evaluated PET/CT with 68Ga-
HBED-PSMA (PSMA PET/CT) in recurrent prostate cancer (8, 9). In these two reports the frequency 
of positive 68Ga-PSMA-generator (68Ga-PSMAgen) studies at a PSA level of less than 0.5 ng/ml was 
48% (13/27) and 58% (11/19), respectively.  
 
While 68Ga-PSMA PET has shown utility in early clinical studies, the potential applicability will be 
limited by the availability and cost of the radioisotope due to its generator production. Proving 
equivalence with a cyclotron produced radioisotope could alleviate these constraints. Moreover, a 
ready source of 68Ga could have implications for diseases beyond prostate cancer , where more 
specific PET tracers can be readily generated by the availability of cyclotron-produced 68Ga. 
 
2.4  Risk/Benefit Assessment  
 
 
2.4.1 
Known Potential Risks 
 
Pharmacologic effects of HBED-PSMA 
HBED-PSMA has been injected for PET imaging in more than 500 published patients. No drug related 
side effects have been observed. This is expected because the mass of compound is minimal, less than 
10 micrograms.  
 
Radiation exposure from PSMA PET/CT imaging 
As part of this scan there is radiation delivered from the 68Ga and from the low dose CT scan that are 
performed as part of the PET/CT 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 
CT scanning. There remains a low theoretical risk of developing 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 would be receiving. 
Participants should not father a baby while on this study. Acceptable birth control methods include 
abstinence, double barrier method, surgically sterilized patient or partner. Radiation exposure due to 
injection of 68Ga-HBED-PSMA and CT imaging is provided in table 1. 
 
 
 

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Table 1: 68Ga-PSMA 11 Patient Dosimetry (per session) 
Dose per 
CT Scan   
rad 
# of 
Injections/CT 
scans 
Activity of 68Ga-PSMA 11 (maximum) 
3.3 
mCi 
  
1 
Low dose WB CT scan 
80 
mA 
0.90
1 
Ultra-low dose WB CT scan 
10 
mA 
0.11
3 
Total CT 
dose:
1.01
Absorbed Doses 
Target Organ 
rad/mCi 
rad/            
admininstration 
rad for 4 
CT scans 
Total          
rad 
Adrenals 
0.0525 
0.173 
1.23 
1.40 
Brain 
0.0333 
0.110 
1.23 
1.34 
Breasts 
0.0326 
0.107 
1.23 
1.34 
Gallbladder Wall 
0.0533 
0.176 
1.23 
1.41 
LLI Wall 
0.0455 
0.150 
1.23 
1.38 
Small Intestine 
0.0603 
0.199 
1.23 
1.43 
Stomach Wall 
0.0444 
0.147 
1.23 
1.38 
ULI Wall 
0.200 
0.66 
1.23 
1.89 
Heart Wall 
0.0403 
0.133 
1.23 
1.36 
Kidneys 
0.969 
3.20 
1.23 
4.43 
Liver 
0.114 
0.377 
1.23 
1.61 
Lungs 
0.0377 
0.125 
1.23 
1.35 
Muscle 
0.0389 
0.128 
1.23 
1.36 
Pancreas 
0.0511 
0.168 
1.23 
1.40 
Red Marrow 
0.0340 
0.112 
1.23 
1.34 
Osteogenic Cells 
0.0525 
0.173 
1.23 
1.40 
Skin 
0.327 
1.08 
1.23 
2.31 
Spleen 
0.165 
0.54 
1.23 
1.77 
Testes 
0.0385 
0.127 
1.23 
1.36 
Thymus 
0.0366 
0.121 
1.23 
1.35 
Thyroid 
0.0359 
0.118 
1.23 
1.35 
Urinary Bladder Wall 
0.481 
1.59 
1.23 
2.82 
Total Body 
0.0459 
0.151 
1.23 
1.38 
Effective Dose (rem) 
0.0873 
0.288 
1.23 
1.52 

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2.4.2 
Known Potential Benefits 
 
This is not a therapeutic study and no direct benefit exists for the participants.  
 
2.4.3 
Assessment of Potential Risks and Benefits 
 
This study will be the basis of expanding access by enabling greater production of gallium.   It will also 
enable our investigative team to look at the value of the information that we get from the Ga-PSMA PET 
scans that they may continue to have after the results of this study are documented and published. 
 
The amount of extra radiation exposure in these scans will not significantly impact the patients in a way 
that has been discovered in any systematic study of PET scanning. 
 
 
2.5 Correlative Studies Background- Preliminary laboratory and small animal experience  
 
The PSMA ligand is a zinc metalloenzyme carboxypeptidase that catalyzes the hydrolysis of glutamate 
from the C terminus of peptides. The antagonist 68Ga-HBED-PSMA targets this ligand and will be 
produced using the following methods. 
 
 
 
2.5.1 
Generator Production 
[68Ga]-gallium chloride is generated from an IGG100 Eckert and Ziegler closed system 68Ga- generator 
consisting of a borosilicate glass column containing a titanium dioxide bed on which 68Ge is absorbed 
and fully shielded. This study will therefore be performed under the specifications set forth by IND 
124495. Both, the HBED-PSMA non-radioactive precursor and the 68Ga radionuclide will be obtained 
from the CBIC core and accompanied by a certificate of analysis as described in the Chemistry, 
Manufacturing, and Controls (CMC) Section of the IND. A single dose will be delivered to the CBIC 
scanner or WCINYP with 2 h expiration. 
 
 
 
2.5.2 
Cyclotron Production  
Gallium-68 will be produced by NCM USA LLC, a NYC-based advanced PET radiopharmaceutical 
manufacturing and distribution company (461 Park Avenue South, New York, NY 10016) with whom we 
have an academic-industrial partnership NIH grant to investigate manufacturing this nuclide based on an 
IND held by the company. In summary, the NCM cyclotron will use enriched (>99% purity) zinc-68 target, 
the target will first be dissolved in 10-12 N HCl and solution will be passed on AG-50W-X8 resin to 
separate Zn-68 and elute gallium Gallium-68 s [68Ga]-GaCl3 in 3N HCl. The cyclotron produced 68Ga that 
will be released by NCM for labeling and formulation of the 68Ga-HBED-PSMA product. The 
radiochemical purity of the in house product will be required to match and be equivalent to the 
specifications of the 68Ga-HBED-PSMA generator produced radiopharmaceutical.  
 
 
 
 

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2.5.2.1 Purity of cyclotron-produced 68Ga (HPLC) 
We measured radionuclide purity and identity using an ORTEC GEM series HPGe (high-purity 
Germanium) coaxial detector system (model GEM20-70-SMP, CFG-SV-70). The purified sample of 68Ga 
showed only two peaks at 511 keV and 1077 keV. 
 
 
 
 
2.5.2.2 Small animal 68Ga-HBED-CC and repeatability 
Several experiments were performed in mice to determine repeatability of the 68Ga- HBED-CC which are 
published at Molecular Imaging and Biology with the following figures representing a synopsis of the 
results.
r 
 
 
 
3. Study Design 
 
3.1 Overall Design 
 
Thirty patients with metastatic prostate cancer that have undergone standard-of-care staging at WCMC 
will be considered for enrollment. For this study, enrolled patients will undergo a total of two whole-
body dynamic 68Ga-PET scan protocols of at least 0-75 min and at most 0-90 min scan time post 
injection, depending on the amount of injected dosage. A 6 to 48 hour gap will be introduced between 
the two scans. The first scan will occur after a baseline clinical evaluation, which will include a history, 
physical, and baseline lab draw. Blood work will be obtained before, during and after the scan. The 
radiotracers will be evaluated for repeatability and equivalence across the different production 
methods. This will include basic pharmacokinetics, distribution, metabolism and excretion.  
Up to 30 patients will undergo each two whole-body dynamic scans, initially with 68Ga-PSMAcyc and 
later with 68Ga-PSMAgen (with a minimum time of 6 h and maximum time of 2 days between the two 
injections). All patients will receive 68Ga-PSMAgen from the CBIC core and 68Ga-PSMAcyc from NCM 
pharmaceuticals at a specific activity of 1-2 Ci/µmol, the typical specific activity used in published clinical 
trials with 68Ga-PSMA (10). 
 
 
Normalized uptake values in mice bearing PC3-PIP  
tumor xenografts that were imaged using 68Ga-HBED-
PSMA either consecutively for three days (Group 2, mice 
4, 5, and 6) or alternative days with 68Ga-HBED-PSMA 
and administered with 68Ga-HBED-PSMA on day 2 
(Group 1, mice 1, 2, and 3) one hour post-administration 
of tracer.
Representative PET images of mice 
bearing PC3-PIP xenografts imaged 
with 68Ga-HBED-PSMA on three 
consecutive days 

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3.2 Scientific Rationale for Study Design 
 
This is a single-arm study. 
 
3.3 Justification for Dose  
 
Patients will be injected with 100-300 MBq of 68Ga-HBED-PSMA (from either the generator or 
cyclotron source) via a catheter. 68Ga-PSMA PET/CT will be acquired using a Siemens Biograph 
mCTTM PET/CT scanner. Please see details in section 7.1.  
The goal is to administer this amount of the imaging probe labeled with 2.5 MBq of 68Ga per kg body 
weight with a minimum of 100 MBq and maximum of 300 MBq 68Ga per patient.  
The whole-body dynamic 68Ga-PSMA scans will involve an initial dynamic scan at a pelvic scanner 
bed position centered over the prostate tissues for the first 10min post injection (p.i.), followed by 
multiple successive whole-body scans (passes) at least 10-75 min and at most 10-90 min post 
injection, depending on the amount of injected dosage. A fixed scan time of 30sec per bed position 
per pass will be used with an adjustable total number of passes. The PET data collected from at least 
the last six passes will be summed at each bed position and combined over all bed positions to 
produce whole-body static 68Ga-PSMA images equivalent of a total acquisition time of 6 x 30 sec = 
180sec or 3 min/bed position from all summed passes.  
Due to the short physical half-life of 68Ga and the decreasing elution efficiency of the 68Ge/68Ga 
generator during its lifetime, the amount of radioactivity injected per patient will necessarily vary. If 
the amount of activity per kg body weight differs by more than 25% from the recommended dose of 
2.5MBq/kg of body weight, the effective total acquisition time per bed position from all passes will 
be adjusted by increasing the total number of passes, in increments of one pass, while keeping fixed 
the scan time per bed per pass. The adjustment of the total number of passes will result in the 
respective adjustment of the total scan time up to 90 min post injection. The total number of passes 
will be adjusted such that the product of total acquisition time per bed position from all summed 
passes participating in the synthesis of the equivalent static PET images and of the injected activity is 
at least 7.5 MBq/kg*min or the total scan time reached 90 min. 
In the meantime, the dynamic PET data from all passes will also be analyzed at each bed position on 
voxel-by-voxel analysis according to the Patlak graphical model to estimate 68Ga-PSMA net uptake 
rate (Ki) whole-body images. The acquired PET data will be corrected for attenuation and scatter 
and adjusted for system sensitivity. Multiple parametric PET images in terms of standardized uptake 
values (SUV) (= MBq measured/gm tissue / MBq injected/gm body mass) and net tissue uptake rate 
Ki (= (MBq measured in tissue/gm tissue / MBq measured in blood plasma/ ml plasma) / post 
injection time) will be provided.  
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including follow-up visit which is the standard of care imaging preformed after treatment. This 
follow-up visit does not require that the patient physically comes back for an in-trial procedure.  The 
end of the study is defined as completion of the last visit or procedure shown in the SoA.  

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4. Subject Selection 
 
4.1 Study Population 
 
Subjects with a diagnosis of metastatic prostatic adenocarcinoma who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
 
4.2 Inclusion Criteria 
 
Subjects must meet all of the following criteria to be enrolled in this study: 
 
Aged 21 years or older and below 100 years of age. 
 
Signed written informed consent and willingness to comply with protocol requirements. 
 
Histologically confirmed diagnosis of metastatic prostate cancer  
 
Staging imaging exam confirming metastatic disease, e.g. total body MRI, or CT 
chest/abdomen/pelvis, 99mTc bone scan, NaF PET. 
 
4.3 Exclusion Criteria  
 
Laboratory values: 
 
Serum creatinine >2.5 mg/dL 
 
AST (SGOT) >2.5x ULN 
 
Bilirubin (total) >1.5x ULN 
 
Serum calcium >11 mg/dL 
 
Presence of any other co-existing condition which, in the judgment of the investigator, might 
increase the risk to the subject. 
 
Presence of serious systemic illness, including: uncontrolled inter-current infection, uncontrolled 
malignancy, significant renal disease, or psychiatric/social situations, which might limit 
compliance with study requirements. 
 
Other severe acute or chronic medical condition(s) or laboratory abnormality(ies) that may 
increase the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and in the judgment of the investigator, 
would make the patient inappropriate for entry into this study. 
 
Inability to lay on the scanner table for the required period of time, e.g., due to bone pain or 
claustrophobia. 
 
4.4 Lifestyle Considerations 
 
No specific patient preparation is required before injection. One intravenous catheter (Hep-Lock) 
will be placed by staff in the CBIC or WCINYP. This will remain in place for the duration of the 
encounter. 
 
4.5 Screen Failures  
 
 Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 

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transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, and 
any serious adverse event (SAE). 
 
4.6 Strategies for Recruitment and Retention 
 
 
Patients will be recruited through the outpatient clinics of the Department of Radiation Oncology and  
Genitourinary Medicine at WCMC. Members of the treatment team and research staff will screen their 
patient’s medical records for suitable research study participants and discuss the study and their 
potential for enrolling in the research study. Potential subjects contacted by their treating physician will 
be referred to the investigator/research staff of the study. If the investigator is a member of the 
treatment team, s/he will screen their patients’ medical records for suitable research study participants 
and discuss the study and their potential for enrolling in the research study. Potential subjects contacted 
by their treating physician will be referred to the investigator/research staff of the study. During the 
initial conversation between the investigator/research staff and the patient, the patient may be asked to 
provide certain health information that is necessary to the recruitment and enrollment process. The 
investigator/research staff may also review portions of their medical records in order to further assess 
eligibility. They will use the information provided by the patient and/or medical record to confirm that 
the patient is eligible and to contact the patient regarding study enrollment. If the patient turns out to 
be ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information that must 
be maintained for screening log purposes. In most cases, the initial contact with the prospective subject 
will be conducted either by the treatment team, investigator or the research staff working in 
consultation with the treatment team. 
Patients will be required to sign a statement of informed consent that meets the requirements of the 
code of Federal Regulations (11) and the IRB of this center. A consent form is appended. The medical 
record will include a statement that written informed consent was obtained (and document in the 
record the date written consent was obtained before) and the patient is enrolled in the study. 
 
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for 
Subject Registration.  
 
 
 
 
 
 
 
 
 
 
 

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6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Table 1. Schedule of trial events 
Screening- Visit 1 
( Baseline or D0) 
Imaging 1*
(Visit 2 or D1) 
Imaging 2*
(Visit 3 or D2) 
ICF
X
Medical History
X
Physical Exam
X
X
Review medications
X
CBC
X
Serum BUN and Creatinine
X
AST, ALT, ALP, bil, albumin
X
Review of prior imaging
X
Adverse event monitoring
X
X
68Ga-PSMA administration
X
X
68Ga-PSMA PET scans
X
X
Research  Blood draws **
X
X
*Two scans with 68Ga-PSMA-cyclotron 
and 68Ga-PSMA-generator radiotracers 
will be performed at least 24h apart 
(max 48h) 
** Research blood draws will be 
performed only in a subset of patients 
(3-5) and are not required for 
participation in the study. The planned 
timepoints are as follows: pre tracer 
injection, 5 minutes (+/- 10 minutes) 15 
minutes (+/- 10 minutes), 30 minutes 
(+/-10 minutes), 60 minutes (+/-10 
minutes). A blood draw will also be 
performed after each scan (12 blood 
draws in total per patient at most) (for 
details refer to section 6.1.2.2).
 
 
 
 
 
 
 

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6.1.1 
Screening Visit  
 
Once a patient signs informed consent, but prior to the initiation of neoadjuvant ADT for prostate cancer 
the following standard of care tests and procedures will be performed prior to the administration of the 
investigational diagnostic agent: 
 
Obtain written informed consent 
 
Obtain medical history 
 
Physical exam including Karnofsky performance status 
 
Confirm adequate venous access 
 
Review medications 
 
Laboratory studies: 
 
CBC, Serum BUN and creatinine, AST, ALT, alkaline phosphatase, bilirubin and albumin 
 
Review of prior imaging studies to confirm metastatic disease status (e.g. 99mTc bone scan 
(prostate cancer), NaF PET (prostate cancer), MRI, or CT) 
 
 
 
 
6.1.2 
Intervention Phase 
 
 
 
 
 
 
6.1.2.1 Patient scans 
 
 
 
Two 68Ga-PSMA PET/CT scans will be performed successively at least 6 hours apart.  
 
 
6.1.2.2 Serum Blood Draws 
 
A subset of patients will have serum blood draws (approximately 5 ml) for pharmacokinetic analysis. This 
is only required in a subset (3-5 patients) as a smaller number of patients will be needed to generalize 
organ and lesional dosimetry.  The planned timepoints are as follows: pre tracer injection, 5 minutes (+/- 
10 minutes) 15 minutes (+/- 10 minutes), 30 minutes (+/-10 minutes), 60 minutes (+/-10 minutes). A 
blood draw will also be performed after each scan (12 blood draws in total per patient at most). This will 
be done through the IV placed to administer the PET tracer during the imaging visit. Apart from routine 
laboratory tests, samples will also be evaluated for the presence of 68Ga, as well as 66Ga, potential 
contaminants for generator-produced and cyclotron-produced products. Blood counts, liver function 
tests, and creatinine levels will also be monitored before, during, and after imaging 
evaluation/radiotracer injection. Apart from routine laboratory tests, samples will also be evaluated for 
the presence of 68Ga, as well as 66Ga, potential contaminants for generator-produced and cyclotron-
produced radiotracers, respectively. Images will also be evaluated for location of radiotracer uptake, as 
well as excretion and organ-specific dosimetry.  
 
6.1.3 
Evaluation during intervention 
 
Performance Status 
Performance status will be assessed using the Karnofsky Performance Status scale. 
 
Vital Signs 
Blood pressure and heart rate will be obtained prior to each PET scan. 
 
Serum Blood Draws 
As described above 

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6.1.4      Follow- up  
 
The patients that are enrolled in the study will afterwards undergo treatment for metastatic prostate 
cancer disease either as per standard of care or after enrollment in clinical trials. During completion of 
the treatment, there is usually a follow- up scan approximately 3mo after treatment where additional 
imaging is performed. This additional imaging will be considered the follow- up visit and will be used to 
correlate imaging with reported outcomes as well as biochemical and genomic analysis. 
 
7. Study Intervention 
 
7.1 Study Intervention/Patient scans   
 
 
Protocol initiation quality assurance 
 
Patient scans will be acquired on one of the Siemens Biograph mCTTM PET/CT scanners with a preference 
for the same instrument on all scans. Quality assurance images from each system will be acquired at the 
beginning of the protocol on all mCT scanners using a 68Ga-filled 20-cm-diameter cylindrical water 
phantom with average SUVs in the range 1.0 +/- 0.5 g/ml with no artifacts on visual inspection. 
Individual patients preferably use the same scanner system for both scans.  
Prior to imaging evaluation, patients will be permitted to eat a light meal. 
An intravenous catheter (Hep-Lock) will be placed in the CBIC or WCINYP for radiopharmaceutical 
administration, scans, and blood sampling. 
 
Patient scans 
 
 
 
Two dynamic whole body 68Ga-PSMA PET/CT scans will be performed successively at least 6 hours apart. 
As there will be an accumulation of activity in the urinary bladder, patients will have pre-treatment 
hydration and encourage voiding immediately prior to imaging, however the short half-life of 68Ga 
should not result in imaging counts from the first scan to appear on the latter scan. 
PET/CT imaging patients will be positioned on a flat couch in radiation treatment position. Custom-made 
immobilization devices, skin markings, PET/CT gantry, and room lasers will be used to ensure accurate 
and reproducible positioning. Imaging will start with low-dose CT scan (80 mA) for attenuation 
correction, followed by a PET scan. A low dose CT scan (80 mA) will be performed over the prostate or a 
pre-determined index lesion.  A 10min dynamic PET scan at the pelvic bed position, centered over the 
prostate tissues, will be initiated concurrently with an intravenous bolus injection of approximately 
2.5MBq/kg of body weight (+/- 10%) of 68Ga-PSMA, followed by a time series of whole-body PET scans 
(passes) at least 10-75 min and at most 10-90 min post injection. The PET acquisition time per bed 
position per pass will be fixed at 30sec and the total number of passes summed post acquisition to 
produce the static 68Ga-PSMA PET images will be at least six. The total number of late passes may be 
increased , if needed, such that the product of total acquisition time per bed position from all passes 
and injected activity is at least 7.5 MBq/kg*min or a total acquisition time of 90min is reached. 
Moreover, the number of bed positions will be adjusted to cover a field of view from top of the skull to 
mid-thigh of an average human adult for each pass. All PET scans will be conducted with patients in a 
supine position with the arms comfortably positioned and secured by the side of the patient. All whole-
body PET passes of each subject will be uni-directional, i.e. they will be performed along the same axial 
direction (cranio-caudal or caudo-cranial). 

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The PET data from at least the last six whole-body scan passes will be summed up and reconstructed at 
each bed position such that the product of total acquisition time per bed position from all passes and 
injected activity is at least 7.5 MBq/kg*min or a total scan time of 90min is reached. The resulting 
composite static PET images will then be combined with the same method as that employed for 
conventional static PET images at each bed position and the composite Standardized Uptake Value (SUV) 
static PET images will be calculated. In the meantime, the dynamic 68Ga-PSMA concentration in the 
blood plasma (input function) will also be derived from the dynamic PET images at the pelvis, as 
estimated from the 0-10min p.i. of the initial dynamic pelvic PET scan and the corresponding pelvic beds 
of the subsequent set of whole-body PET passes. For that purpose, regions of interest will be drawn in 
the lumen of the abdominal section of the descending aorta that is included in the pelvic bed position. 
The blood pool image regions will be drawn as far as possible from the neighboring aortic wall to 
minimize any partial volume effects. The image derived input function data will then be fitted to the 
measured blood samples data for validation and enhanced accuracy. Subsequently, the images from all 
the dynamic PET whole-body passes and the image-derived input function will be fitted to the Patlak 
graphical model on a voxel-by-voxel basis to produce whole-body 68Ga-PSMA net uptake rate constant 
(Ki) images. During the PET scan procedure, the patient will be allowed to get off from the couch in 
between the dynamic whole-body passes, if required (such as for a bathroom break).  
 
The PET data will be used to determine the repeatability of the multi-parametric (SUV and Ki) features of 
the 68Ga-PSMA organ biodistribution between two successive 68Ga-PSMA-generator and cyclotron 
PET/CT scans. Moreover, the same data will be utilized to evaluate the equivalence of the SUV and Ki 
features between the organ biodistributions of generator- and cyclotron-produced 68Ga-PSMA 
radiopharmaceuticals as estimated from respective dynamic whole-body 68Ga-PSMA PET/CT scans. 
Following standard image processing, regions of interest (ROI) will be drawn on the summed dynamic 
image data set, and then copied onto the individual dynamic frames, in order to analyze the tumor 
activity as a function of time. Reconstructed whole body static 68Ga-PSMA PET images will be analyzed 
on a standard workstation. 
After 24-48 hours, patients will be asked to repeat PET imaging after injection of the second 
experimental radiotracer. The same procedures will apply. The radiopharmacy will keep a log of all 
doses administered. The intravenous catheter will be removed at the conclusion of imaging.  
 
 
7.2 Availability 
 
Radiotracer production described in section 2.5 
 
7.3 Acquisition and Accountability  
 
 
 
Radiotracer production described in section 2.5 
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Radiotracer production described in section 2.5 
 
7.5 Product Storage and Stability 
 
Radiotracer production described in section 2.5 

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7.6 Preparation 
 
Radiotracer production described in section 2.5 
 
7.7 Dosing and Administration 
 
Radiotracer dose described in section 3.3 
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
Not applicable 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
Participation in this study is entirely voluntary. Patients may be removed from the protocol for the 
following reasons: 
 
Patient decides to withdraw from the study. 
 
Intercurrent illness that prevents treatment and/or follow-up imaging  
 
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 
further treatment, in the judgment of the investigator 
 
Does not meet inclusion/exclusion criteria 
 
7.10  Duration of Follow Up 
 
Not applicable.  
This is a protocol designed to conform to RDRC regulations and has the specific purpose to study the 
equivalence of a radiopharmaceutical made using generator and cyclotron produced 68Ga. It is not a 
therapeutic study and therefore does not have end point of treatment outcome. 
 
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
  
The patients’ doses will not be randomized as per FDA guidance documents for bioequivalence -- 21 CFR 
320.24(b) where a crossover design would be plausible, but instead will be conducted in a parallel 
design since the shipments of Ga-PSMAcyc will always be in the afternoon. That said the reader will be 
blinded as to which of the imaging pair emanated from the Ga-PSMAcyc or PSMAgen as the images will 
be delivered in pairs separate from the imaging sessions. In this way, the rigor of the bioequivalence is 
retained in the reader/analyst being blinded to the imaging session. 
 
7.12 Study Intervention/Follow-up Compliance 
 
Not applicable 
 
 
 

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8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
Participants may withdraw voluntarily from the study. A dedicated Case Report Form (CRF) page should 
capture the date and the specific underlying reason for discontinuation of study intervention or 
participant discontinuation/withdrawal.  
 
8.1 Discontinuation of Study Intervention 
 
Not applicable. This is not a therapeutic study. 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
This is not a therapeutic study. Participants can withdraw by refusing to perform the scans at any point 
during the study. 
 
8.3 Lost to Follow Up 
A participant will be considered lost to follow-up if we fail to obtain his imaging scan 3 months post-
treatment. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 
The site will attempt to contact the participant and reschedule the missed visit. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
 
9. Correlative/Special Studies  
 
Not applicable 
 
10.  Measurement of Effect 
 
This is a protocol designed to conform to RDRC regulations and has the specific purpose to study the 
equivalence of a radiopharmaceutical made using generator and cyclotron produced 68Ga. It is not a 
therapeutic study and therefore does not have end point of treatment outcome. 
 
10.1 Response Criteria 
 
 
Not applicable. This is not a therapeutic study. 
 
10.2 Duration of Response  
 
Not applicable. This is not a therapeutic study. 

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10.3 Progression-Free Survival  
 
Not applicable. This is not a therapeutic study. 
 
 
10.4 Other Response Parameters 
 
 Not applicable. This is not a therapeutic study. 
 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, efficacy, and 
adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system 
that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the 
creation of customized, secure data management systems that include Web-based data-
entry forms, reporting tools, and a full array of security features including user and 
group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures.  REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate Ethics Committee. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the IP is released to the Investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study, such as amendments to the protocol, the ICF, or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files.  
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit written 

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summaries of the study status to the IEC/IRB as required. On completion of the study, the IEC/IRB 
will be notified that the study has ended.  
 
Neither the Investigator nor BMS will modify or alter this protocol without the agreement of the 
other. All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IEC/IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this case, 
the necessary action will be taken first, with the relevant protocol amendment following shortly 
thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead site, Weill 
Cornell Medicine, updated documents will be provided to participating sites. Weill Cornell 
Medicine must approve all consent form changes prior to local IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable national 
and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-GCP 
and local regulations, as applicable, from each potential subject or each subject’s legally 
authorized representative prior to participating in the research study. Subjects who agree to 
participate will sign the approved informed consent form and will be provided a copy of the signed 
document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided to the 
subject must approved by IRB prior to use. The ICF will adhere to IRB/IEC requirements, applicable 
laws and regulations. 
 
 
 
 

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If consent cannot be obtained in person, written consent can be obtained via a HIPAA-
compliant method per the following procedure: 
 
 The participant receives a copy of the informed consent document (e.g., via mail, 
fax or email) in advance of discussion regarding the study. If mailed, two copies 
must be mailed. This allows the participant to retain a copy for reference when 
their signed document is returned to the site. A final copy with all necessary 
signatures will be sent back to the participant from the site.  
 The investigator or designee discusses the study with the potential participant 
either via telephone or video conferencing. The investigator/designee must have 
the same consent discussion via telephone/video conferencing that they would 
have had with the participant during an in-person meeting. The 
investigator/designee must also implement a method to ensure the identity of 
the participant (e.g., verification of state identification or other identifying 
documents or use of personal questions or visual methods). The 
investigator/designee will also remind the potential participant to conduct this 
informed consent discussion in a private location to ensure privacy.  
 The investigator or designee will provide a comprehensive explanation of the 
purpose, procedures, and possible risks/benefits of the study in language that is 
understandable to a non-medically trained person; explain the participant 
responsibilities and the fact that participation is voluntary; that the participant 
may withdraw from the study at any time; and that the decision not to 
participate or to withdraw will not affect the patient’s care in any way. The 
investigator or designee will provide ample opportunity for the participant to ask 
questions and to consider the decision.  
 If the participant expresses a sustained interest, instructions will be given about 
how the participant needs to sign and date the consent form and how to 
transmit the signed form back.  
 Once the research team receives the signed informed consent document from 
the participant, the investigator/designee who conducted the consent process 
must sign and date the document using the current date. Under the signature 
line, the investigator/designee must document whether consent was obtained 
over the telephone or video conferencing, the date of the telephone/video 
conference, and the date the signed consent was received. For example, 
“Discussed with [participant name] via [telephone or videoconferencing] on 
[insert date] and received signed consent form on [insert date].” Include a brief 
reason for performing the informed consent discussion over the 
telephone/videoconferencing.  
 The date the investigator/designee signs the informed consent document, not 
the date the consent discussion with the participant took place, is the official 
date of informed consent for the participant on the trial. The informed consent 

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form is not valid and study enrollment cannot proceed unless all pages are 
received and appropriately filled out/signed/dated by the participant.  
 The final informed consent document must be filed in the designated 
investigator/site regulatory file location. A copy of the final informed consent 
document, signed by the participant and the investigator or designee, must be 
sent back to the participant via email/scan, fax, or postal mail.  
 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to http://www.clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information. 
 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced.  After completion of the study, all documents and 
data relating to the study will be kept in an orderly manner by the Investigator in a secure study 
file.  Essential documents should be retained for 2 years after the final marketing approval in an 
ICH region or for at least 2 years since the discontinuation of clinical development of the IP. In 
addition, all subjects medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
Up to 30 patients will undergo a dynamic whole-body scan with 68Ga-PSMAGen and later 68Ga-PSMAcyc 
with a maximum time of 2 days and a minimum time of 6 h between the two injections. All 22 patients 
will receive 68Ga-PSMAGen at a specific activity of 1-2 Ci/µmol, the typical specific activity used in clinical 
trials with 68Ga-PSMA. We expect the 68Ga-PSMAcyc to be delivered and injected at a specific activity of 
0.1- 2.0 Ci/umol given the rigors of delivery.  We will accept doses in this range as the prior small animal 
imaging was designed to understand the affect of specific activity over a 20X range. 
For a power of 80% a calculation of the sample size needed to test odds ratio (equality test) was 
performed. A sample size of 22 would give a power percentage of 18.47 with a type 1 error of 5%.  This 
power percentage is sufficient in providing confidence that the findings will reflect a true effect.   The 
median statistical power of studies in the neurosciences is between ∼8% and ∼31%. 
We will not and should not be focusing on p-values but rather the estimates of the effect size with its 
confidence intervals. 

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Estimating repeatabilities using a mixed effects model framework has proven to be powerful, the 
repeatability (r)is calculated as the variance among group means (group-level variance) over the sum of 
group-level and data-level (residual) variance (v).  A pearson’s correlation coefficient will demonstrate 
also present the repeatability of results.  Intraclass correlation values for both groups will be calculated 
to test if the groups differ in repeatability.  These collection of tests(functions) for estimating 
repeatability of measurements with a single grouping factor are all performed in R statistical software.   
To quantify the agreement between the two scans, we will use the repeated measures correlation 
coefficient to account for multiple observations per subject. We will calculate the repeated measures 
correlation-coefficient for the SUVmax and SUVmean for reference regions as well as regions suspicious 
for metastatic disease. We will measure SUVmean and SUVmax of the same Regions of Interest (ROI) in 
both scans using the PET analysis software we use in our clinical practice. The two scans will be retrieved 
and the exact same ROIs will be drawn at the same time for the two scans (software offers a copy-paste 
function so that no discrepancies exist between the two measurements). The SUVmean and SUVmax 
obtained from both scans for each Region of Interest will then be analyzed to determine the within-
subject coefficient of variation value as measured by the Bland Altman analysis. If the agreement 
between the two scans lies within an acceptable rate (which we consider 30% based on previously 
published data), we will consider the two methods equivalent. 
Also, as aforementioned the Bland-Altman Test presents proof of repeatability analysis. 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The investigator will 
be required to provide appropriate information concerning any findings that suggest significant hazards, 
contraindications, side effects, or precautions pertinent to the safe use of the drug or device under 
investigation.  Safety will be monitored by evaluation of adverse events reported by subjects or 
observed by investigators or research staff, as well as by other investigations such as clinical laboratory 
tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, and does not imply any judgment about causality. An adverse event can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose.  
 
 
 
 
 
 
 

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13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
The non-radiation exposure related risks that may be experienced during the scans are related 
to the radiotracer infusion and can be: 
 
Bruising or bleeding at the site of the radiotracer injection 
 
Infection at the site of injection 
 
Allergic type reaction 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized 
for AE reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
- 
 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be maintained by 
the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
 
13.2 Definition of SAE 
 
SAEs include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other 
serious events that may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. (Modify as necessary) 
 

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13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
13.2.2 Reporting of SAE to FDA  
 
IND application sponsor must report any suspected adverse reaction or adverse reaction 
to study intervention that is both serious and unexpected. Unexpected fatal or life-
threatening suspected adverse reactions represent especially important safety 
information and must be reported to FDA as soon as possible but no later than 7 
calendar days following the sponsor’s initial receipt of the information. 
i. death, 
ii. a life-threatening adverse event,   
iii. in-patient hospitalization or prolongation of existing hospitalization, 
iv. a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or   
v. a congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or research subject and may require medical 
or surgical intervention to prevent one of the outcomes listed as serious 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Investigational Products  
5901-B Ammendale Road  
Beltsville, MD 20705-1266   
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the investigator 
confirms that the AE/SAE has stabilized and no more follow-up is required. This requirement indicates 
that follow-up may be required for some events after the subject discontinues participation from the 
study.  
 
 
 
 

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13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
All reportable events will be recorded with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) 
 
The reporting of UPIRTSOs applies to non-exempt human subjects research conducted or supported by 
HHS. Provide the definition of an UPIRTSO being used for this clinical trial. An incident, experience, or 
outcome that meets the definition of an UPIRTSO generally will warrant consideration of changes to the 
protocol or consent in order to protect the safety, welfare, or rights of participants or others. Other 
UPIRTSOs may warrant corrective actions at a specific study site. Examples of corrective actions or 
changes that might need to be considered in response to an UPIRTSO include: 
 
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks 
• 
Implementation of additional safety monitoring procedures 
• 
Suspension of enrollment of new participants or halting of study procedures for enrolled 
participants  
• 
Modification of informed consent documents to include a description of newly recognized risks 
• 
Provision of additional information about newly recognized risks to previously enrolled 
participants. 
 

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14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing Institutional 
Review Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). 
The UPIRTSO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the following 
timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study sponsor within <insert timeline in accordance with policy> of the investigator 
becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor within 
<insert timeline in accordance with policy> of the investigator becoming aware of the 
problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
Food and Drug Administration (FDA), and the Office for Human Research Protections 
(OHRP) within <insert timeline in accordance with policy> of the IRB’s receipt of the 
report of the problem from the investigator.] 
 
 
 
 
 
 
 

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