Clinical trial NCT04186819
Conditions: Prostate Cancer
Keywords: Primary Prostate Cancer Diagnostic Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) Scan
Sponsor: Blue Earth Diagnostics
Start date: 2020-03-02; Completion date: 2021-06-21
Enrollment: 356 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A prospective, Phase 3, multi center, single-arm, imaging study investigating the safety and diagnostic performance of Radio-hybrid Prostate Specific Membrane Antigen (rhPSMA) 7.3 (18F) Positron Emission Tomography (PET) ligand in men with newly diagnosed prostate cancer.

Detailed description:
Main objective is to assess the sensitivity and specificity of rhPSMA-7.3 (18F) positron emission tomography (PET) in detecting N1 disease (as determined by the central blinded image evaluation \[BIE\]) on a patient level compared to the histopathology of pelvic lymphatic tissue removed during radical prostatectomy (RP) and pelvic lymph node dissection (PLND). At least one positive pelvic LN on PET (N1) and one positive lymph node (LN) as determined by histopathology (pN1) on the same side of the pelvis (left or right) will be deemed a True Positive (TP) at the patient level.

Arms: arm 1: Single intravenous administration of rhPSMA-7.3 (18F) for PET Scan
Interventions: intervention 1: rhPSMA-7.3 (18F) Injection intervention 2: Positron Emission Tomography scan
Intervention descriptions: intervention 1: Radioligand for PET CT scanning intervention 2: imaging test with radioligand

Protocol documents:
SAP_002.pdf: 
Conﬁdential 
 
Blue Earth Diagnostics/Paraxel International 
 
                                                                    SAP V3.0 01Oct2021 
 
 
 
Statistical Analysis Plan 
Version 3.0 01 October 2021 
  
 
Protocol Title:  Prospective, Phase 3, multi center, single-arm, imaging study 
investigating the safety and diagnostic performance of rhPSMA-7.3 (¹⁸F) PET 
ligand in men with newly diagnosed prostate cancer 
 
Protocol Number:  BED-PSMA-301  
Compound Number: Flotufolastat (18F) injection  
Short Title: LIGHTHOUSE 
  
Sponsor Name: Blue Earth Diagnostics Ltd.  
Legal Registered Address:  Magdalen Centre, Robert Robinson Avenue, The 
Oxford Science Park. Oxford, OX4 4GA, UK  
  
IND  
141,561  
NCT  
 04186819 
 


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 1 of 37 
 
 PAREXEL International 
Blue Earth Diagnostics 
BED-PSMA-301 
A prospective, Phase 3, multi center, single-arm, imaging study investigating the safety and 
diagnostic performance of rhPSMA-7.3 (¹⁸F) PET ligand in men with newly diagnosed prostate 
cancer 
 Statistical Analysis Plan 
Version: 3.0  
PAREXEL Project Number: 245596 
 
 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 2 of 37 
 
SPONSOR SIGNATURE PAGE 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
 
 
Albert Chau 
 
 
 
 
Date 
 
 
 
Director of Biometrics (interim) 
 
 
 
Blue Earth Diagnostics Ltd. 
 
 
 
 
 
 
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01-Oct-2021


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 3 of 37 
 
PAREXEL SIGNATURE PAGE 
 
Signature(s) below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
 
This document has been approved and signed electronically by the following:  
 
 
 
 
 
 
Signatory 
Author 
Kees Duineveld 
Project Role: Biostatistics Lead/Biostatistician   
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 4 of 37 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS 
7 
1 
INTRODUCTION 
9 
2 
STUDY OBJECTIVES 
10 
2.1 
Primary Objective(s) 
10 
2.2 
Secondary Objective(s) 
10 
2.3 
Exploratory Objective(s) 
11 
3 
INVESTIGATIONAL PLAN 
11 
3.1 
Overall Study Design and Plan 
11 
3.2 
Endpoints 
12 
3.2.1 
Primary Efficacy Endpoint 
12 
3.2.2 
Secondary Efficacy Endpoints 
12 
3.2.3 
Exploratory Efficacy Endpoints 
13 
3.2.4 
Safety Variables 
13 
4 
STATISTICAL METHODS 
13 
4.1 
Data Quality Assurance 
13 
4.2 
General Presentation Considerations 
13 
4.3 
Software 
14 
4.4 
Study Patients 
15 
4.4.1 
Disposition of Patients 
15 
4.4.2 
Protocol Deviations 
15 
4.5 
Analysis Sets 
16 
4.6 
Demographic and Other Baseline Characteristics 
17 
4.6.1 
Demographics 
17 
4.6.2 
Baseline conventional imaging 
17 
4.6.3 
Prostate Cancer History 
17 
4.6.4 
Baseline Risk Category 
18 
4.6.5 
Medical history 
19 
4.7 
Prior and Concomitant Medications and Procedures 
19 
4.8 
Exposure and Treatment Compliance 
19 
4.9 
rhPSMA-7.3 (18F) Image reading 
20 
4.10 
Biopsy/Surgery 
20 
4.11 
TNM staging and Gleason score 
21 
4.12 
Standard of Truth 
21 
4.13 
Hemipelvis Region Categorization and Patient Level Categorization 
22 
4.14 
Efficacy Evaluation 
24 
4.14.1 
Analysis and Data Conventions 
24 
4.14.1.1 Adjustments for Covariates 
24 
4.14.1.2 Handling of Dropouts or Missing Data 
24 
4.14.1.3 Interim Analyses 
25 
4.14.1.4 Examination of Subgroups 
25 
4.14.1.5 Clustered binary data estimate of variance 
25 
4.14.1.5.1 Sensitivity 
25 
4.14.1.5.2 Additional Confidence interval Sensitivity 
26 
4.14.1.5.3 Specificity 
26 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Effective Date:  30 Jan 19 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 5 of 37 
4.14.2 
Primary Efficacy Variable 
26 
4.14.2.1 Sensitivity Analysis; patients with FN and FP results 
27 
4.14.3 
Secondary Efficacy Variables 
27 
4.14.3.1 Percentage of patients in whom rhPSMA-7.3 (18F) imaging detects at least one verified 
M1 metastasis, as determined by central BIE. 
27 
4.14.3.2 Percentage of patients with negative conventional imaging for M1 disease in whom 
rhPSMA-7.3 (18F) PET detects at least one verified M1 metastasis, as determined by 
central BIE. 
28 
4.14.3.3 Patient level PPV of rhPSMA-7.3 (18F) PET BIE for N1 and M1 lesions compared to 
histopathology or confirmatory imaging (M1 lesions only). 
28 
4.14.3.4 PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to 
surgical pathology on a patient level in which a FP patient is defined as having at least 
one FP region (right or left pelvis), regardless of any coexisting TP findings. 
29 
4.14.3.5 NPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to 
surgical pathology on a patient level in which a FN patient is defined as having at least 
one FN region (right or left pelvis), regardless of any coexisting TN findings. 
29 
4.14.3.6 Upstaging 
29 
4.14.3.7 Kappa statistic for the agreement between and within blinded independent readers on 
the interpretation of rhPSMA-7.3 (18F) scans. 
30 
4.14.3.7.1 Inter-reader agreement analysis 
30 
4.14.3.7.2 Intra-reader agreement analysis 
30 
4.14.4 
Exploratory Efficacy Variables 
30 
4.14.4.1 Diagnostic performance (sensitivity and specificity) of rhPSMA-7.3 (18F) PET for 
detecting pelvic LN metastases compared to surgical pathology on a regional level. 30 
4.15 
Safety Evaluation 
31 
4.15.1 
Adverse Events 
31 
4.15.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events 
32 
4.15.3 
Clinical Laboratory Evaluation 
32 
4.15.4 
Vital Signs, Physical Findings and Other Observations Related to Safety 
33 
4.15.5 
Other safety 
33 
4.15.6 
Safety Monitoring (Independent Data Monitoring Committee [IDMC], Data 
Monitoring Committee [DMC], Data and Safety Monitoring Board [DSMB]) 
33 
4.16 
Determination of Sample Size 
34 
4.17 
Changes in the Conduct of the Study or Planned Analysis 
34 
5 
REFERENCES 
35 
6 
Appendix 
36 
6.1 
SAS program to reproduce data in Zhou et al [10]. 
36 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 6 of 37 
REVISION HISTORY 
 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
03 July 2020 
Finalized document 
2.0 
18 Aug 2021 
Added BMI 
Wording: Replaced consensus between blinded readers with 
majority of blinded readers. 
Added that within analysis of subcategories, categories with 
low counts may be collapsed. 
Removed second exploratory objective and endpoint 
Updated first exploratory endpoint to use cluster binary data 
estimation of Confidence Interval 
3.0 
Date of Last 
Signature 
Changed TEAE definition from on or before Visit 3 to on or 
before Day 4.  
Changed medications and/procedures starting after Day 4 not 
to be summarized. 
Changed summaries of TEAE leading to death, serious 
adverse events, and discontinuation will only display TEAE. 
 
 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 7 of 37 
LIST OF ABBREVIATIONS 
 
 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
BIE 
blinded image evaluation  
CI 
Confidence interval 
CSP 
Clinical Study Protocol 
COVID-19 
Coronavirus disease 2019 
CT 
Computed tomography 
DRM 
Data Review Meeting 
EBRT 
External beam radiation therapy 
EAP 
Efficacy Analysis Population 
ECG 
electrocardiogram  
eCRF 
electronic Case Report Form 
EEP 
Extended Efficacy Population 
FAS 
Full Analysis Set 
FN 
False Negative 
FP 
False Positive 
FSP 
Full Safety Population 
GGG 
Gleason Grade Grouping 
IP 
Investigational product 
IMP 
Investigational Medicinal Product 
IV 
Intravenous  
LN 
Lymph Node 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NPV 
Negative Predictive Value 
PCa 
Prostate Cancer 
PET 
Positron emission tomography 
PLND 
Pelvic lymph node dissection 
PP 
Per Protocol Population 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 8 of 37 
Abbreviation / Acronym 
Definition / Expansion 
PPV 
Positive predictive value 
PSA 
prostate-specific antigen 
PT 
Preferred Term 
RP 
Radical prostatectomy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SoT 
Standard of Truth 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, Listings and Figures,  
TN 
True Negative 
TP 
True Positive 
VDR 
Verified Detection Rate 
WHO-DD 
WHO Drug Global 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 9 of 37 
1 
INTRODUCTION 
Prostate cancer (PCa) is the most prevalent cancer in men in the developed world and the third 
leading cause of death (Jemal, 2011).  It is most commonly diagnosed in men aged 65 years and 
over and in its early stages it is largely asymptomatic, with tumors detected by identification of 
increased levels of prostate-specific antigen (PSA) in peripheral blood. If detected early, and when 
the disease is organ confined, the 5-year survival rate approaches 100%. 
Accurate staging of newly diagnosed PCa assists in directing appropriate treatment strategies. The 
National Comprehensive Cancer Network (NCCN Guidelines; Version 1.2020; PROS-2) 
recommend bone imaging and abdominal/pelvic imaging as the initial work-up in patients with 
newly-diagnosed high- and very high-risk PCa, as well as in a subgroup of patients with 
unfavorable intermediate-risk PCa. The primary goal of such imaging is to detect extra-prostatic 
disease (M1: non-regional nodal involvement, bone, or other sites [UICC, TNM Classification of 
Malignant Tumours]); the identification of which would likely significantly change the planned 
treatment regimen from locoregional to systemic therapy. 
The overwhelming need for improved imaging should focus on the identification of N1 (metastasis 
in regional node(s)) and M1 disease, which may potentially have a meaningful impact on patient 
treatment and outcomes. Ideally, a staging technique that detects extra-prostatic disease should: 1) 
image the whole body, 2) not be limited to the skeleton, and 3) be both sensitive and specific for 
identifying PCa extent. 
This study is designed to assess the performance of rhPSMA-7.3 (18F) for detecting N1 and M1 
disease in patients with newly diagnosed PCa eligible for curative intent, standard of care 
locoregional therapy, who have elected to undergo radical prostatectomy (RP) with regional pelvic 
lymph node dissection (PLND).  Evaluation of the sensitivity and specificity of rhPSMA-7.3 (18F) 
imaging by central blinded image evaluation (BIE) for detecting regional pelvic lymph node (LN) 
involvement, compared to histopathology, will be performed as the co-primary endpoints.  
Therefore, only patients who are scheduled to undergo RP and a PLND will be included in this 
study. 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures (TLFs).  It describes the variables and populations, anticipated data transformations and 
manipulations and other details of the analyses not provided in the Clinical Study Protocol (CSP). 
In case of discrepancies between Study Protocol and SAP the SAP supersedes the Study Protocol. 
 
 
The SAP will be finalized prior to database lock and describes the statistical analysis as it is 
foreseen when the study is being planned.  If circumstances should arise during the study rendering 
this analysis inappropriate, or if improved methods of analysis should arise, updates to the analyses 
may be made. 
 
The analyses described in this SAP are based upon the following study documents: 
• Study Protocol, Version 3.0 (July 01, 2020) 
• Electronic Case Report Form (eCRF), Version 4.0 (February 8, 2021) 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 10 of 37 
• Invicro Independent Review Charter (IRC), Version 2.0 (June 18, 2021)  
• Invicro Technical Operations Manual Version 4.0 (August 04, 2020) 
• Invicro Review Session Methodology: Conventional Imaging Version 1.0 (June 08, 2021) 
 
The following guidance document has been used: 
 
Guidance for Industry and FDA Staff - Statistical Guidance on Reporting Results from Studies 
Evaluating Diagnostic Tests (13 March 2007) 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
The primary objective of the study is to assess the sensitivity and specificity of rhPSMA-7.3 (18F) 
positron emission tomography (PET) in detecting N1 disease (as determined by the central BIE) 
on a patient level compared to the histopathology of pelvic lymphatic tissue removed during RP 
and PLND.  At least one positive pelvic LN on PET (N1) and one positive LN as determined by 
histopathology (pN1) on the same side of the pelvis (left or right) will be deemed a True Positive 
(TP) at the patient level.  In patients who have no TP regions (left or right), the translation of 
varying combinations of False Positive (FP), True Negative (TN) and False Negative (FN) regions 
to patient level categorizations is described in detail in Section 4.13. 
 
 
2.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
1. To assess the Verified Detection Rate (VDR) for M1 disease of rhPSMA-7.3 (18F) PET findings 
(as determined by central BIE) on a patient level in patients with newly diagnosed unfavorable 
intermediate-, high-, or very high-risk PCa using histopathology or confirmatory imaging. 
2. To assess the VDR for M1 disease of rhPSMA-7.3 (18F) PET findings (as determined by central 
BIE) on a patient level in patients with negative conventional imaging. 
3. To assess the positive predictive value (PPV) of rhPSMA-7.3 (18F) PET for N1 and M1 lesions 
(as determined by central BIE) compared to histopathology or confirmatory imaging (M1 
lesions only). 
4. To assess the PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to 
surgical pathology on a patient level in which a FP patient is defined as having at least one FP 
region (right or left pelvis), regardless of any coexisting TP findings. 
5. To assess the negative predictive value (NPV) of rhPSMA-7.3 (18F) PET for detecting pelvic 
LN metastases compared to surgical pathology on a patient level in which a FN patient is 
defined as having at least one FN region (right or left pelvis), regardless of any coexisting TN 
findings. 
6. To assess the impact of rhPSMA-7.3 (18F) PET BIE on a) upstaging patients planned for RP or 
b) converting planned RP to external beam radiation therapy (EBRT). 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 11 of 37 
7. To determine the inter- and intra-reader agreement of rhPSMA-7.3 (18F) scan interpretation by 
blinded independent readers. 
8. To assess the safety of rhPSMA-7.3 (18F) injection in patients. 
 
 
2.3 
Exploratory Objective(s) 
The exploratory objectives of the study are: 
1. To assess the sensitivity and specificity of rhPSMA-7.3 (18F) PET in detecting nodal metastases 
(as determined by central BIE) on a regional level compared to the histopathology of pelvic 
lymphatic tissue removed during RP and PLND. 
 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a prospective, Phase 3, multi-center, single-arm, diagnostic imaging study designed to 
evaluate the safety and diagnostic performance of rhPSMA-7.3 (18F) PET ligand for the detection 
of N1 and M1 metastases in men with newly diagnosed unfavorable intermediate-, high- or very 
high-risk PCa (per NCCN Guidelines Version 1.2020; PROS-2). 
Up to approximately 375 patients will be enrolled into the study to ensure inclusion of at least 
300 evaluable patients undergoing RP and PLND.  Consented patients will be screened at Visit 1 
to determine eligibility for the study up to 28 days (up to 45 days due to the Coronavirus 
Disease-2019 [COVID-19] pandemic) before Investigational product (IP) administration at Visit 
2. Due to the COVID-19 pandemic, Visit 1 and Visit 2 may be combined.  Patients who meet all 
of the inclusion criteria and none of the exclusion criteria will be assigned a patient identifier (ID) 
and entered into the study at screening. In addition to their routine clinical work-up, which may 
include 99mtechnetium-biphosphonate and abdominal/pelvic computed tomography (CT) or 
magnetic resonance imaging (MRI) and chest CT per local practice, and before the scheduled RP, 
patients will be administered a dose of rhPSMA-7.3 (18F), an administered activity of 8 mCi (296 
MBq) ± 20% delivered as an intravenous (IV) bolus injection with a 10 mL fast 0.9% sodium 
chloride flush, followed by PET imaging. 
Note: The screening/eligibility evaluation may take place on the day of rhPSMA-7.3 (18F) 
administration (with pre-screening via telephone), if necessary, to ensure the safety of enrolled 
patients (see Visit 1 and 2 combined; CSP Section 10.3). Alternatively, the time from Visit 1 (initial 
screening) to Visit 2 (rhPSMA-7.3 (18F) PET scan) may be extended to 45 days due to the COVID-
19 pandemic.  
The PET imaging results for each patient will be reported to the responsible physician prior to the 
planned RP. If safe and feasible, within 1 to 3 days post-IP administration, the patient must return 
to the clinic for safety follow-up including an electrocardiogram (ECG), blood safety laboratory 
tests and a focused physical examination. Clinical review of the imaging results and discussion of 
further procedures/treatments with the patient should also take place at this visit if the results are 
available. In cases where the rhPSMA-7.3 (18F) PET imaging results are not available at the safety 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 12 of 37 
follow-up visit, imaging results and further procedures/treatment plan should be discussed with the 
patient within 7 days after rhPSMA-7.3 (18F) imaging (this review may be conducted by telephone 
at the clinician’s discretion). Note: due to the COVID-19 pandemic, the post-IP safety follow-up 
(laboratory and ECG assessments and focused physical examination) may be conducted within 1 
to 5 days post-IP administration to ensure the safety of enrolled patients.  
Within 45 days post-IP administration (may be extended to 60 days due to the COVID-19 
pandemic), the patient will receive treatment as follows, with further detail provided in CSP 
Section 9.1.6. 
• Standard of care surgical treatment of PCa, including a PLND; or  
• If the rhPSMA-7.3 (18F) PET scan detects M1 lesion(s): 
o A biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be 
required prior to initiation of treatment. 
Safety will include adverse events (AEs) and vital signs monitoring, clinical laboratory evaluations, 
12-lead ECG and focused physical examinations performed in all patients. 
 
 
3.2 
Endpoints 
3.2.1 Primary Efficacy Endpoint 
 
The co-primary endpoints for this study will be the: 
• Sensitivity of rhPSMA-7.3 (18F) PET (as determined by central BIE) for detecting pelvic 
LN metastases compared to surgical pathology on a patient level. 
• Specificity of rhPSMA-7.3 (18F) PET (as determined by central BIE) for detecting pelvic 
LN metastases compared to surgical pathology on a patient level 
 
 
3.2.2 Secondary Efficacy Endpoints 
 
The secondary endpoints for this study will be: 
1. Percentage of patients in whom rhPSMA-7.3 (18F) imaging detects at least one verified M1 
metastasis, as determined by central BIE. 
2. Percentage of patients with negative conventional imaging for M1 disease in whom rhPSMA-
7.3 (18F) PET detects at least one verified M1 metastasis, as determined by central BIE. 
3. Patient level PPV of rhPSMA-7.3 (18F) PET BIE for N1 and M1 lesions compared to 
histopathology or confirmatory imaging (M1 lesions only). 
4. PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FP patient is defined as having at least one FP region 
(right or left pelvis), regardless of any coexisting TP findings. 
5. NPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FN patient is defined as having at least one FN region 
(right or left pelvis), regardless of any coexisting TN findings. 
6.  
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 13 of 37 
a. The percentage of patients being upstaged to N1 or M1 disease; 
b. The percentage of patients in whom planned RP is converted to EBRT. 
7. Kappa statistic for the agreement between and within blinded independent readers on the 
interpretation of rhPSMA-7.3 (18F) scans. 
8. Safety (AEs, vital signs clinical laboratory evaluations, 12-lead ECG and focused physical 
examinations) of rhPSMA-7.3 (18F) injection in patients 
 
 
3.2.3 Exploratory Efficacy Endpoints 
1. Diagnostic performance (sensitivity and specificity) of rhPSMA-7.3 (18F) PET for detecting 
pelvic LN metastases compared to surgical pathology on a regional level. 
 
 
3.2.4 Safety Variables 
In all patients, safety evaluations will include AE monitoring and reporting from the time of 
informed consent throughout the study.  
Vital sign assessments will also be conducted at screening and pre- and post-IP administration on 
the day of rhPSMA-7.3 (18F) injection. 
In addition, a focused physical examination will be performed at screening and at the safety 
follow-up visit within 1 to 3 days post-IP administration (may occur within 1 to 5 days post-IP 
administration due to the COVID-19 pandemic), and a 12-lead ECG will be performed pre-IP 
administration on the day of rhPSMA-7.3 (18F) injection and at the safety follow-up visit within 1 
to 3 days post-IP administration (may occur within 1 to 5 days post-IP administration due to the 
COVID-19 pandemic). Baseline blood safety laboratory tests, including hematology (full blood 
count), biochemistry (urea and electrolytes, liver function tests) and coagulation will be performed 
pre-IP administration on the day of rhPSMA-7.3 (18F) injection and repeated at the safety follow-
up visit within 1 to 3 days post-IP administration (may occur within 1 to 5 days post-IP 
administration due to the COVID-19 pandemic). 
 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures. 
 
 
4.2 
General Presentation Considerations 
‘Baseline’ is defined as the last available pre-IP administration assessment.   
‘End of Study’ is defined as the last available post-IP administration assessment.   
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 14 of 37 
‘Study Day’ will be calculated relative to the date of rhPSMA-7.3 (18F) injection day, and is equal 
to: 
•  Assessment Date – IP Administration Date + 1 if the assessment date is on or after IP 
administration date.  
• Assessment Date – IP Administration Date, if the assessment date is before IP 
administration date. 
 
 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum and number of observations, unless otherwise stated.  Continuous data (e.g. 
counts) that are expected to be skewed will be presented in terms of the maximum, upper quartile, 
median, lower quartile, minimum and number of observations.  The minimum and maximum will 
be reported to the same number of decimal places as the raw data recorded in the database.  The 
mean, median, lower quartile and upper quartile will be reported to one more decimal place than 
the raw data recorded in the database.  The SD will be reported to two more decimal places than 
the raw data recorded in the database.  In case the rules result in more than four decimal places, the 
number of decimal places reported shall be four for any summary statistic, irrespective of the 
previous rules. 
 
Categorical data will be summarized in terms of the number of patients providing data at the 
relevant time point (n), frequency counts and percentages.  Any planned collapsing of categories 
will be detailed in the SAP text and the data displays.   
 
Percentages will be presented to one decimal place.  Percentages will not be presented for zero 
counts.  Percentages will be calculated using n as the denominator.  If sample sizes are small, the 
data displays will show the percentages, but any textual report will describe frequencies only.   
 
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001”. 
 
Confidence intervals (CIs) of continuous variables will be presented to one more decimal place 
than the raw data. CIs of proportions will be presented to three decimal places (e.g. 1/3 will be a 
proportion of 0.333) and exact intervals (Clopper-Pearson) will be employed unless specified 
otherwise. CI for percentages will be to one decimal place. 
 
 
4.3 
Software 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and 
validated environment.   
 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 15 of 37 
4.4 
Study Patients 
4.4.1 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion as per CONSORT guidance. 
The following summaries will be provided: 
• 
A summary of the number of patients screened for entry into the study and the number and 
percentage of patients excluded prior to IP administration by major reason and overall 
(Analysis set: All enrolled Patients) 
• 
A summary of the number of patients enrolled (See section 4.5) per center, and per country 
(Analysis set: Full Analysis Set [FAS]). 
• 
A summary of the number of patients who received IP, number of patients who had an 
evaluable PET scan following IP administration, and the number and percentage of patients 
withdrawing from the study and completing each phase.  (Analysis set: FAS).   
• 
A summary of withdrawals from the study and from IP administration by major reason 
(Analysis set: FAS). 
 
 
By-patient listings of eligibility details, enrollment details, visit dates (including impact of COVID-
19 on visits), withdrawal/study completion details (including reason for discontinuation and time 
since IP administration prior to discontinuation) will be provided. 
 
 
4.4.2 Protocol Deviations 
Protocol deviations will be handled in accordance with Parexel Standard Operating Procedures 
(SOPs). 
 
Protocol deviations occur when the patient, investigator, or Sponsor fails to adhere to protocol 
requirements or where there is a significant non-compliance to ICH-GCP, affecting patient safety 
or the scientific value of the trial. 
 
Major protocol deviations are defined as those deviations from the protocol likely to have an impact 
on the perceived efficacy and/or safety of study treatments.  The impact of major protocol 
deviations on the efficacy and/or safety results will be investigated by assessing the robustness of 
the study results and conclusions to the choice of analysis set, both including and excluding data 
potentially affected by major protocol deviations at a Data Review Meeting (DRM) shortly before 
database lock.  Results and population assignments will be summarized in a DRM report which 
will be signed off by all relevant scientific experts. 
 
Major protocol deviations and any action to be taken regarding the exclusion of patients or affected 
data from specific analyses are defined in the project-specific Protocol Deviation Specification 
which is agreed and signed off before analysis.  
Major protocol deviations which lead to withdrawal and replacement of the patient include, but not 
limited to: 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 16 of 37 
• Failure to meet inclusion/exclusion criteria (see CSP Sections 6.2 and 6.3).  
• Use of a prohibited concomitant medication (see CSP Section 7.1). 
• IP administration but no subsequent PET scan. 
• Significant non-compliance with IP administration. 
Patients will be withdrawn from the study and be included in the All Enrolled Patients and Full 
Safety Population as applicable.  
Deviations due to COVID-19 will be listed separately. 
 
A by-patient listing of major protocol deviations will be provided. 
A summary of the number and percentage of patients with a major protocol deviation by type of 
deviation (Analysis set: FAS) will be provided. 
 
 
4.5 
Analysis Sets 
All enrolled patients: all patients who signed the informed consent form. 
 
Full Analysis Set (FAS): all patients who were scheduled to receive the rhPSMA-7.3 (18F) 
injection having met the inclusion/exclusion criteria. 
 
Full Safety Population (FSP): all patients who received the rhPSMA-7.3 (18F) injection. 
 
Efficacy Analysis Population (EAP): all patients who received rhPSMA-7.3 (18F) injection 
followed by a PET/CT scan and who underwent RP and PLND. 
 
Extended Efficacy Population (EEP): all patients who received rhPSMA-7.3 (18F) injection 
followed by a PET/CT scan.  This population includes M0 and M1 patients independent of 
performance of RP and PLND and will be used for M1 related efficacy and Kappa statistics.  
 
Per Protocol Population (PP): All patients in the EAP population who have histology available 
from surgery that allows SoT determination, and without any major protocol deviations that will 
affect the evaluations of the PET scan or histology. 
 
The primary analysis will be based on the EAP.  The FSP will be used for all safety summaries.  
 
Upon database release, protocol deviation and analysis set outputs will be produced and will be to 
BED for review.  An analysis set classification meeting will be arranged to discuss the outputs and 
to decide which patients and/or patient data will be excluded from certain analyses.  Decisions 
made regarding the exclusion of patients and/or patient data from the analyses, and the agreement 
of population inclusion for each patient, will be made prior to database lock and will be documented 
and approved by the Sponsor.   
 
A by-patient listing of analysis set details will be provided.  This listing will include: center, 
country, patient identifier, and inclusion/exclusion flag for each set and reason for exclusion from 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 17 of 37 
each set.  All enrolled patients will appear on this listing.  If patient data have been partially 
excluded, visit will also appear on this listing. 
 
The number and percentage of patients in each population will be provided using all enrolled 
patients.  
 
 
4.6 
Demographic and Other Baseline Characteristics 
4.6.1 Demographics 
All demographics (e.g. age [including age groups of <65, ≥65 and the subgroup of ≥75], sex, race, 
height, weight and BMI at screening and on Day 1 ) and baseline characteristics will be listed, and 
their baseline characteristics summarized (with weight and BMI on day 1) using the FAS, FSP, 
EAP, EEP and PP. 
 
BMI will be calculated as 𝐵𝑀𝐼(𝑘𝑔𝑚2
⁄
) = 
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
ℎ𝑒𝑖𝑔ℎ𝑡 (𝑚)2 
 
 
4.6.2 Baseline conventional imaging 
Baseline conventional imaging will be taken from imaging performed within the 60 days before 
screening or will be performed prior to IP administration.  
The imaging results classified as baseline (above) will be summarized using FAS, EAP, EEP and 
PP by imaging modality and as positive or negative for detection of N1 or M1 disease.  Patients 
with more than one baseline scan will be summarized for the combination of baseline scans and 
include all applicable anatomical areas covered.  A listing will contain all these baseline parameters 
and include the imaging modality (CT, MRI, bone Scan, etc). 
 
 
4.6.3 Prostate Cancer History 
Prostate cancer history will be summarized using the FAS, FSP, EAP, EEP and PP for time of 
initial prostate cancer diagnosis to informed consent (in months), for TNM stage, total Gleason 
score (Frequencies), Gleason Grade Group (GGG) based on prostate biopsy, most recent PSA 
including frequency by categorization (0-0.5, >0.5-1.0, >1.0-2.0, >2.0-5.0, >5.0-10.0, >10.0 
[ug/L]).  
This same information will be listed by patient. 
 
Gleason Grade Group is defined by the International Society of Urological Pathologists, and the 
categories are as follows: 
• Grade Group 1 is defined as Total Gleason score ≤6 
• Grade Group 2 is defined as Gleason score 3+4=7 
• Grade Group 3 is defined as Gleason score 4+3=7 
• Grade Group 4 is defined as Total Gleason score of 8 
• Grade Group 5 is defined as Total Gleason scores 9-10 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 18 of 37 
 
TNM staging will be displayed at observed level and combined at levels T2, T3, T4, M0, M1, MX, 
where each of these contain underlying categories (i.e. T2 -All contains subjects with observed at 
T2, T2a, T2b, T2c) 
 
4.6.4 Baseline Risk Category 
Risk Category will be assigned using the NCCN Guidelines, version 1.2020; PROS-2.  A listing 
of risk category and underlying variables will be provided.  Risk category will be summarized into 
categories using the EAP.  Risk Categories are shown in Table 1. Per the CSP, risk categories of 
unfavorable intermediate-risk, high-risk or very high-risk are expected. 
 
Table 1: Risk Categories from NCCN guidelines. 
Risk Group 
Clinical/Pathologic Features 
Very Low 
T1c AND 
Grade Group 1 AND 
PSA <10 ng/mL AND 
Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core AND 
PSA density < 0.15 ng/mL/g 
Low 
Has all following but does not qualify for very low risk 
T1-T2a AND 
Grade Group 1 AND 
PSA < 10 ng/mL 
Favorable 
intermediate 
No High or Very High-risk features 
1 Intermediate Risk Factors and  
Grade Group 1 or 2 and 
<50% biopsy cores positive 
Unfavorable 
Intermediate 
No High or Very High-risk features 
2 or 3 Intermediate Risk Factors. and/or  
Grade Group 3 and/or 
≥50% biopsy cores positive 
High 
No very-high risk features and has at least one high-risk feature: 
T3a OR 
Grade Group 4 or Grade Group 5 OR 
PSA>20 ng/mL 
Very High 
Has at least one of the following 
T3b-T4 OR 
Primary Gleason pattern 5 OR 
2 or 3 high-risk features 
>4 cores with Grade Group 4 or 5 
Intermediate risk factors are: T2b-T2c, PSA 10-20 ng/mL, Grade Group 2 or 3  
 
In this study, the risk groups will be categorized into: 
• “High or Very High Risk” – defined as meeting any one of these criteria: T-stage T3 
(including T3a and T3b) or T4, Gleason Grade Group 4 or 5, Primary Gleason pattern 5, or 
PSA >20ng/mL 
• “Not High or Very High Risk” – defined as not meeting any of the criteria meeting the high 
or very high-risk criteria.  
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 19 of 37 
 
 
4.6.5 Medical history 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1 or higher – the data will be listed and include start date, end date, ongoing at study 
start, Preferred Term (PT) and System Organ Class (SOC). Medical history will also be 
summarized using FSP by SOC and PT. 
 
 
4.7 
Prior and Concomitant Medications and Procedures 
Medication and/or procedure start and stop dates will be compared to the date of IP administration 
to allow medications/procedures to be classified as either Prior only, both Prior and Concomitant, 
or Concomitant only.  Medications and/or procedures starting after Day 4 will be listed but will 
not be classified or summarized. 
Medications/procedures that start and stop prior to the date of dose of IP administration will be 
classified as Prior only.  If a medication/procedure starts before the date of IP administration and 
stops on or after the date of IP administration, then the medication/procedure will be classified as 
both Prior and Concomitant.  Medications/procedures will be classified as Concomitant only if 
they have a start date on or after the date of first dose of study medication. 
If medication/procedure start and/or stop dates are missing or partial, the dates will be compared 
as far as possible with the date of IP administration.  Medications/procedures will be assumed to 
be Concomitant only, unless there is clear evidence (through comparison of partial dates) to suggest 
that the medication/procedure started prior to the IP administration.  If there is clear evidence to 
suggest that the medication/procedure started prior to the IP administration, the 
medication/procedure will be assumed to be both Prior and Concomitant, unless there is clear 
evidence to suggest that the medication/procedure stopped prior to the IP administration.  If there 
is clear evidence to suggest that the medication/procedure stopped prior to the IP administration, 
the medication will be assumed to be Prior only. 
Medications will be coded using WHODrug Global Dictionary and summarized by ATC code 
(levels 2 and 4) and Preferred term and listed by patient using the FSP. In case of missing level 4 
coding the level 3 coding will be used. 
Procedures will be summarized by System Organ Class (SOC) and Preferred Term (PT) using 
MedDRA dictionary and listed by patient. 
 
All prior and concomitant medications and procedures will be listed by patient.  Concomitant 
medications will be summarized using the FSP. 
 
 
4.8 
Exposure and Treatment Compliance 
A patient listing of rhPSMA-7.3 (18F) administration including total administered activity, injection 
site reactions, local imaging results, incidental findings, and evaluations of the independent blinded 
central PET readers will be provided. 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
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Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 20 of 37 
A summary of total administered activity will be provided using the FAS and PP. All activity will 
be converted to MBq using the conversion 1mCi=37 MBq. 
 
 
4.9 
rhPSMA-7.3 (18F) Image reading 
Each rhPSMA-7.3 (18F) image will initially be read by a site-based local reader, and the results 
will be listed including incidental findings.  In addition, for the primary endpoint analysis, imaging 
will be read by three blinded independent PET readers (see the study Independent Review Charter 
for further details).  The results of the blinded PET readers will be used in the primary analysis, 
thus requiring each (statistical) analysis to be performed three times.  In addition, the majority 
interpretation will be displayed. 
 
Table 2 Derivation of Overall Interpretation (2 out of 3 readers consensus) 
Reader 1 
Reader 2 
Reader 3 
Majority 
Positive 
Positive 
Positive 
Positive 
Positive  
Positive  
Negative 
Positive  
Negative 
Negative 
Positive 
Negative 
Negative 
Negative 
Negative 
Negative 
 
PET imaging results (i.e. positive/negative) will be summarized using the EEP by anatomical 
location by category and anatomical location within category.  Categories will be prostate, pelvic 
lymph nodes, lymph nodes outside of pelvis, soft tissue/parenchyma and bones, as well as extra-
pelvic (which would include lymph nodes outside of pelvis, soft tissue/parenchyma and bones 
together).  All categories will be presented in the summary, but anatomical locations will only be 
presented where data are collected, i.e. lesion investigated in that anatomical location.  
 
 
4.10 Biopsy/Surgery 
If the rhPSMA-7.3 (18F) PET shows M1 metastatic disease, the patient will be asked to undergo a 
biopsy or confirmatory imaging of the PET-positive lesion(s) to confirm the presence of a 
metastasis.  If a surgical intervention of this lesion is carried out as part of the treatment, this may 
substitute for a biopsy.  If the patient has proven M1 metastatic disease, the disease management 
may be altered, based on the responsible physician’s clinical judgement.  This change in disease 
management will be documented on the eCRF.  
 
If rhPSMA-7.3 (18F) PET does not detect M1 disease, the patient will undergo the scheduled RP 
and PLND. In patients without M1 lesions identified and in whom the patient and physician 
believe, after obtaining the results of the rhPSMA-7.3 (18F) PET, that EBRT would be a better 
therapeutic option than surgery, the patient may proceed to EBRT and the rationale for this change 
of disease management will be documented on the eCRF. 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 21 of 37 
The regional PLND must be performed by a suitably qualified surgeon and should include, at 
minimum, resection of lymphatic tissue for histological analysis from the following nodal groups: 
1) hypogastric (internal iliac), 2) external iliac, and 3) obturator LNs.  Extended LN dissection may 
be performed if clinically appropriate and the anatomical regions (e.g. presacral, common iliac, 
peri-rectal) with left/right designations, should be recorded on the eCRF.  The location of the 
dissected material shall be marked in order to allow matching with their anatomical origin (left and 
right pelvis); the left and the right side of the specimen shall be clearly marked.  The dissected LNs 
will be sectioned and analyzed by a pathologist for the presence or absence of PCa according to 
standard of care at the clinical site. The number of lymph nodes sampled and found positive for 
PCa will be registered and summarized. 
Patients with PET M1 will be summarized using the EEP by confirmatory method(s), result of 
confirmation, change in disease management, surgery (radical prostatectomy and pelvic lymph 
node dissection) performed, Lymph node dissection and (additional) treatment received.  All 
counts will be presented including percentage of patients categorized as PET M1. 
 
Patients will be summarized using the EEP by surgery (RP and PLND) received, extended lymph 
node dissection and (additional) treatment received.  All counts will be presented including the 
percentage of patients categorized as PET M0. 
 
Results by patient will be listed for both M0 and M1 patients.  A display of Histopathology of 
Pelvic Lymph Nodes and a display of confirmatory procedures will be created for all patients. For 
M1 patients, a listing of PSMA Positive M1 Lesions (by anatomic location), including method 
(Biopsy/histopathology, CT Scan, MRI, Bone scan, Other) and result, will be created.  
A summary will be provided on methods to obtain standard of truth. 
 
 
4.11 TNM staging and Gleason score 
In addition to baseline values (Section 4.6.3), baseline and post-surgery staging will be summarized 
for TNM stage, primary and secondary and total Gleason score similar to baseline using the EEP. 
In addition, for GGG, a shift table will be presented from baseline to final staging. 
 
 
4.12 Standard of Truth 
Histology or confirmatory imaging will be used as the Standard of Truth (SoT), as defined below. 
1. Histology 
a. Histology of surgically removed pelvic LNs; 
b. Histology obtained by biopsy of M1 lesion. 
2. Confirmatory Imaging 
a. In patients without available histopathology, confirmatory conventional imaging is 
acceptable as proof of M1 disease in case of unequivocal findings (e.g. sclerotic 
bone lesions on CT, positive bone lesions on bone scan, evidently enlarged LNs 
radiologically considered metastases, lesions in the liver representing metastases 
as determined by ultrasound, CT or MRI, multiple pulmonary nodules on CT). 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 22 of 37 
b. Confirmatory imaging for proof of M1 disease will be read centrally. Three central 
reviewers will review all submitted imaging and reach consensus on the nature of 
the target lesion. Reads of the confirmatory imaging as SoT will be directed by 
rhPSMA-7.3 (18F) PET findings (for confirmation of lesion location only).  A brief 
summary of clinical information will be available to the SoT readers (e.g. 67-year-
old male with newly diagnosed, localized prostate cancer prior to rhPSMA-7.3 
(18F) scan). Readers will be blinded to all other information. Further details are 
given in the study Independent Review Charter. 
3. Baseline Conventional Imaging only 
a. If M1 lesion identified by blinded PET reader but not site reader, or if M1 lesion is 
identified by site reader but no histology or no confirmatory imaging is available, 
then only conventional imaging at baseline will be used to determine the SoT.  
 
 
SoT will be listed next to the results of the blinded independent reads and include method 
(Histology/Confirmatory Imaging/Baseline Imaging only), anatomical location and Result(s) using 
the EEP.  Histology SoT will be assessed based on local reads of the PET scan, and these results 
will be included irrespective of BIE reading.  The SoT will be summarized by method and 
anatomical location. 
 
 
4.13  Hemipelvis Region Categorization and Patient Level Categorization 
At least one positive pelvic LN on PET (N1) and one positive LN as determined by histopathology 
(pN1) on the same side of the pelvis (left or right), as depicted in Table 3, will be deemed a TP on 
a patient level.  
 
Table 3 Hemipelvis Region Categorization Method 
 
At Least One Pathology-positive LN 
in the Region 
No Pathology-positive LN in the 
Region 
At Least One PET-Positive LN in 
the Region 
True Positive (TP) region 
False Positive (FP) region 
No PET-positive LN in the Region 
False Negative (FN) region 
True Negative (TN) region 
LN=lymph node; PET=positron emission tomography. 
 
For patients who have no TP regions, Table 4 depicts the method for assigning patient level 
categorizations based on by-region results (i.e. for the different possible hemipelvis combinations 
of TN, FN and FP regions).  
Two analyses will be performed based on the classification of patients with one positive region 
and one negative region. The primary analysis will include patients as FN if they only had one 
positive region by histopathology and it was missed by PET. Full diagnostic statistics will be 
provided for both patient level classifications.  
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 23 of 37 
Table 4: Translation of Region Level to Patient Level Categorizations in Patients with No TP Regions 
a)  
Patient Level Categorization 
At Least one True 
Negative (TN) 
Region 
At Least one False 
Negative (FN) Region 
At Least one False 
Positive (FP) Region 
True Negative (TN) 
Yes 
No 
No 
False Negative (FN) 
Yes 
Yes 
No 
False Negative (FN) 
No 
Yes 
No 
False Positive (FP) 
Yes 
No 
Yes 
False Positive (FP) 
No 
No 
Yes 
False Negative (FN) for Primary 
Analysis; False Positive (FP) for 
Secondary Analysis* 
No 
Yes 
Yes 
PPV=positive predictive value.  
* 
Patient contributes to the primary efficacy analysis for Sensitivity (False Negative categorization) and a secondary analysis of 
PPV (False Positive categorization). 
b)  
Histopathology 
PET Patient Level Classification 
True Positive 
(TP) 
False Negative (FN) 
False Positive (FP) 
True Negative 
(TN) 
Two Positive 
Regions  
1 or 2 positive 
regions on PET 
Both regions negative on 
PET 
NA 
NA 
One Positive 
Region; One 
Negative 
Region 
PET is correct on 
positive region 
Primary analysis: PET is 
negative on the positive 
region 
Primary analysis: NA 
NA 
Secondary analysis: PET 
is negative on both 
regions only 
Secondary analysis: PET is 
negative on histopathology 
positive region and PET is 
positive on histopathology 
negative region 
Two Negative 
Regions 
NA 
NA 
PET-positive on one or two 
regions 
PET is negative 
on both regions 
NA=cell classification is not applicable; PET=positron emission tomography. 
 
Results of the Hemipelvis Categorization will be listed by region and summarized by region status 
using the EAP. This summary will include a category for missing Hemipelvis Categorization. 
The patient’s by region and patient level classification will be listed including classification for the 
secondary analysis (Section 4.14.3.4 and 4.14.3.5). 
A cross table of patients PET image diagnostic and SoT diagnostic will be provided.  
 
 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 24 of 37 
4.14 Efficacy Evaluation 
Unless otherwise stated, all efficacy evaluations will be done using the EAP as defined in Section 
4.5. 
4.14.1 Analysis and Data Conventions 
The primary hypothesis involves a joint assessment of sensitivity and specificity against individual 
performance goals: 
H0: Sensitivity ≤ Se0 or Specificity ≤ Sp0 versus H1: Sensitivity > Se0 and Specificity > Sp0 
Where Se0 and Sp0 are performance goals for sensitivity and specificity, respectively.  Performance 
goals of 22.5% (Se0) for sensitivity and 82.5% (Sp0) were selected based on the low sensitivity but 
high specificity of other PSMA ligands used for lymph node staging.  
 
The definition of Sensitivity will be: 
True Positive / (True Positive + False Negative) 
The definition of Specificity will be: 
 
True Negative / (True Negative + False Positive) 
 
Additional analysis will be performed for PPV and NPV. 
The definition of PPV will be: 
 
True Positive / (True Positive + False Positive) 
The definition of NPV will be: 
 
True Negative / (True Negative + False Negative) 
 
The sensitivity, specificity, PPV and NPV, together with the corresponding 95% CIs, will be 
estimated for each of the three blinded PET readers. All analyses performed for the three blinded 
PET readers will be repeated for their majority evaluation (Section 4.9).  
 
 
4.14.1.1 Adjustments for Covariates 
Not applicable. 
 
 
4.14.1.2 Handling of Dropouts or Missing Data 
Missing evaluation results in the biopsy/surgery will be assigned the worst value.  Hence, a side 
with a positive rhPSMA-7.3 (18F) PET will be considered as false positive (i.e. SoT will be set to 
negative), while a side with negative rhPSMA-7.3 (18F) PET will be a false negative (i.e. SoT set 
to positive). 
 
The number and percentage of patients with missing data for the biopsy/surgery will be 
summarized by major reason, as indicated in Section 4.13. 
 
Imputation of missing dates for concomitant medications and procedures is described in Section 
4.7, imputation of missing dates for AEs is described in Section 4.15.1. 
 
 
DocuSign Envelope ID: 06D06F4C-86F7-406B-9120-81145A223308


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 25 of 37 
4.14.1.3 Interim Analyses 
 
Using the first 150 patients an interim analysis of safety data will be created. The actual outputs 
for this are indicated in the shells. 
 
 
4.14.1.4 Examination of Subgroups 
The attributes of the primary efficacy variable will be examined across subgroups based on: 
• PCa risk categories (high- or very high-risk vs not high or very high risk). 
• Most recent PSA values (0- 0.5, >0.5-1.0, >1.0-2.0, >2.0-5.0, >5.0-10.0,>10.0 [ng/mL])  
• Race (Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or Other Pacific Islander, White, Not Reported, Other) 
• Age ( <65, >=65 and >=75) 
The analysis within subgroups will involve the confidence intervals (CI) but not the hypothesis 
testing. For each of these analyses, if a category has low counts (less than 10) it may be collapsed 
with another category, for ordinal parameters only with neighboring categories. 
 
A cross table of N1 disease status from rhPSMA-7.3 (18F) PET against to histopathology of pelvic 
LNs will be provided by risk category and associated 95% CI for Sensitivity and Specificity will 
be presented. 
 
 
4.14.1.5 Clustered binary data estimate of variance 
 
4.14.1.5.1 Sensitivity 
Following Zhou et al. the following estimators will be used: 
𝑆𝑒
̂ = ∑𝑁𝑖∗𝑆𝑒𝑖
̂
𝐼
𝑖=1
∑𝑁𝑖
𝐼
𝑖=1
⁄
 
𝑉𝑎𝑟
̂ (𝑆𝑒
̂) =
1
𝐼(I −1) ∑[𝑁𝑖
𝑁̅ (𝑆𝑒𝑖
̂ −𝑆𝑒
̂)
2]
𝐼
𝑖=1
 
With:  
 
Se 
 
 
: Sensitivity 
 
i 
 
 
: individual patient 
 
I 
 
 
: total number of patients 
 
Ni 
 
 
: Number of elements (True Positive + False Negative) for patient i 
 
𝑆𝑒
̂𝑖 
 
 
: Sensitivity for patient i 
 
N̅ 
 
 
: Mean cluster size 
The example in Zhou et al. is coded in SAS in Appendix 6.1. 
An asymptotic normal distribution for the sampling distribution of 𝑃𝑃𝑉
̂ is assumed and the 95% 
confidence interval will be derived as: 
𝑆𝑒
̂ ± 𝑍1−𝛼/2√𝑉𝑎𝑟
̂ (𝑆𝑒
̂) 
where Z1-α/2 is the upper 1-α/2 value for the standard normal distribution. 
 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 26 of 37 
4.14.1.5.2 Additional Confidence interval Sensitivity 
Normal approximation in constructing 95% CIs might lead to bounds exceed [0, 1] for 𝑃𝑃𝑉
̂. Hence 
an additional CI will be derived. Logit transformation will be applied to PPV and Delta Method 
(Casella and Berger, 2021) will be utilized to obtain to approximate the variance of 𝑙𝑜𝑔𝑖𝑡(𝑃𝑃𝑉). 
Accordingly, the asymptotical distribution of 𝑙𝑜𝑔𝑖𝑡(𝑃𝑃𝑉) is 
 
 
√𝑛[𝑙𝑜𝑔 (
𝑆𝑒
̂
1−𝑆𝑒
̂) −𝑙𝑜𝑔 (
𝑆𝑒
1−𝑠𝑒)]
𝑑→N (0,
1
[𝑆𝑒(1−𝑆𝑒)]2 𝑉𝑎𝑟 (𝑆𝑒)). 
 
Accordingly, an asymptotic normal distribution for the sampling distribution of 𝑙𝑜𝑔𝑖𝑡(𝑆𝑒)
̂  is 
assumed and the 95% confidence interval will be derived as: 
𝑙𝑜𝑔𝑖𝑡(𝑆𝑒)
̂ ± 𝑍1−𝛼/2√𝑉𝑎𝑟
̂ (𝑙𝑜𝑔𝑖𝑡(𝑆𝑒
̂)) 
where Z1-α/2 is the upper 1-α/2 value for the standard normal distribution and √𝑉𝑎𝑟
̂ (𝑙𝑜𝑔𝑖𝑡(𝑆𝑒
̂)) ≈
1
[𝑆𝑒
̂(1−𝑆𝑒
̂)]2 𝑉𝑎𝑟
̂ (𝑆𝑒
̂) . Lower and upper confidence intervals values will be reported in [0,1] scale 
by the logit inverse transformation, as follows 
𝐶𝐼[0,1] 𝑠𝑐𝑎𝑙𝑒= 
𝑒𝐶𝐼_𝑙𝑜𝑔𝑖𝑡
1 + 𝑒𝐶𝐼_𝑙𝑜𝑔𝑖𝑡 
 
4.14.1.5.3 Specificity 
The formulas for sensitivity can be used with appropriate substitution.  
Sensitivity=True Positive / (True Positive + False Negative) 
Specificity=True Negative / (True Negative + False Positive) 
 
 
4.14.2 Primary Efficacy Variable  
The co-primary endpoints for the study are based on the sensitivity and specificity of rhPSMA-7.3 
(18F) PET (by central BIE) in detecting N1 disease compared to histopathology of pelvic LNs. The 
primary analysis involves a joint assessment of sensitivity and specificity against individual 
performance goals: 
H0: Sensitivity ≤ Se0 or Specificity ≤ Sp0 versus H1: Sensitivity > Se0 and Specificity > Sp0 
Where Se0 and Sp0 are performance goals for sensitivity and specificity, respectively. Performance 
goals of 22.5% (Se0) for sensitivity and 82.5% (Sp0) for specificity were selected based on the low 
sensitivity but high specificity of other PSMA ligands used for LN staging.  The analyses for 
sensitivity and specificity will be performed using one-sided 0.025 exact binomial tests.  In addition 
to the rates, exact two-sided 95% CIs will also be provided.  If the predefined sensitivity and 
specificity goals are met by the same two of three blinded independent readers (both tests reach 
statistical significance [P<0.05] for the same two readers), the study will be considered to have 
successfully demonstrated the effectiveness of the rhPSMA-7.3 (18F) in detecting N1 disease. 
The TP, FP, TN and FN regions will be categorized according to Table 3 (Section 4.13) using a 
right and left hemipelvis regional classification method. For the primary analysis, patients who 
have one TP region will be categorized as a TP patient. 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 27 of 37 
For patients who have no TP regions, Table 4 depicts the method for assigning patient level 
categorizations based on by-region results (i.e. for the different possible hemipelvis combinations 
of TN, FN and FP regions).  
Classification will be summarized via a cross table of region status using the layout of Table 4b.  
A summary of frequency of PET Patient level Classifications will be supplied including estimates 
and CI of Sensitivity and Specificity according to each blinded reader. Sensitivity and Specificity 
will be plotted for each reader including CI and performance goals. 
 
The primary analysis will be repeated using the PP following methods of the primary analysis: 
A summary of frequency of PET Patient level Classifications will be supplied including estimates 
and CI of Sensitivity and Specificity according to each blinded reader.  Frequencies will be 
displayed in a bar chart.  Sensitivity and Specificity will be plotted for each reader including CI 
and performance goals. 
 
 
4.14.2.1 Sensitivity Analysis; patients with FN and FP results 
The primary efficacy analysis will be repeated with a reclassification of patients with one FN and 
one FP region.  In particular, in the sensitivity analysis, these patients will be classified as FN. The 
results will be displayed in a summary of frequency of PET Patient level Classifications including 
estimates and CI of Sensitivity and Specificity according to each blinded reader.  Frequencies will 
be displayed in a bar chart. Sensitivity and Specificity will be plotted for each reader including CI 
and performance goals. 
 
 
4.14.3 Secondary Efficacy Variables 
All secondary efficacy variables will be analyzed descriptively, with the exception of item 7; 
Kappa statistic. 
Patient pathway through the study (PET scan, M0/M1, subsequent RP-PLND (Yes/No) and 
additional steps will be summarized and listed. 
The following items are presented per secondary efficacy variable.  
 
4.14.3.1 Percentage of patients in whom rhPSMA-7.3 (18F) imaging detects at least one verified 
M1 metastasis, as determined by central BIE. 
This analysis concerns patients in the EEP with rhPSMA-7.3 (18F) imaging and confirmation tested 
(biopsy or additional imaging).  
The percentage of patients with at least one M1 metastasis will be provided for each blinded 
independent reader.  M1 metastasis requires the reader to identify a positive lesion in one of the 
three following locations: lymph nodes outside the pelvis, soft tissue/parenchyma or the bones.  
Patients will be counted to have M1 metastasis for this variable if a BIE detects M1 on the 
rhPSMA-7.3 (18F) and M1 is confirmed (biopsy, additional imaging) at the same location.  
Patients where M1 was not verified (e.g. because the local reader did not detect M1) will be 
included in this analysis, as long as the BIE reader has detected M1 – in this case, the patients’ 
metastasis will be considered as not verified. An additional table will be made using the EEP to 
summarize for each blinded reader the number of patients who have M1 by BIE and the presence 
/ absence of confirmation of M1 metastasis. 
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PAREXEL International 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 28 of 37 
 
The endpoint for the secondary objective 1 of Verified Detection Rate (VDR) for M1 disease on a 
patient level is the percentage of patients with True-Positive M1 disease in the EEP. 
 
VDR = (TP)/(TP+FP+TN+FN) 
where: 
• TP = BIE PET positive and SoT positive 
• FP = either: (1) BIE PET positive and SoT negative  or (2) BIE PET positive and SoT not 
done or not proven  (NB: If site PET = M0, we would still have baseline imaging and so 
will count in SoT) 
• FN = BIE PET negative and SoT positive 
• TN = either: (1) BIE PET negative and SoT negative or (2) BIE PET negative and SoT not 
done 
 
Results for M1 detections by central, blinded readers will be reported overall and by SOT method 
used (histopathology, and imaging only) to confirm M1 detection as True Positive or False 
Positive. 
 
4.14.3.2 Percentage of patients with negative conventional imaging for M1 disease in whom 
rhPSMA-7.3 (18F) PET detects at least one verified M1 metastasis, as determined by 
central BIE. 
This analysis concerns patients in the EEP with rhPSMA-7.3 (18F) imaging and confirmation tested 
(biopsy or additional imaging) and with conventional imaging yielding negative M1 disease. 
The patients counted in this variable are a subset of ‘Percentage of patients in whom rhPSMA-7.3 
(18F) imaging detects at least one verified M1 metastasis, as determined by central BIE’, where 
both the numerator and denominator are only counting patients with negative conventional imaging 
(according to investigator assessment) for M1 disease.  
 
The endpoint for the secondary objective 2 of Verified Detection Rate (VDR) for M1 disease on a 
patient level with negative conventional imaging is the percentage of patients with negative 
conventional imaging (according to investigator assessment) for M1 disease and with True-
Positive M1 disease according to rhPSMA-7.3 (18F) PET in the EEP. 
 
 
4.14.3.3 Patient level PPV of rhPSMA-7.3 (18F) PET BIE for N1 and M1 lesions compared to 
histopathology or confirmatory imaging (M1 lesions only). 
This analysis concerns EEP patients with rhPSMA-7.3 (18F) imaging and either N1 or M1 lesions 
detected.   
 
PPV of N1 lesions is the proportion of patients with a positive PET BIE finding in pelvic lymph 
nodes and confirmed by histopathology, out of the patients with a positive PET BIE finding in 
pelvic lymph nodes. 
 
PPV of M1 lesions is the proportion of patients with a positive PET BIE finding in other (extra-
pelvic) areas and confirmed by SoT (histopathology or confirmatory imaging (as determined by 
central SoT)), out of the patients with a positive PET BIE finding in other (extra-pelvic) areas. 
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PAREXEL International 
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BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 29 of 37 
 
 
4.14.3.4 PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FP patient is defined as having at least one 
FP region (right or left pelvis), regardless of any coexisting TP findings. 
This analysis concerns patients in the EAP where rhPSMA-7.3 (18F) imaging detected pelvic LN 
metastasis.  Regions where rhPSMA-7.3 (18F) imaging detected no LN metastasis are not part of 
this by definition of PPV, hence only TP and FP regions will be taken into account.  
 
PPV = TP / (TP + FP) 
True positives will be all patients with a surgical pathology confirmed positive region and without 
a false positive region.  False Positive patients will be those patients with any rhPSMA-7.3 (18F) 
PET positive region with negative surgical pathology or no surgical pathology. 
 
 
4.14.3.5 NPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FN patient is defined as having at least one FN 
region (right or left pelvis), regardless of any coexisting TN findings. 
This analysis concerns patients in the EAP with rhPSMA-7.3 (18F) imaging, where no LN 
metastases were detected and LN surgical pathology is available. 
Regions where rhPSMA-7.3 (18F) imaging detected positive LN are not part of this by definition 
of NPV, hence only TN and FN regions will be taken into account. 
 
NPV = TN / (TN + FN) 
 
True negatives will be all patients with a surgical pathology confirmed negative region and without 
a false negative region.  False negative patients will be those patients with any rhPSMA-7.3 (18F) 
PET negative region with positive surgical pathology.   
 
 
4.14.3.6 Upstaging 
a) The percentage of patients being upstaged to N1 or M1 disease; 
b) The percentage of patients in whom planned RP is converted to EBRT. 
 
The endpoints will be calculated as follows: 
 
• Upstaging to N1 = Proportion of patients with positive BIE PET finding by BIE and 
negative conventional imaging finding from local investigator in pelvic lymph nodes, out 
of all the patients with evaluable scans. 
 
• Upstaging to M1 = Proportion of patients with positive BIE PET finding and negative 
conventional imaging finding from local investigator in other (extra-pelvic) areas, out of 
all the patients with evaluable scans.  
 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 30 of 37 
• Planned RP converted to EBRT = Proportion of patients with positive BIE PET finding and 
planned RP changed to EBRT by local investigator, out of all the patients with evaluable 
scans. 
 
 
4.14.3.7 Kappa statistic for the agreement between and within blinded independent readers on the 
interpretation of rhPSMA-7.3 (18F) scans. 
This analysis concerns all EEP patients. 
For this analysis, the patient’s categorization to positive or negative by the blinded readers will be 
used, in pelvic lymph nodes and in extra-pelvic region. 
 
 
4.14.3.7.1 Inter-reader agreement analysis 
The Cohen’s kappa statistic will be used to assess pairwise agreement between 2 readers including 
95% exact CIs giving three kappa statistics (SAS® nomenclature: simple kappa). In addition, the 
Fleiss’ kappa across the 3 readers including 95% (approximate) CIs will be shown (SAS® 
nomenclature: overall kappa Coefficient).  
This same calculation will be repeated for the regions:  
Prostate/Prostate Bed 
Pelvic Lymph Nodes 
Other 
Other: Lymph nodes outside pelvis 
Other: Soft Tissue/parenchyma 
Other: Bones. 
 
 
4.14.3.7.2 Intra-reader agreement analysis 
Cohen’s Kappa will be used to assess intra-reader agreements in the first read and the repeat read 
of 10% of the randomly selected images for each of the three readers. 
This same calculation will be repeated for the regions:  
Prostate/Prostate Bed 
Pelvic Lymph Nodes 
Other 
Other: Lymph nodes outside pelvis 
Other: Soft Tissue/parenchyma 
Other: Bones. 
 
 
4.14.4 Exploratory Efficacy Variables 
4.14.4.1 Diagnostic performance (sensitivity and specificity) of rhPSMA-7.3 (18F) PET for 
detecting pelvic LN metastases compared to surgical pathology on a regional level. 
This analysis will be performed using the EAP on all patients who were not diagnosed as M1 in 
the rhPSMA-7.3 (18F) PET imaging and for all sides where surgical pathology was performed. 
DocuSign Envelope ID: 06D06F4C-86F7-406B-9120-81145A223308


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 31 of 37 
In this analysis, each patient will be considered as a cluster, with left hemi-pelvis and right hemi-
pelvis considered as two observations within each cluster.  Regions will be classified according to 
Table 3.  
The descriptive parts of the primary analysis; cross table, sensitivity and specificity, will be 
repeated using region level analysis. 
 
 
4.15 Safety Evaluation 
All safety summaries and analyses will be based upon the FSP as defined in Section 4.5. 
 
 
4.15.1 Adverse Events 
For AEs and Serious AEs (SAEs), the MedDRA Version 22.1 or later will be used to code the 
reported events.  
 
Treatment-emergent adverse events (TEAEs) will be tabulated and are defined as those AEs that 
either start or worsen in severity on or after the date/time of IP administration and on or before Day 
4. 
 
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the AE started 
prior to IP administration or more than 4 days after IP administration.   
In particular this means the following rules will be applied until a classification is given: 
 
1. An AE with a missing start date and missing end date will be a TEAE 
2. An AE with a missing start date and end date after IP administration will be TEAE 
3. A start date with a missing year but month present will be assumed to have a year such 
that the start date is after informed consent and before Day 90.  If these rules conflict then 
the rule ‘after informed consent’ prevails. 
4. An AE will not be a TEAE if the start date is incomplete and 
a. The end date of the AE is before the dosing date 
b. The end date/time of an AE is before the dosing date/time 
c. The day of the AE end date is missing and the month of the AE end date is before 
the month of dosing date 
5. An AE will not be a TEAE if the AE start day of month is missing and 
a. The last day of the AE start month is before the dosing date 
b. The first day of the AE start month is more than 4 days after dosing 
 
All AE summaries will provide the number of patients reporting at least one AE and the total 
number of events reported.   
 
The following summaries will be provided: 
• A summary of the number and percentage of patients reporting an AE, including counts of 
TEAEs, IP-related TEAEs, SAEs and IP-related SAEs. 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 32 of 37 
• A summary of the number and percentage of patients reporting a TEAE by SOC, and PT 
• A summary of the number and percentage of patients reporting a TEAE by Common 
Terminology Criteria for Adverse Events (CTCAE) grade, SOC and PT 
• A summary of the number and percentage of patients reporting a TEAE by causality, SOC 
and PT 
 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT within 
an SOC and then alphabetically for SOC, and PT within SOC. 
 
For each patient and each adverse event, the worst CTCAE Toxicity grade (Version 5) recorded 
will be attributed and used in the by-severity summaries.  Similarly, the worst causality (most 
related to treatment) will be attributed and used in the by-causality summaries.  If CTCAE is 
missing for, the missing category will be used as worst category. If causality is missing, the worst 
case will be assumed. 
 
A by-patient listing of all adverse events (including non-treatment-emergent events) will be 
provided.  This listing will include center, patient identifier, age, race, adverse event (SOC, PT, 
and verbatim term), date of onset, date of resolution, duration, CTCAE, seriousness, action taken, 
outcome and causality.  
 
 
4.15.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Deaths, SAEs, and Other Significant AEs will be listed and summarized if numbers allow. 
The following summaries are planned. 
• A summary of the number and percentage of TEAE leading to death 
• A summary of the number and percentage of patients reporting a serious TEAE, by SOC 
and PT 
• A summary of the number and percentage of patients with TEAEs leading to 
discontinuation of study treatment, by SOC and PT 
 
 
The following listings will be created: 
 
• A by-patient listing of all deaths that occurred during the study 
• A by-patient listing of all SAEs 
• A by-patient listing of all AEs leading to discontinuation of study treatment 
 
Listings will follow the format described for AEs in Section 4.15.2. 
 
 
4.15.3 Clinical Laboratory Evaluation 
Blood safety laboratory values (hematology, biochemistry and coagulation) will be listed by patient 
and study time point including changes from baseline.  The baseline for the laboratory values will 
be the pre-dose results obtained on Day 1. 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 33 of 37 
All values outside the clinical reference ranges will be flagged in the data listings.  The abnormal 
values will be flagged with ‘L’ for values below the lower limit of the clinical reference range and 
‘H’ for values above the upper limit of the clinical reference range and included in the listings.   
Descriptive statistics (for non-categorical data including hematology and blood chemistry) will be 
presented for both individual values (N, mean, SD, median, minimum, maximum) and changes 
from baseline. 
 
The following summaries will be provided: 
 
• A summary of each laboratory parameter at visit 2 (pre-dose at day 1) and visit 3 
• A summary of the change from baseline to visit 3 in each laboratory parameter  
• A shift table of the number and percentage of patients experiencing treatment-emergent 
laboratory abnormalities at baseline vs visit 3, by laboratory parameter  
 
 
4.15.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital signs will be listed, including change from baseline. Baseline will be the last assessment 
before dosing, this is planned to be Visit 2 (Day 1), but may be any other assessment.  
A summary of each vital sign parameter, including change from baseline to visit 3 will be given.  
 
12-lead ECG results will be listed, including change from baseline by patient and time point.  
Baseline will be the pre-dose assessment at Visit 2 (Day 1). A summary of each ECG parameter, 
including change from baseline to visit 3 will be given.  
 
Physical examinations results (Normal, Abnormal Not Clinically Significant, Abnormal Clinically 
Significant) will be listed by patient and time point.  Physical examination findings will be 
summarized by visit. 
 
Heart rate category (<40 bpm, 40-59 bpm, 60-100 bpm, 101-130 bpm, >130 bpm) will be 
summarized and a shift table will be presented. 
Shift tables will be presented for QTc and physical examinations. 
 
 
4.15.5 Other safety 
A summary of injection site reactions during or immediately after the dose will be provided. 
 
 
4.15.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], Data 
Monitoring Committee [DMC], Data and Safety Monitoring Board [DSMB])  
Not applicable. 
 
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PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 34 of 37 
 
4.16 Determination of Sample Size 
A total sample size of approximately 375 patients is planned in order to obtain 300 evaluable 
patients for analysis of the primary endpoint. Assuming a sensitivity of 40% of PSMA ligands for 
detecting N1 disease (based on the previous OSPREY [NCT02981368]), a sample size of 
75 positive cases provides 90% power to reject the performance goal of 22.5%. Assuming a 
specificity of 90% for rhPSMA-7.3 (18F) PET, a sample size of 225 negative cases provides 90% 
power to reject the performance goal of 82.5%. Assuming the true prevalence rate of N1 disease is 
25%, a sample size of 300 evaluable patients is expected to provide 75 positive cases and 225 
negative cases.  
Up to approximately 375 patients with unfavorable intermediate-, high- and very high-risk PCa 
will be enrolled into the study. Since some patients will have M1 disease and some patients will 
receive EBRT instead of RP following the PET scan, enrollment of up to approximately 
375 patients will ensure inclusion of at least 300 evaluable patients undergoing RP and PLND. 
In order to have sufficient numbers of histologically positive and negative cases, an interim look 
will be allowed to ensure a distribution of pN1 disease as would be anticipated in this patient 
population. After the inclusion of approximately 150 patients, the percentages of pN0 and pN1 will 
be monitored. If the percentage of pN1 exceeds 35%, inclusion of very high-risk and/or high-risk 
patients will be suspended. If the percentage of pN1 is less than 15%, the inclusion of intermediate-
risk patients will be suspended.  
 
 
4.17 Changes in the Conduct of the Study or Planned Analysis 
An additional analysis set (Extended Efficacy Population) was created to accommodate analysis 
of patients where no RP and PLND was performed, such as patients with M1 lesions. 
 
The second exploratory Efficacy objective and endpoint were removed. 
Objective: 
To evaluate diagnostic performance of rhPSMA-7.3 (18F) PET (as determined by central 
BIE) in patients with a) pelvic LN metastatic deposits <5 mm (short axis) and LN metastatic 
deposits ≥5 mm (short axis) and b) pelvic LN metastatic deposits <10 mm (short axis) and 
LN metastatic deposits ≥10 mm (short axis), if feasible. 
Endpoint: 
Diagnostic performance of rhPSMA-7.3 (18F) PET in patients with a) pelvic LN metastatic 
deposits <5 mm (short axis) and LN metastatic deposits ≥5 mm (short axis) and b) pelvic 
LN metastatic deposits <10 mm (short axis) and LN metastatic deposits ≥10 mm (short 
axis) 
 
Two changes were documented to make the analysis description consistent.  
• In Table 4 part b, which originated as table 6b in the CSP, the following text was changed: 
CSP: "Secondary analysis: PET is negative on True Positive (TP) region and PET is 
positive on True Negative (TN) region"  
DocuSign Envelope ID: 06D06F4C-86F7-406B-9120-81145A223308


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 35 of 37 
SAP: "Secondary analysis: PET is negative in a histopathology positive region, and PET is 
positive in a histopathology negative region". 
 
• In section 16.4 the text was adapted: 
CSP: “Two analyses will be performed based on the classification of patients with one TP 
region and one TN region. The primary analysis will include patients as FN if they only 
had one positive region by histopathology and it was missed by PET. Full diagnostic 
statistics will be provided for both patient level classifications.” 
SAP will interpret this as: “Two analyses will be performed based on the classification of 
patients with one positive region and one negative region by histopathology. The primary 
analysis will include patients as FN if they only had one positive region by histopathology 
and it was missed by PET. Full diagnostic statistics will be provided for both patient level 
classifications.” 
 
 
5 
REFERENCES 
[1] SAS® Version 9.3 of the SAS® System for Personal Computers. Copyright © 2011. SAS® 
Institute Inc. SAS® and all other SAS® Institute Inc. product or service names are registered 
trademarks or trademarks of SAS® Institute Inc., Cary, NC, USA. 
 
[2] Guidance for Industry and FDA Staff Statistical Guidance on Reporting Results from Studies 
Evaluating Diagnostic Tests. Available at: https://www.fda.gov/media/71147/download [Accessed 
09 March 2020] 
 
[3] Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-
90 
 
[4] Klevečka V, Musch M, Roggenbuck U, et al. The incidence of lymph node metastases in 
prostate carcinoma depends not only on tumor characteristics but also on surgical performance and 
extent of pelvic lymphadenectomy. Medicina (Kaunas) 2008;44(8):601-8. 
 
[5] MSKCC, Nomogram. Available at: https://www.evidencio.com/models/show/440 [Accessed 
23 January 2020].  
 
[6] NCCN Clinical Practice Guidelines in Oncology – Prostate Cancer, 1.2020 16 March 2020.  
 
[7] OSPREY: Rowe S, Gorin M, Pienta K, et al. Results from the OSPREY trial: a prospective 
phase 2/3 multi-center study of 18F-DCFPyL PET/CT imaging in patients with prostate cancer - 
examination of diagnostic accuracy. J Nucl Med 2019;60(Suppl 1):586. 
 
DocuSign Envelope ID: 06D06F4C-86F7-406B-9120-81145A223308


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 36 of 37 
[8] Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials.  BMJ 2010;340:c332  
 
[9] 
UICC, 
TNM 
Classification 
of 
Malignant 
Tumors. 
Available 
at: 
https://www.uicc.org/resources/tnm [Accessed 23 January 2020] 
 
[10] Zhou XH, Obuchowski NA and McClish, DK. Statistical Methods in Diagnostic Medicine. 
Wiley, New York, 2002 pp 104-6 
 
6 
Appendix 
6.1 
SAS program to reproduce data in Zhou et al [10]. 
data one; 
input TN 
No_Polyps; 
Cards; 
1 
1 
2 
2 
2 
2 
1 
1 
2 
2 
2 
2 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
0 
1 
2 
3 
2 
2 
1 
1 
1 
1 
1 
1 
2 
2 
1 
2 
0 
2 
1 
1 
2 
2 
2 
2 
2 
2 
0 
1 
;;;; 
run; 
 
proc sql; 
   create table two as 
      select  
         TN , 
         No_Polyps, 
         TN/No_Polyps as Sei_hat, 
         Se_hat, 
         No_Polyps/mNo as Ni_N, 
         (calculated Ni_N)*(calculated Ni_N)  
             * (calculated Sei_hat-Se_hat)* (calculated Sei_hat-Se_hat) as fc, 
         sum(calculated fc) as sfc, 
         calculated sfc/(n*(n-1)) as varSe_hat 
DocuSign Envelope ID: 06D06F4C-86F7-406B-9120-81145A223308


PAREXEL International 
Blue Earth Diagnostics 
 
BED-PSMA-301                                                                                                                       Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
   Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                               Page 37 of 37 
      from  
         (select  
            sum(TN) as sTN,  
            sum(No_Polyps) as sNo, 
            mean(No_Polyps) as mNo, 
            count(*) as n, 
            calculated sTN/calculated SNo as Se_hat 
            from one ) as o,  
         one; 
quit;  
 
data final; 
   set two; 
   if _n_=1; 
   CI_L = Se_hat - (quantile('NORMAL', .975)*varSe_hat**0.5); 
   CI_U = Se_hat + (quantile('NORMAL', .975)*varSe_hat**0.5); 
   p_value = 1 - CDF('NORMAL', (Se_hat-0.625)/varSe_hat**0.5); 
   keep Se_hat varSe_hat CI_L CI_U  p_value; 
run;  
data final_logit; 
   set final; 
   logit_Se_hat = log(Se_hat/(1-Se_hat)); 
   logit_varSe_hat = varSe_hat*((1/(Se_hat*(1-Se_hat)))**2); 
   logit_CI_L = logit_Se_hat - (quantile('NORMAL', .975)*logit_varSe_hat**0.5); 
   logit_CI_U = logit_Se_hat + (quantile('NORMAL', .975)*logit_varSe_hat**0.5); 
   logit_zero_one_CI_L = (CONSTANT('E')**logit_CI_L)/((CONSTANT('E')**logit_CI_L)+1); 
   logit_zero_one_CI_U = (CONSTANT('E')**logit_CI_U)/((CONSTANT('E')**logit_CI_U)+1); 
run; 
 
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Prot_000.pdf: 
Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 1 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
 
 
CLINICAL STUDY PROTOCOL 
 
A prospective, Phase 3, multi-center, single-arm, imaging study investigating the safety 
and diagnostic performance of rhPSMA-7.3 (18F) PET ligand in men with newly 
diagnosed prostate cancer 
 
LIGHTHOUSE 
 
BED-PSMA-301 
 
Phase: 3 
 
EudraCT Number: 2019-003381-40 
IND Number: 141,561 
 
Revision Chronology:  
Protocol Version 1, 25-Sept-2019 
Protocol Version 2, 07-Jan-2020 
Protocol Version 3, 01-Jul-2020 
 
 
Sponsor: Blue Earth Diagnostics 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other 
than the Sponsor, the Investigator Team, host organization, and members of the Research 
Ethics Committee, unless authorized to do so. 


Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 2 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
Blue Earth Diagnostics 
Clinical Study Protocol 
A prospective, Phase 3, multi-center, single-arm, imaging study investigating the safety 
and diagnostic performance of rhPSMA-7.3 (18F) PET ligand in men with newly 
diagnosed prostate cancer 
Protocol Number: 
BED-PSMA-301 
Protocol Version / Date: 
Protocol Version 3, 01-Jul-2020 
Investigational Product: 
rhPSMA-7.3 (18F) 
EudraCT Number: 
2019-003381-40 
IND Number: 
141,561 
Development Phase: 
3 
Sponsor: 
Blue Earth Diagnostics  
UK office: 
The Oxford Science Park, Magdalen Centre, Robert Robinson 
Avenue, Oxford, OX4 4GA, United Kingdom 
Telephone: +44 1865 784186 
IE Office:  
6th Floor, 2 Grand Canal Square, Dublin 2, Ireland. 
Telephone: +353 1 761 7403 
Funding Organization: 
Blue Earth Diagnostics Ltd 
Coordinating Investigator: 
Name: Brian Chapin, MD, FACS 
Telephone: +1 713 794 4166 
Fax: +1 713 794 4824 
E-mail: bfchapin@mdanderson.org 
Medical Monitor: 
 
Name: Matthew Cooney, MD 
Parexel International 
Telephone: +1 216 374 8221 
E-mail: matthew.cooney@parexel.com 
Coordinating Center: 
The University of Texas, MD Anderson Cancer Center, Houston, 
TX, 77030, United States 
 
Approval: 
 
 
 
 
 
Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document may 
not be disclosed unless federal or state law or regulations require such disclosure. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  


Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 3 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
PROTOCOL AGREEMENT 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include providing Blue Earth Diagnostics with the information, as outlined in the protocol. It 
is understood that all information pertaining to the study will be held strictly confidential and 
that this confidentiality requirement applies to all study staff at this site. Furthermore, on 
behalf of the study staff and myself, I agree to maintain the procedures required to carry out 
the study in accordance with accepted Good Clinical Practice principles, applicable 
regulatory requirements, and to abide by the terms of this protocol. 
 
Protocol Number: BED-PSMA-301 
 
Protocol Title: A prospective, Phase 3, multi-center, single-arm, imaging study investigating 
the safety and diagnostic performance of rhPSMA-7.3 (18F) PET ligand in men with newly 
diagnosed prostate cancer 
 
Protocol Version: 3 
Protocol Date: 01-Jul-2020 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 
 


Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 4 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
CONTENTS 
CONTENTS ................................................................................................................................ 4 
LIST OF TABLES ....................................................................................................................... 8 
LIST OF FIGURES ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................................ 9 
PROTOCOL SYNOPSIS ............................................................................................................ 11 
1 
BACKGROUND ................................................................................................................ 19 
1.1 
Overview of Non-clinical Studies.................................................................................. 19 
1.2 
Overview of Clinical Studies ........................................................................................ 20 
2 
STUDY RATIONALE ........................................................................................................ 22 
2.1 
Risk-benefit Assessment............................................................................................... 24 
2.1.1 
Benefits ............................................................................................................... 24 
2.1.2 
Risks ................................................................................................................... 24 
3 
STUDY OBJECTIVES ....................................................................................................... 26 
3.1 
Primary Objective ........................................................................................................ 26 
3.2 
Secondary Objectives ................................................................................................... 26 
3.3 
Exploratory Objectives ................................................................................................. 26 
4 
STUDY DESIGN................................................................................................................ 28 
4.1 
Study Overview ........................................................................................................... 28 
4.2 
Sub-studies .................................................................................................................. 29 
5 
CRITERIA FOR EVALUATION......................................................................................... 30 
5.1 
Primary Efficacy Endpoint............................................................................................ 30 
5.2 
Secondary Endpoints .................................................................................................... 30 
5.3 
Exploratory Efficacy Endpoints .................................................................................... 30 
5.4 
Safety Evaluations ....................................................................................................... 30 
6 
PATIENT SELECTION ...................................................................................................... 32 
6.1 
Study Population.......................................................................................................... 32 
6.2 
Inclusion Criteria ......................................................................................................... 32 
6.3 
Exclusion Criteria ........................................................................................................ 32 
7 
CONCURRENT MEDICATIONS ....................................................................................... 33 
7.1 
Prohibited Medications................................................................................................. 33 
8 
STUDY TREATMENTS ..................................................................................................... 34 
8.1 
Method of Assigning Patients to Treatment Groups ........................................................ 34 
8.2 
Blinding ...................................................................................................................... 34 
8.3 
Formulation of Test and Control Products...................................................................... 34 


Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 5 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
8.3.1 
Formulation of Test Product .................................................................................. 34 
8.3.2 
Formulation of Control Product ............................................................................. 34 
8.3.3 
Packaging and Labeling ........................................................................................ 34 
8.4 
Supply of IP at the Site ................................................................................................. 34 
8.4.1 
Dispensing ........................................................................................................... 35 
8.4.2 
Administration Instructions ................................................................................... 35 
8.4.3 
Storage ................................................................................................................ 35 
8.5 
IP Accountability ......................................................................................................... 35 
8.6 
Measures of Treatment Compliance .............................................................................. 35 
8.7 
End of Trial ................................................................................................................. 36 
9 
STUDY PROCEDURES AND GUIDELINES...................................................................... 37 
9.1 
Clinical Assessments .................................................................................................... 37 
9.1.1 
Concomitant Medications...................................................................................... 37 
9.1.2 
Demographics ...................................................................................................... 37 
9.1.3 
Medical History.................................................................................................... 37 
9.1.4 
Physical Examination............................................................................................ 37 
9.1.5 
Vital Signs ........................................................................................................... 38 
9.1.6 
Diagnostic Imaging............................................................................................... 38 
9.1.7 
Biopsy/Surgery..................................................................................................... 38 
9.1.8 
Standard of Truth.................................................................................................. 39 
9.1.9 
Adverse Events .................................................................................................... 40 
9.2 
Clinical Laboratory Measurements ................................................................................ 40 
9.2.1 
Hematology ......................................................................................................... 40 
9.2.2 
Biochemistry ........................................................................................................ 40 
9.2.3 
Coagulation.......................................................................................................... 40 
10 
EVALUATIONS BY VISIT ............................................................................................ 41 
10.1 
Visit 1 (Screening; Day -28 [Within 28 Days before IP Administration]) ......................... 41 
10.2 
Visit 2 (Day 1; IP Administration)................................................................................. 41 
10.3 
Visit 1 and Visit 2 combined (Day 1; IP Administration) ................................................ 42 
10.4 
Visit 3 (Day 2 to 4; Follow-up Visit) ............................................................................. 42 
10.5 
Follow-up Procedures (Within 45 Days after IP Administration]) .................................... 43 
10.6 
Early Withdrawal ......................................................................................................... 43 
11 
IMAGING PROTOCOL .................................................................................................. 44 
11.1 
PET Scanner ................................................................................................................ 44 
11.2 
rhPSMA-7.3 (18F) Injection Administration ................................................................... 44 
11.3 
rhPSMA-7.3 (18F) PET Acquisition ............................................................................... 44 


Study BED-PSMA-301, Protocol Version 3, 01-Jul-2020 
Page 6 of 66 
 
CONFIDENTIAL Blue Earth Diagnostics  
Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
11.4 
Image Transfer............................................................................................................. 44 
11.5 
rhPSMA-7.3 (18F) Image Reads .................................................................................... 44 
12 
ADVERSE EVENT REPORTING AND DOCUMENTATION ......................................... 45 
12.1 
Adverse Events ............................................................................................................ 45 
12.1.1 
Severity of Adverse Events ................................................................................... 45 
12.1.2 
Relationship of Adverse Events to IP ..................................................................... 46 
12.2 
Serious Adverse Events (SAEs) .................................................................................... 46 
12.2.1 
Serious Adverse Event Reporting .......................................................................... 47 
12.3 
Urgent Safety Measures................................................................................................ 47 
12.4 
Medical Monitoring ..................................................................................................... 47 
13 
DISCONTINUATION AND REPLACEMENT OF PATIENTS......................................... 48 
13.1 
Discontinuation of IP ................................................................................................... 48 
13.2 
Discontinuation/Withdrawal from the Study .................................................................. 48 
13.3 
Replacement of Patients ............................................................................................... 48 
13.4 
Lost to Follow-up......................................................................................................... 48 
13.5 
Study Discontinuation or Termination ........................................................................... 49 
14 
PROTOCOL DEVIATIONS ............................................................................................ 50 
15 
DATA SAFETY MONITORING ..................................................................................... 51 
16 
STATISTICAL METHODS AND CONSIDERATIONS ................................................... 52 
16.1 
Data Sets Analyzed ...................................................................................................... 52 
16.2 
Accountability of Patients and Imaging ......................................................................... 52 
16.3 
Demographic and Baseline Characteristics..................................................................... 52 
16.4 
Analysis of Primary Endpoint(s) ................................................................................... 52 
16.5 
Analysis of Secondary and Exploratory Endpoint(s) ....................................................... 54 
16.6 
Analysis of Safety Endpoint(s)...................................................................................... 54 
16.7 
Planned Interim Analysis .............................................................................................. 54 
16.8 
Sample Size and Randomization ................................................................................... 54 
17 
DATA COLLECTION, RETENTION AND MONITORING ............................................. 55 
17.1 
Data Collection Instruments.......................................................................................... 55 
17.2 
Data Management Procedures ....................................................................................... 55 
17.3 
Data Quality Control and Reporting .............................................................................. 55 
17.4 
Archive of Data ........................................................................................................... 55 
17.5 
Availability and Retention of Investigational Records..................................................... 56 
17.6 
Monitoring and Auditing .............................................................................................. 56 
17.7 
Patient Confidentiality .................................................................................................. 56 
18 
REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS ................ 58 


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18.1 
Institutional Review Boards and Independent Ethics Committees .................................... 58 
18.2 
Amendments ............................................................................................................... 58 
18.3 
Patient Information and Consent ................................................................................... 58 
18.4 
Post-trial Care .............................................................................................................. 60 
18.5 
Publications ................................................................................................................. 60 
19 
REFERENCES................................................................................................................ 61 
APPENDIX 1. STUDY SCHEDULE........................................................................................... 64 
 


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LIST OF TABLES 
Table 1: 
Evaluation of 68Ga-PSMA-11 PET and 18F-DCFPyL PSMA PET in N1 Disease........... 23 
Table 2: 
Hemipelvis Region Categorization Method ................................................................ 39 
Table 3: 
CTCAE (V5) AE Severity Grading ........................................................................... 45 
Table 4: 
AE Severity Grading ................................................................................................ 46 
Table 5: 
Relationship of AEs to IP.......................................................................................... 46 
Table 6: 
Translation of Region Level to Patient Level Categorizations in Patients with No TP 
Regions ................................................................................................................... 53 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .......................................................................................................... 17 
Figure 2: 
Structure of rhPSMA-7.3 (18F) .................................................................................. 19 
 


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Based on Protocol Template, SOP-MED-002-AD-2, Version 3 
LIST OF ABBREVIATIONS 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
BCR 
Biochemical recurrence 
CI 
Confidence interval 
COVID-19 
Corona Virus Disease-19 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
EAP 
Efficacy Analysis Population 
EBRT 
External beam radiation therapy 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eTMF 
Electronic trial master file 
EU 
European Union 
18F 
Fluorine-18 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FN 
False Negative 
FP 
False Positive 
FSP 
Full Safety Population 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GGG 
Gleason Grade Grouping 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICRP 
International Commission on Radiological Protection 
ID 
Identifier 
IEC 
Independent Ethics Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LHRH 
Luteinizing hormone-releasing hormone 
LN(s) 
Lymph node(s) 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
NCCN 
National Comprehensive Cancer Network 
NPV 
Negative predictive value 
PCa 
Prostate cancer 
PET 
Positron emission tomography 
PLND 
Pelvic lymph node dissection 
PP 
Per Protocol Population 
PPV 
Positive predictive value 
PSA 
Prostate-specific antigen 
PSMA 
Prostate-specific membrane antigen 
rh 
Radiohybrid 
RP 
Radical prostatectomy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCID 
Severe combined immunodeficiency 
SoT 
Standard of Truth 
SOP 
Standard Operating Procedure 
99mTc-HDP  
99m Technetium-hydroxydiphosphate  
99mTc-MDP 
99m Technetium-methyldiphosphonate 
TN 
True Negative 
TP 
True Positive 
TUM 
Technical University of Munich 
US 
United States 
VDR 
Verified detection rate 
 
 


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CONFIDENTIAL Blue Earth Diagnostics  
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PROTOCOL SYNOPSIS 
Study Title 
A prospective, Phase 3, multi-center single-arm, imaging study 
investigating the safety and diagnostic performance of rhPSMA-7.3 (18F) 
PET ligand in men with newly diagnosed prostate cancer 
Protocol Number 
BED-PSMA-301 
Phase 
3 
Sponsor 
Blue Earth Diagnostics 
Funding Organization 
Blue Earth Diagnostics Ltd 
Study Design 
This is a Phase 3, multi-center, single-arm, diagnostic imaging study 
designed to evaluate the safety and diagnostic performance of radiohybrid 
prostate-specific membrane antigen (rhPSMA)-7.3 positron emission 
tomography (PET) ligand for the detection of N1 and M1 metastases in 
men with newly diagnosed unfavorable intermediate-, high- or very 
high-risk prostate cancer (PCa; per National Comprehensive Cancer 
Network [NCCN] Guidelines Version 1.2020; PROS-2). 
A number of measures have now been put in place to streamline the study 
for patients’ safety due to the continued impact of the Corona Virus 
Disease-19 (COVID-19) pandemic on daily life. 
Consented patients will be screened to determine eligibility for the study 
up to 28 days (up to 45 days due to the COVID-19 pandemic) before 
investigational 
product 
(IP) 
administration. 
Alternatively, 
this 
screening/eligibility evaluation may take place on the day of rhPSMA-7.3 
(18F) administration (with pre-screening via telephone), if necessary, to 
ensure the safety of enrolled patients (named “Visit 1 and Visit 2 
combined”). In addition to their routine clinical work-up, which may 
include 99mtechnetium-biphosphonate bone scan and abdominal/pelvic 
computed tomography (CT) or magnetic resonance imaging (MRI) and 
chest CT per local practice, and before the scheduled radical prostatectomy 
(RP) and pelvic lymph node dissection (PLND), patients will receive 
8 mCi (296 MBq) ± 20% rhPSMA-7.3 (18F), delivered as an intravenous 
(IV) bolus injection, followed by PET imaging. 
For each patient, the PET imaging results will be reported to the 
responsible physician prior to the planned RP. If safe and feasible, within 
1 to 3 days post-IP administration, the patient must return to the clinic for 
safety follow-up including electrocardiogram (ECG), blood safety 
laboratory tests and focused physical examination. Clinical review of 
imaging results and discussion of further procedures/treatments with the 
patient should also take place at this visit if the results are available. In 
cases where the rhPSMA-7.3 (18F) PET imaging results are not available at 
the safety follow-up visit, imaging results and further procedures/treatment 
plan should be discussed with the patient within 7 days after rhPSMA-7.3 
(18F) imaging (this review may be conducted by telephone at the clinician’s 
discretion). Within 45 days post-IP administration, the patient will receive 
treatment as follows:  
• 
Standard of care surgical treatment of PCa, including PLND; or 
• 
If the rhPSMA-7.3 (18F) PET scan detects M1 lesion(s): 
o A biopsy/surgery and/or additional imaging to confirm M1 
lesion(s) will be required prior to initiation of treatment.  


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Safety will be monitored throughout the study. This will include adverse 
event (AE) and vital signs monitoring, clinical laboratory evaluations, 
12-lead ECG and focused physical examinations performed in all patients. 
Note: due to the COVID-19 pandemic, the post-IP safety follow-up 
(laboratory and ECG assessments and focused physical examination) may 
be conducted within 1 to 5 days post-IP administration. In addition, the 
standard of care treatment and follow-up procedures to confirm M1 
lesions(s) by PET may occur up to 60 days post-IP administration. 
Study Rationale 
The purpose of this study is to assess the performance of rhPSMA-7.3 (18F) 
for detecting N1 and M1 disease in patients with newly diagnosed PCa 
eligible for curative intent, standard of care locoregional therapy, who have 
elected to undergo RP with regional PLND. Accurate staging of newly 
diagnosed PCa assists in directing appropriate treatment strategies. In 
patients with unfavorable intermediate, high or very high risk PCa, the 
primary goal of imaging is to detect extra-prostatic disease. The 
identification of metastatic disease may significantly change the planned 
treatment regimen from locoregional to systemic therapy.  
The 
prostate-specific 
membrane 
antigen 
(PSMA) 
receptor 
is 
over-expressed in the majority of PCa. Although not approved in any 
country or region, PSMA PET tracers have been used in many centers 
around the world to image PCa patients. Initial results have demonstrated 
promising diagnostic performance. The variable production capacity of the 
radiometal 68Ga represents a practical disadvantage when considering the 
large number of patients with PCa eligible to undergo PSMA PET 
imaging. To overcome this shortcoming, 18F-labeled PSMA ligands, such 
as rhPSMA-7.3 (18F), have been developed. rhPSMA-7.3 (18F) injection is 
a PET ligand for the detection of PCa. The rhPSMA-7 (18F) isomer mixture 
and the rhPSMA-7.3 (18F) stereoisomer have already been administered to 
patients at the Technical University of Munich (TUM). 
Evaluation of the sensitivity and specificity of rhPSMA-7.3 (18F) imaging 
by blinded image evaluation (BIE) for detecting regional pelvic lymph 
node (LN) involvement, compared to histopathology, will be performed as 
the co-primary endpoints.  
Primary Objective and 
Endpoints 
Objective: 
To assess the sensitivity and 
specificity of rhPSMA-7.3 (18F) PET 
in detecting N1 disease (as determined 
by the central BIE) on a patient level 
compared to the histopathology of 
pelvic lymphatic tissue removed 
during RP and PLND. At least one 
positive pelvic LN on PET (N1) and 
one positive LN as determined by 
histopathology (pN1) on the same side 
of the pelvis (left or right) will be 
deemed a True Positive (TP) on a 
patient level.  
Endpoints: 
• 
Sensitivity of rhPSMA-7.3 
(18F) PET (as determined by 
central BIE) for detecting 
pelvic LN metastases 
compared to surgical 
pathology on a patient level. 
• 
Specificity of rhPSMA-7.3 
(18F) PET (as determined by 
central BIE) for detecting 
pelvic LN metastases 
compared to surgical 
pathology on a patient level. 


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Secondary Objectives 
and Endpoints 
Objective: 
1. To assess the Verified Detection 
Rate (VDR) for M1 disease of 
rhPSMA-7.3 (18F) PET findings 
(as determined by central BIE) on 
a patient level in patients with 
newly diagnosed unfavorable 
intermediate-, high-, or very high-
risk PCa using histopathology or 
confirmatory imaging. 
Endpoints: 
1. Percentage of patients in 
whom rhPSMA-7.3 (18F) 
imaging detects at least one 
verified M1 metastasis, as 
determined by central BIE. 
Secondary Objectives 
and Endpoints (Cont.) 
2. To assess the VDR for M1 disease 
of rhPSMA-7.3 (18F) PET 
findings (as determined by central 
BIE) on a patient level in patients 
with negative conventional 
imaging. 
2. Percentage of patients with 
negative conventional 
imaging for M1 disease in 
whom rhPSMA-7.3 (18F) PET 
detects at least one verified 
M1 metastasis, as determined 
by central BIE. 
 
3. To assess the positive predictive 
value (PPV) of rhPSMA-7.3 (18F) 
PET for N1 and M1 lesions (as 
determined by central BIE) 
compared to histopathology or 
confirmatory imaging (M1 lesions 
only). 
3. Patient level PPV of 
rhPSMA-7.3 (18F) PET BIE 
for N1 and M1 lesions 
compared to histopathology 
or confirmatory imaging (M1 
lesions only). 
 
4. To assess the PPV of rhPSMA-7.3 
(18F) PET for detecting pelvic LN 
metastases compared to surgical 
pathology on a patient level in 
which a False Positive (FP) 
patient is defined as having at 
least one FP region (right or left 
pelvis), regardless of any 
coexisting TP findings. 
4. PPV of rhPSMA-7.3 (18F) 
PET for detecting pelvic LN 
metastases compared to 
surgical pathology on a 
patient level in which a FP 
patient is defined as having at 
least one FP region (right or 
left pelvis), regardless of any 
coexisting TP findings. 
 
5. To assess the negative predictive 
value (NPV) of rhPSMA-7.3 (18F) 
PET for detecting pelvic LN 
metastases compared to surgical 
pathology on a patient level in 
which a False Negative (FN) 
patient is defined as having at 
least one FN region (right or left 
pelvis), regardless of any 
coexisting True Negative (TN) 
findings. 
5. NPV of rhPSMA-7.3 (18F) 
PET for detecting pelvic LN 
metastases compared to 
surgical pathology on a 
patient level in which a FN 
patient is defined as having at 
least one FN region (right or 
left pelvis), regardless of any 
coexisting TN findings. 
 
6. To assess the impact of rhPSMA-
7.3 (18F) PET BIE on a) upstaging 
patients planned for RP or b) 
converting planned RP to external 
beam radiation therapy (EBRT). 
6. a) The percentage of patients 
being upstaged to N1 or M1 
disease; 
b) The percentage of patients 
in whom planned RP is 
converted to EBRT. 


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7. To determine the inter- and intra-
reader agreement of rhPSMA-7.3 
(18F) scan interpretation by 
blinded independent readers. 
7. Kappa statistic for the 
agreement between and 
within blinded independent 
readers on the interpretation 
of rhPSMA-7.3 (18F) scans.  
 
8. To assess the safety of rhPSMA-
7.3 (18F) injection in patients. 
8. Safety (AEs, vital signs 
clinical laboratory 
evaluations, 12-lead ECG and 
focused physical 
examinations) of rhPSMA-
7.3 (18F) injection in patients. 
Exploratory Objectives 
and Endpoints 
Objective: 
1. To assess the sensitivity and 
specificity of rhPSMA-7.3 (18F) 
PET in detecting nodal metastases 
(as determined by central BIE) on 
a regional level compared to the 
histopathology of pelvic 
lymphatic tissue removed during 
RP and PLND. 
Endpoint: 
1. Diagnostic performance 
(sensitivity and specificity) of 
rhPSMA-7.3 (18F) PET for 
detecting pelvic LN 
metastases compared to 
surgical pathology on a 
regional level. 
 
2. To evaluate diagnostic 
performance of rhPSMA-7.3 (18F) 
PET (as determined by central 
BIE) in patients with a) pelvic LN 
metastatic deposits <5 mm (short 
axis) and LN metastatic deposits 
≥5 mm (short axis) and b) pelvic 
LN metastatic deposits <10 mm 
(short axis) and LN metastatic 
deposits ≥10 mm (short axis), if 
feasible. 
2. Diagnostic performance of 
rhPSMA-7.3 (18F) PET in 
patients with a) pelvic LN 
metastatic deposits <5 mm 
(short axis) and LN metastatic 
deposits ≥5 mm (short axis) 
and b) pelvic LN metastatic 
deposits <10 mm (short axis) 
and LN metastatic deposits 
≥10 mm (short axis). 
Study Sites 
This study will be conducted at up to approximately 35 sites in the United 
States (US) and Europe. 
Investigational 
Product(s), including 
control products 
IP: 8 mCi (296 MBq) ± 20% rhPSMA-7.3 (18F), delivered as an IV bolus 
injection with a 10 mL fast 0.9% sodium chloride flush. 
Control: Not applicable. 
Study and Participant 
Duration 
Study Duration: The total study duration from first site activation to data 
analysis is estimated to be 15 months. 
Participant Duration: Will be approximately 90 days (assuming the longest 
possible participation). Patients will be screened for inclusion into the 
study up to 28 days (up to 45 days due to the COVID-19 pandemic) before 
IP administration. Each patient will have a safety visit within 1 to 3 days 
following IP administration (due to the COVID-19 pandemic, this visit 
may be conducted within 1 to 5 days post-IP administration). Future study 
procedures such as surgery, biopsy or further imaging should be scheduled 
at this visit and based on the results of the PET scan and standard of care. 
Patients will remain in the study until the results of the histology or 
confirmatory imaging are obtained in order to satisfy the Standard of Truth 
(SoT). If confirmatory procedures for suspected M1 disease are required, 
this should be prior to initiation of treatment. 


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Planned Interim 
Analyses 
No formal interim analysis is planned. In order to have inclusion of 
sufficient numbers of histopathologically positive and negative N1 cases, 
an interim look will be allowed to ensure a distribution of pN1 disease as 
would be anticipated in this patient population. 
STATISTICS 
Primary Analysis Plan 
The co-primary endpoints for the study are based on the sensitivity and 
specificity of rhPSMA-7.3 (18F) PET (as determined by central BIE) in 
detecting N1 disease compared to histopathology of pelvic LNs. The 
primary analysis involves a joint assessment of sensitivity and specificity 
against individual performance goals: 
H0: Sensitivity ≤ Se0 or Specificity ≤ Sp0 versus H1: Sensitivity > Se0 
and Specificity > Sp0 
Where Se0 and Sp0 are performance goals for sensitivity and specificity, 
respectively. Performance goals of 22.5% (Se0) for sensitivity and 82.5% 
(Sp0) for specificity were selected based on the low sensitivity but high 
specificity of other PSMA ligands used for LN staging. The analyses for 
sensitivity and specificity will be performed using one-sided 0.025 exact 
binomial tests. In addition to the rates, exact two-sided 95% confidence 
intervals (CIs) will also be provided. If the predefined sensitivity and 
specificity goals are met by the same two of three readers (both tests reach 
statistical significance for the same two readers), the study will be 
considered to have successfully demonstrated the effectiveness of the 
rhPSMA-7.3 (18F) in detecting N1 disease. 
Secondary and exploratory endpoints will be summarized descriptively, 
with the exception of consistency of rhPSMA-7.3 (18F) scan interpretation 
by blinded independent readers which will be presented utilizing Kappa 
statistics. Two-sided 95% CIs will be presented, where applicable. 
Rationale for Number 
of Patients 
A total sample size of approximately 375 patients is planned in order to 
obtain 300 evaluable patients for analysis of the primary endpoint. 
Assuming a sensitivity of 40% of PSMA ligands for detecting N1 disease 
(based on the previous OSPREY study [NCT02981368]), a sample size of 
75 positive cases provides 90% power to reject the performance goal of 
22.5%. Assuming a specificity of 90% for rhPSMA-7.3 (18F) PET, a 
sample size of 225 negative cases provides 90% power to reject the 
performance goal of 82.5%. Assuming the true prevalence rate of N1 
disease is 25% (Klevečka, 2008; MSKCC, Nomogram; Internal Report: 
PSMA: TUM Data Report), a sample size of 300 evaluable patients is 
expected to provide 75 positive cases and 225 negative cases.  
Approximately 375 patients with unfavorable intermediate-, high- and very 
high-risk PCa will be enrolled into the study. Since some patients will have 
M1 disease and some patients will receive EBRT instead of RP following 
the PET scan, enrollment of up to approximately 375 patients will ensure 
inclusion of at least 300 evaluable patients undergoing RP and PLND. 
In order to have inclusion of sufficient numbers of histopathologically 
positive and negative cases, an interim look will be allowed to ensure a 
distribution of pN1 disease as would be anticipated in this patient 
population. After the inclusion of approximately 150 patients, the 
percentages of pN0 and pN1 will be monitored. If the percentage of pN1 
exceeds 35%, inclusion of very high-risk and/or high-risk patients will be 
suspended. If the percentage of pN1 is less than 15%, the inclusion of 
intermediate-risk patients will be suspended. 
Dropouts who fail to complete all study procedures, for reasons other than 


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due to adverse reactions/AEs deemed related to IP, will be withdrawn from 
the study and replaced. No more than 15% of patients enrolled, who did 
not have M1 disease or EBRT, will be replaced.  


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Figure 1: 
Study Schema 
 
COVID-19=Corona 
Virus 
Disease-19; 
CT=computed 
tomography; 
EBRT=external 
beam 
radiation 
therapy; 
eCRF=electronic case report form; 
18F=fluorine-18; GGG=Gleason Grade Grouping; IP=investigational product; 
MRI=magnetic resonance imaging; NCCN=National Comprehensive Cancer Network; PCa=prostate cancer; PET=positron 
emission tomography; PLND=pelvic lymph node dissection; PSA=prostate-specific antigen; RP=radical prostatectomy; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
99mTc-HDP=99mtechnetium-hydroxydiphosphate; 
99mTc-HDP=99mtechnetium-methyldiphosphonate. 
a 
Unfavorable intermediate-risk (GGG 2 with ≥50% of biopsy cores positive for PCa and/or >1 Intermediate Risk Factor 
[T2b; T2c; PSA 10-20] or Any GGG 3), high-risk or very high-risk disease (per NCCN Guidelines Version 1.2020; 
PROS-2). 
b 
If not already performed within 60 days prior to screening, conventional imaging will be performed as part of routine 
clinical practice, which may include bone scan (99mTc-HDP, 99mTc-MDP), abdominal/pelvic CT or MRI, and chest CT 
as per local practice. Conventional imaging that has been performed at non-participating institutions will be accepted 
provided the scans are retrievable and reviewed by the participating institution. Note: baseline conventional imaging 
performed as part of routine clinical practice should be performed at least 24 hours prior to the investigational 
rhPSMA-7.3 (18F) PET scan.  
c 
Due to the COVID-19 pandemic, for patients who already have baseline conventional imaging, Visit 1 and Visit 2 may 
be combined (named “Visit 1 and Visit 2 combined”) if judged by the investigator to be necessary to decrease potential 
exposure to SARS-CoV-2 for patients. For all patients enrolled through the Visit 1 and Visit 2 combined pathway, 
pre-screening via telephone contact with the patient is required prior to Day 1 to review the study eligibility criteria, 
obtain initial consent (remote consent is acceptable if permitted under local regulations and approvals), to promote study 
visit compliance and to ensure patient understanding of the combined study visit and planned IP administration, as well 
as ask about baseline conventional imaging that may already have been performed or needs to be scheduled. Full written 
informed consent will be taken on Day 1 (Visit 1 and Visit 2 combined). For sites with on-site manufacturing, the visits 
may be combined if mutually agreed by the Radiopharmacy and investigator even post-COVID-19 pandemic 
restrictions.  
Alternatively, the time from Visit 1 (initial screening) to Visit 2 (rhPSMA-7.3 (18F) PET scan) may be extended up to 
45 days due to the COVID-19 pandemic. 
d 
If rhPSMA-7.3 (18F) PET does not detect M1 disease, the patient will undergo the scheduled RP and PLND. In patients 
without M1 lesions identified and in whom the patient and physician believe, after obtaining the results of the 
rhPSMA-7.3 (18F) PET, that EBRT would be a better therapeutic option than RP, the patient may proceed to EBRT and 
the rationale for this change of management will be documented on the eCRF. 
 Patients in whom the rhPSMA-7.3 (18F) PET shows M1 metastatic disease will be asked to undergo a biopsy or 
confirmatory imaging of the PET-positive lesion(s) to confirm the presence of a metastasis. If a surgical intervention of 
this lesion is carried out as part of the treatment, this may substitute for a biopsy. If the patient has proven M1 metastatic 
disease, the treatment decision may be altered, based on the responsible physician’s clinical judgement. This change will 
be documented on the eCRF. Any confirmatory procedure for suspected M1 disease, as described above, should be 
performed prior to initiation of treatment.  
e 
Within 1 to 3 days post-IP administration, the patient must return to the clinic for safety follow-up. Clinical review of 
imaging results and discussion of further procedures/treatments with the patient should also take place at this visit if 
Visit 1c 
(Screening from 
Day -28) 
Visit 2c 
(Day 1) 
Visit 3 
(Follow-up 
visit Day 2 to 
Day 4)e 
Follow-up 
Procedures 
Patients with 
unfavourable 
intermediate, high-risk 
or very high-risk PCaa 
Consent, screening, 
medical history, 
assessments and, if not 
already performed, 
conventional imagingb 
Assessments and 
rhPSMA-7.3 (18F) 
PET scan 
Clinical review, 
assessments 
and schedule 
treatmentd 
Treatmentf 
within 45 days 
post-IP 


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feasible. In cases where the rhPSMA-7.3 (18F) PET imaging results are not available, imaging results and further 
procedures/treatment plan should be discussed with the patient within 7 days after rhPSMA-7.3 (18F) imaging (this may 
be conducted by telephone at the clinician’s discretion). Details of this review will be entered under Visit 3 on the eCRF. 
Note: Due to the COVID-19 pandemic, the post-IP safety follow-up (laboratory and ECG assessments and focused 
physical examination) may be conducted within 1 to 5 days post-IP administration to ensure the safety of enrolled 
patients. 
f 
Due to the COVID-19 pandemic, the time period from Visit 2 to the scheduled surgery and/or follow procedures (e.g. to 
confirm M1 lesion(s)) may be extended up to 60 days. 
 


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1 
BACKGROUND 
The investigational product (IP) is fluorine-18 (18F) radiohybrid prostate-specific membrane 
antigen (rhPSMA)-7.3 injection, a positron emission tomography (PET) ligand for the 
detection of prostate cancer (PCa). 
It is designed to target the extracellular epitope of the prostate-specific membrane antigen 
(PSMA) molecule and is administered as a single intravenous (IV) bolus microdose (i.e. the 
mass dose administered is less than 100 µg/patient). 
The molecular structure of the drug substance comprises a PSMA binding motif, a peptide 
spacer, an 18F-radiolabeled silicon fluoride acceptor moiety and a gallium chelator complex 
(Figure 2). 
Figure 2: 
Structure of rhPSMA-7.3 (18F) 
 
1.1 
Overview of Non-clinical Studies 
A non-clinical biodistribution and dosimetry study has been performed (Internal Report: 
BEDPSMADEV002), in which 100 pmol rhPSMA-7.3 (18F) (N=27) was administered IV to 
severe combined immunodeficiency (SCID) male mice. Animals were sacrificed at 10, 60, 
120, 180 and 300 minutes post-administration, with urine and blood samples collected 
immediately after sacrifice and tissues harvested and weighed for the measurement of 18F 
radioactivity. Human dosimetry was calculated by extrapolation from the mouse 
biodistribution data using scaling factors to account for the differences between animals and 
humans. The data demonstrated that for rhPSMA-7.3 (18F), the largest accumulation of 
radioactivity was in the kidney, spleen, lung, liver and heart. Clearance from the blood and 
clearance to the urine was rapid for rhPSMA-7.3 (18F), but there was a relatively slow 
build-up of radioactivity in the kidney. Using a 3.5-hour bladder voiding interval, as 
recommended by the International Commission on Radiological Protection (ICRP, 1992), the 
effective dose for humans extrapolated from the animal data was 21.7 µSv/MBq for 
rhPSMA-7.3 (18F). Using a 1.0-hour bladder voiding interval, based on the time at which 
patients will be encouraged to void in the clinical setting, the effective dose for humans was 
12.8 µSv/MBq. Based on these data, an injection of 8 mCi (296 MBq) ± 20% for a clinical 
scan would result in a favorable radiation effective dose of less than 5 mSv, assuming a 
1-hour voiding interval.  


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Consistent with the development of a radiodiagnostic agent, rhPSMA-7.3 (18F) is not 
designed to elicit pharmacological activity and an in vitro secondary pharmacology screen 
has confirmed there is no unintended pharmacological activity in a panel of 44 potential 
targets. A concentration of 5 µg/mL was used in the in vitro pharmacology profiling which 
compares to a maximum concentration in human plasma of 0.04 µg/mL (based on 2500 mL 
plasma and a maximum human dose of 100 µg). In a pivotal single IV bolus dose extended 
toxicity study in rats to determine tolerance and potential target organ toxicity to rhPSMA-7.3 
at IV dosages of 0, 0.1, 1 and 10 mg/kg, the no-observed-adverse-effect-level was the 
maximum dose administered of 10 mg/kg (allometrically scaled human dose equivalent of 
1.6 mg/kg). This represents a 1000-fold multiple of the maximum clinical microdose of 
100 µg based on a 60 kg human. No target organs of toxicity were identified. Systemic 
exposure demonstrated rat plasma concentrations above the intended maximum human actual 
dose. In vitro protein binding in rat and human indicated moderate binding of 75% and 82% 
in rat and human, respectively, with no concentration dependence. In vitro human 
cytochrome P450 (CYP) reaction phenotyping indicated rhPSMA-7.3 is not metabolized. In 
vitro rhPSMA-7.3 does not inhibit or induce human CYP isoforms and is not a substrate or 
inhibitor of human drug transporters suggesting drug interaction with rhPSMA-7.3 is 
unlikely. 
Further details of the non-clinical studies performed with rhPSMA-7.3 or rhPSMA-7.3 (18F) 
are provided in the rhPSMA-7.3 (18F) Investigator’s Brochure (IB). 
1.2 
Overview of Clinical Studies 
Although no PSMA-targeted imaging agents are licensed as radiodiagnostic agents for use in 
either Europe or the United States (US), they are widely used by many imaging centers 
(Rowe, 2018). This includes use of rhPSMA-7.3 (18F) (single diastereoisomer), as well as 
rhPSMA-7 (18F) (a mixture of four diastereoisomers, including rhPSMA-7.3 [18F]), at the 
Technical University of Munich (TUM). To date, data for rhPSMA-7 (18F), administered 
under the physician’s personal responsibility, (exempt from a manufacturing authorization as 
per Section 13, Subsection 2b of the German Medicinal Products Act), have been reported. In 
a retrospective, non-interventional review of data from patients (N=1189) with known or 
suspected PCa who underwent a clinically indicated rhPSMA-7 (18F) PET/computed 
tomography (CT) or PET/magnetic resonance imaging (MRI) scans at TUM, diagnostic 
performance, biodistribution and safety data for rhPSMA-7 (18F) were analyzed (Internal 
Report: PSMA: TUM Data Report). Data sources included hospital records and imaging 
results, as well as routine follow-up data. Given the retrospective nature of the data 
collection, informed consent was not obtained from each individual patient; thus, routine 
clinical data included in the study database were totally anonymized and only aggregated 
anonymized data from chart review were available for analysis.  
No clinical data on rhPSMA-7.3 (18F) diagnostic performance are currently available; 
however, clinical data available for rhPSMA-7 (18F) are broadly expected to be consistent 
with that of the rhPSMA-7.3 (18F) isomer alone. The single isomer product (rhPSMA-7.3 
[18F]) is being developed as it is preferable to a diastereoisomer mix for the purposes of 
manufacturing control.  
A total of 1189 patients, with known or suspected PCa, underwent a clinically indicated 
rhPSMA-7 (18F) PET/CT or PET/MRI scan at TUM between 30 June 2017 and 30 June 2018. 
Based on the retrospective chart review, rhPSMA-7 (18F) was well-tolerated, with no safety 
concerns identified. A total of 58 consecutive patients with high risk PCa (defined by 
D’Amico, 1998) staged with rhPSMA-7 (18F) PET/CT or PET/MRI were analyzed. Results 


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were compared to histopathological findings (patient-based analysis; template region based 
analysis; right- versus left-based analysis). For the patient-based analysis, the sensitivity, 
specificity and accuracy of rhPSMA-7 (18F) PET were 72.2%, 92.5% and 86.2%, 
respectively. For morphological imaging, values were 50.0%, 72.5% and 65.5%, respectively. 
On receiver operating characteristic analyses, rhPSMA-7 (18F) PET performed statistically 
significantly better than morphological imaging in the patient-based analyses (area under the 
curve of 0.858 versus 0.649; p=0.012). For the template region-based and the right- versus 
left-based analysis, similar results were obtained with rhPSMA-7 (18F) PET compared to 
morphological imaging. These efficacy data demonstrated that rhPSMA-7 (18F) PET imaging 
is superior to morphological imaging for N-staging of primary high risk PCa. 
Furthermore, rhPSMA-7 (18F) PET imaging offers excellent detection rates in early 
biochemical recurrence (BCR) after radical prostatectomy (RP; 423/532 had positive findings 
on rhPSMA-7 (18F) PET/CT imaging, including 333/418 and 90/114 patients with and 
without pelvic lymph node dissection (PLND), respectively, and 185/225 and 
238/307 patients with and without salvage external beam radiation therapy [EBRT], 
respectively), as well as in early BCR after primary radiation therapy with curative intent 
(60/65 had positive findings on rhPSMA-7 (18F) PET/CT imaging). 
Further details of the clinical studies performed or planned for rhPSMA-7.3 (18F) are 
provided in the rhPSMA-7.3 (18F) IB. 


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2 
STUDY RATIONALE 
rhPSMA-7.3 (18F) injection is a PET ligand for the detection of PCa. The rhPSMA-7 (18F) 
isomer mixture and the rhPSMA-7.3 (18F) stereoisomer have already been administered to 
patients at the TUM (see Section 1.2). To date, several hundred patients with PCa have been 
imaged clinically with rhPSMA (18F), which has informed the design of this proposed study. 
rhPSMA-7.3 (18F) is currently being formally evaluated by Blue Earth Diagnostics in a 
Phase 1, open label, study designed to assess the safety, biodistribution and internal radiation 
dosimetry of rhPSMA-7.3 (18F) injection in healthy volunteers, and to assess safety and 
investigate the imaging characteristics in patients with PCa (Study BED-PSMA-101; 
EudraCT No. 2018-004703-39).  
Prostate cancer is the most prevalent cancer in men in the developed world and the third 
leading cause of death (Jemal, 2011). It is most commonly diagnosed in men aged 65 years 
and over and in its early stages, it is largely asymptomatic, with tumors detected by 
identification of increased levels of prostate-specific antigen (PSA) in peripheral blood. If 
detected early, and when the disease is organ confined, the 5-year survival rate approaches 
100%. 
Accurate staging of newly diagnosed PCa assists in directing appropriate treatment strategies. 
The recently updated National Comprehensive Cancer Network (NCCN Guidelines 
Version 1.2020; PROS-2) recommend bone imaging and abdominal/pelvic imaging as the 
initial work-up in patients newly-diagnosed high- and very high-risk PCa, as well as in a 
subgroup of patients with unfavorable intermediate-risk PCa. The primary goal of such 
imaging is to detect extra-prostatic disease (M1: non-regional nodal involvement, bone, or 
other sites [UICC, TNM Classification of Malignant Tumours]); the identification of which 
would likely significantly change the planned treatment regimen from locoregional to 
systemic therapy. 
Various retrospective studies have evaluated the utility of bone scans as a staging tool, with 
an incidence of bone metastases ranging from 3.5% (Ito, 2013) or 6.4% (De Nunzio, 2013) 
up to 20% (Chong, 2014) reported in patients with intermediate- and high-risk PCa. A 
false-positive rate of these bone scans of 20% has been reported (Chong, 2014), with MRI 
proving no better at detecting bone metastases. Specifically, a recent publication highlights 
the low probability of finding bone metastases on a staging MRI of the pelvis, with bone 
metastases identified in only 1.5% (57 of 3765) of cases and only in those with 
intermediate- and high-risk PCa (Vargas, 2017). 
In the absence of confirmed M1 disease, PLND at the time of RP is recommended to assess 
for nodal disease and predict patient outcome (Moschini, 2016; Swanson, 2006). 
Furthermore, in cases where disease is limited to the prostate and regional lymph nodes (LNs; 
N1 disease), removal of regional LN metastases is performed with curative intent. Similarly, 
diagnosis of M1 disease beyond the field of surgery or radiotherapy allows both the patient 
and clinician to make more informed decisions about appropriate adjuvant, often systemic, 
treatments (Roach, 2018). Several methods to predict the absence or presence of M1 disease 
have been used with limited success, including nomograms, CT, MRI and PET imaging 
(Cagiannos, 2003; Schiavina, 2008; Park, 2015; Zarzour, 2017).  
With respect to the detection of N1 disease, a recent meta-analysis of 24 studies including 
2928 patients demonstrated a pooled overall sensitivity of MRI for the detection of LN 
metastases of only 56% (Woo, 2018). PET using 11C-choline did not perform materially 
better, with a sensitivity of 59% for the detection of LN metastases (Huang, 2018). A variety 


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of studies have recently evaluated 68Ga-PSMA-11 PET or 18F-DCFPyL PSMA PET as a 
decision-making aid in the prediction of N1 disease (Table 1). Although specificity was 
relatively high in these studies, the sensitivity compared to LN dissection and pathological 
examination was rather low, with point estimates ranging from 31% to 71%.  
Table 1: 
Evaluation of 68Ga-PSMA-11 PET and 18F-DCFPyL PSMA PET in N1 
Disease 
Tracer 
Study 
Sensitivity 
Specificity 
No. Patients 
68Ga-PSMA 
van Kalmthout, 2019; prospective, 
controlled study 
42% 
(27% to 58%)a 
91% 
(79% to 97%)a 
96 
68Ga-PSMA 
Pooled analysis of four studies 
(Von Eyben, 2018) 
61% 
(47% to 72%)a 
97% 
(85% to 99%)a 
224 
18F-DCFPyL 
Gorin, 2018; prospective; controlled 
study 
71% 
(29% to 96%)a 
89% 
(65% to 99%)a 
25 
18F-DCFPyL 
OSPREY [NCT02981368]; prospective 
controlled clinical trial 
31% to 42%b 
(19% to 30%)c 
96% to 99%b 
(94% to 96%)c 
268 
CI=confidence interval; PET=positron emission tomography; PSMA=prostate-specific membrane antigen 
a 
95% CI 
b 
range of point estimates among three readers 
c 
range of lower bound of the 95% CIs for three readers (upper bound of CIs not reported). 
The overwhelming need for improved imaging should focus on the identification of N1 and 
M1 disease, which may potentially have a meaningful impact on patient treatment and 
outcomes. Ideally, a staging technique that detects extra-prostatic disease should: 1) image 
the whole body, 2) not be limited to the skeleton, and 3) be both sensitive and specific for 
identifying PCa extent. 
The PSMA receptor is a 100 kD transmembrane glycoprotein that is over-expressed in the 
majority of PCa (Israeli, 1994; Silver, 1997; Osborne, 2013). Peptidomimetic 
glu-ureido-based PSMA inhibitors, initially described in 2001 (Kozikowski, 2001), bind to a 
carboxypeptidase active site on the extracellular motif of the PSMA receptor. Although not 
approved in any country or region, in the last 5 years, many centers around the world have 
imaged patients using PSMA PET tracers based on this targeting technology (Perera, 2016). 
Whilst these initial results have demonstrated promising diagnostic performance, there 
remains no licensed or approved PSMA PET imaging agents. Ongoing clinical use of these 
technologies is only through compassionate use and research protocols. The variable 
production capacity of the radiometal 68Ga represents a practical disadvantage when 
considering the large number of patients with PCa eligible to undergo PSMA PET imaging. 
To overcome this shortcoming, 18F-labeled PSMA ligands have also been developed. 
This study is designed to assess the performance of rhPSMA-7.3 (18F) for detecting N1 and 
M1 disease in patients with newly diagnosed PCa eligible for curative intent, standard of care 
locoregional therapy, who have elected to undergo RP with regional PLND. Evaluation of the 
sensitivity and specificity of rhPSMA-7.3 (18F) imaging by central BIE for detecting regional 
pelvic LN involvement, compared to histopathology, will be performed as the co-primary 
endpoints. Therefore, only patients who choose to undergo RP and a PLND will be included 
in this study. 


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2.1 
Risk-benefit Assessment 
2.1.1 
Benefits 
As rhPSMA-7.3 (18F) represents approximately 39% of the rhPSMA-7 (18F) mixture, clinical 
data obtained to date with rhPSMA-7 (18F) are relevant to the understanding of 
rhPSMA-7.3 (18F). 
rhPSMA-7 (18F) has been shown to be an effective PET radiotracer and is considered an 
improvement over morphological imaging for staging of primary high-risk PCa in terms of 
diagnostic accuracy (Internal Report: PSMA: TUM Data Report). rhPSMA-7 (18F) PET also 
showed good detection rates in early BCR of PCa after RP or curative radiation therapy 
(Internal Report: PSMA: TUM Data Report). The data compare favorably with those 
published for 68Ga-PSMA-11, the most widely used small-molecule inhibitor of PSMA used 
for PCa imaging (Rowe, 2016). 
The rhPSMA-7.3 (18F) PET scans may provide further clinical information regarding the 
patient’s disease status that may not have been appreciated by routine clinical testing. If such 
information arises, this will be reported back to the responsible clinician to help direct the 
patient’s further management. This may provide a direct benefit to the patient. 
2.1.2 
Risks 
The risks from the imaging studies to patients mainly relate to the IV injection and the 
radiation emitted by the radiopharmaceutical and the CT transmission scan (when the PET 
scan is acquired on a PET/CT scanner). Intravenous injection carries a small risk of infection 
and hematoma. 
A non-clinical biodistribution and dosimetry study has been performed (see Section 1.1). 
Using a 1.0-hour bladder voiding interval, based on the time at which patients will be 
encouraged to void in the clinical setting, the effective dose for humans extrapolated from the 
animal data was 12.8 µSv/MBq for rhPSMA-7.3 (18F). The administered activity in this study 
will be 8 mCi 296 MBq ± 20%. Based on the results of the non-clinical study, this would 
result in an effective dose of less than 5 mSv. Full details are in the Study Imaging Manual. 
rhPSMA-7.3 (18F) is currently being formally evaluated by Blue Earth Diagnostics in a 
Phase 1, open-label, study designed to assess the safety, biodistribution and internal radiation 
dosimetry of rhPSMA-7.3 (18F) injection in healthy volunteers, and to assess safety and 
investigate the imaging characteristics in patients with PCa (Study BED-PSMA-101; 
EudraCT No. 2018-004703-39). 
The maximum effective dose due to the CT transmission scan on a PET/CT scanner will vary 
from site-to-site, but as a guide a dose of 7 mSv would be expected. The effective dose due to 
the CT acquisition will be in accordance with ALARA (As Low As Reasonably Achievable) 
principles. The estimated total dose of 12 mSv (PET and CT transmission scan) is in line with 
other common nuclear medicine procedures. 
Patients in whom the rhPSMA-7.3 (18F) PET shows M1 metastatic disease will be asked to 
undergo a biopsy or confirmatory imaging of the PET-positive lesion(s) to confirm the 
presence of a metastasis.  
A CT-guided biopsy may be required in these patients; mean effective doses of between 4.3 
and 13.9 mSv have been reported (Guberina, 2018) during CT-guided biopsies and is 
dependent on the organ region and CT-scanner generation. A biopsy will cause discomfort 
and pain and may incidentally lead to complications, like prolonged bleeding at the site of the 
biopsy or infection.  


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Confirmatory imaging may include the use of diagnostic ultrasound, CT or PET (see 
Section 9.1.8). Examples of effective doses from such procedures are as follows: 
abdominal/pelvic 
CT, 
6 
to 
8 mSv 
(McCollough, 
2015); 
chest 
CT, 
7 
mSv 
(McCollough, 2015); 18F-sodium fluoride PET, 8.9 mSv (Beheshti, 2015). 
As with all imaging techniques, there is the risk that the PET scan may provide a False 
Positive image (FP; giving the appearance of cancer) in sites where it is not present, due to 
other events in the body or False Negative (FN; failing to detect a nidus of cancer). Thus, 
patients should continue to be reviewed and may require other investigations, to confirm scan 
findings. 
To date, rhPSMA-7 (18F) has been administered to over 1200 patients undergoing clinically 
indicated rhPSMA-7 (18F) PET/CT or PET/MRI scan in a single center (formal data available 
for 1189 patients). rhPSMA-7 (18F) was well tolerated in these patients, and adverse events 
(AEs) primarily related to the underlying tumor, with few serious adverse events (SAEs) and 
only three events with a possible causal association with rhPSMA-7 (18F). This is consistent 
with AE reporting for other PSMA agents in the literature (Literature Review of PSMA for 
the Detection and Management of Prostate Cancer, data on file). In addition, as of 
15 February 2019, rhPSMA-7.3 (18F) has been administered at TUM, under the physician’s 
personal responsibility, to a total of 558 men with known or suspected PCa. Although 
35 patients had AEs or SAEs within the 30-day observation period, there were no reports of 
adverse reactions or serious adverse reactions attributed to injection of rhPSMA-7.3 (18F) 
(M Eiber, TUM; personal communication).  


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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to assess the sensitivity and specificity of rhPSMA-7.3 
(18F) PET in detecting N1 disease (as determined by the central BIE) on a patient level 
compared to the histopathology of pelvic lymphatic tissue removed during RP and PLND. At 
least one positive pelvic LN on PET (N1) and one positive LN as determined by 
histopathology (pN1) on the same side of the pelvis (left or right) will be deemed a True 
Positive (TP) at the patient level. In patients who have no TP regions (left or right), the 
translation of varying combinations of FP, True Negative (TN) and FN regions to patient 
level categorizations is described in detail in Section 16.4. 
3.2 
Secondary Objectives 
The secondary objectives of the study are: 
1. To assess the Verified Detection Rate (VDR) for M1 disease of rhPSMA-7.3 (18F) PET 
findings (as determined by central BIE) on a patient level in patients with newly 
diagnosed unfavorable intermediate-, high-, or very high-risk PCa using histopathology 
or confirmatory imaging. 
2. To assess the VDR for M1 disease of rhPSMA-7.3 (18F) PET findings (as determined by 
central BIE) on a patient level in patients with negative conventional imaging. 
3. To assess the positive predictive value (PPV) of rhPSMA-7.3 (18F) PET for N1 and M1 
lesions (as determined by central BIE) compared to histopathology or confirmatory 
imaging (M1 lesions only). 
4. To assess the PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases 
compared to surgical pathology on a patient level in which a FP patient is defined as 
having at least one FP region (right or left pelvis), regardless of any coexisting 
TP findings. 
5. To assess the negative predictive value (NPV) of rhPSMA-7.3 (18F) PET for detecting 
pelvic LN metastases compared to surgical pathology on a patient level in which a 
FN patient is defined as having at least one FN region (right or left pelvis), regardless of 
any coexisting TN findings. 
6. To assess the impact of rhPSMA-7.3 (18F) PET BIE on a) upstaging patients planned for 
RP or b) converting planned RP to EBRT. 
7. To determine the inter- and intra-reader agreement of rhPSMA-7.3 (18F) scan 
interpretation by blinded independent readers. 
8. To assess the safety of rhPSMA-7.3 (18F) injection in patients. 
3.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
1. To assess the sensitivity and specificity of rhPSMA-7.3 (18F) PET in detecting nodal 
metastases (as determined by central BIE) on a regional level compared to the 
histopathology of pelvic lymphatic tissue removed during RP and PLND. 
2. To evaluate diagnostic performance of rhPSMA-7.3 (18F) PET (as determined by central 
BIE) in patients with a) pelvic LN metastatic deposits <5 mm (short axis) and LN 


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metastatic deposits ≥5 mm (short axis) and b) pelvic LN metastatic deposits <10 mm 
(short axis) and LN metastatic deposits ≥10 mm (short axis), if feasible. 


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4 
STUDY DESIGN 
4.1 
Study Overview 
This is a prospective, Phase 3, multi-center, single-arm, diagnostic imaging study designed to 
evaluate the safety and diagnostic performance of rhPSMA-7.3 (18F) PET ligand for the 
detection of N1 and M1 metastases in men with newly diagnosed unfavorable intermediate-, 
high- or very high-risk PCa (per NCCN Guidelines Version 1.2020; PROS-2).  
Up to approximately 375 patients will be enrolled into the study to ensure inclusion of at least 
300 evaluable patients undergoing RP and PLND. Consented patients will be screened at 
Visit 1 to determine eligibility for the study up to 28 days (up to 45 days due to the Corona 
Virus Disease-19 [COVID-19] pandemic) before IP administration at Visit 2. Patients who 
meet all of the inclusion criteria and none of the exclusion criteria will be assigned a patient 
identifier (ID) and entered into the study at screening. In addition to their routine clinical 
work-up, which may include 99mtechnetium-biphosphonate and abdominal/pelvic CT or MRI 
and chest CT per local practice, and before the scheduled RP, patients will be administered a 
dose of rhPSMA-7.3 (18F), an administered activity of 8 mCi (296 MBq) ± 20% delivered as 
an IV bolus injection with a 10 mL fast 0.9% sodium chloride flush, followed by PET 
imaging. 
Note: Due to the COVID-19 pandemic, for patients who already have baseline conventional 
imaging, the screening/eligibility evaluation may take place on the day of rhPSMA-7.3 (18F) 
administration (with pre-screening via telephone), if necessary, to ensure the safety of 
enrolled patients (see Visit 1 and Visit 2 combined; Section 10.3). Alternatively, the time 
from Visit 1 (initial screening) to Visit 2 (rhPSMA-7.3 (18F) PET scan) may be extended up 
to 45 days due to the COVID-19 pandemic. 
The PET imaging results for each patient will be reported to the responsible physician prior 
to the planned RP. If safe and feasible, within 1 to 3 days post-IP administration, the patient 
must return to the clinic for safety follow-up including electrocardiogram (ECG), blood 
safety laboratory tests and focused physical examination. Clinical review of imaging results 
and discussion of further procedures/treatments with the patient should also take place at this 
visit if the results are available. In cases where the rhPSMA-7.3 (18F) PET imaging results are 
not available at the safety follow-up visit, imaging results and further procedures/treatment 
plan should be discussed with the patient within 7 days after rhPSMA-7.3 (18F) imaging (this 
review may be conducted by telephone at the clinician’s discretion). Note: due to the 
COVID-19 pandemic, the post-IP safety follow-up (laboratory and ECG assessments and 
focused physical examination) may be conducted within 1 to 5 days post-IP administration to 
ensure the safety of enrolled patients.  
Within 45 days post-IP administration (may be extended up to 60 days due to the COVID-19 
pandemic), the patient will receive treatment as follows, with further detail provided in 
Section 9.1.6.  
• Standard of care surgical treatment of PCa, including a PLND; or 
• If the rhPSMA-7.3 (18F) PET scan detects M1 lesion(s): 
o 
A biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required 
prior to initiation of treatment. 


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Safety will be monitored throughout the study. This will include AE and vital signs 
monitoring, clinical laboratory evaluations, 12-lead ECG and focused physical examinations 
performed in all patients. 
An overview of the study is provided in the study schema (Figure 1). 
4.2 
Sub-studies 
Not applicable. 


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5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The co-primary endpoints for this study will be the: 
• Sensitivity of rhPSMA-7.3 (18F) PET (as determined by central BIE) for detecting pelvic 
LN metastases compared to surgical pathology on a patient level. 
• Specificity of rhPSMA-7.3 (18F) PET (as determined by central BIE) for detecting pelvic 
LN metastases compared to surgical pathology on a patient level. 
5.2 
Secondary Endpoints 
The secondary endpoints for this study will be: 
1. Percentage of patients in whom rhPSMA-7.3 (18F) imaging detects at least one verified 
M1 metastasis, as determined by central BIE. 
2. Percentage of patients with negative conventional imaging for M1 disease in whom 
rhPSMA-7.3 (18F) PET detects at least one verified M1 metastasis, as determined by 
central BIE. 
3. Patient level PPV of rhPSMA-7.3 (18F) PET BIE for N1 and M1 lesions compared to 
histopathology or confirmatory imaging (M1 lesions only). 
4. PPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FP patient is defined as having at least one 
FP region (right or left pelvis), regardless of any coexisting TP findings. 
5. NPV of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases compared to surgical 
pathology on a patient level in which a FN patient is defined as having at least one FN 
region (right or left pelvis), regardless of any coexisting TN findings. 
6. a) The percentage of patients being upstaged to N1 or M1 disease; 
b) The percentage of patients in whom planned RP is converted to EBRT. 
7. Kappa statistic for the agreement between and within blinded independent readers on the 
interpretation of rhPSMA-7.3 (18F) scans.  
8. Safety (AEs, vital signs clinical laboratory evaluations, 12-lead ECG and focused 
physical examinations) of rhPSMA-7.3 (18F) injection in patients. 
5.3 
Exploratory Efficacy Endpoints 
1. Diagnostic performance (sensitivity and specificity) of rhPSMA-7.3 (18F) PET for 
detecting pelvic LN metastases compared to surgical pathology on a regional level. 
2. Diagnostic performance of rhPSMA-7.3 (18F) PET in patients with a) pelvic LN 
metastatic deposits <5 mm (short axis) and LN metastatic deposits ≥5 mm (short axis) 
and b) pelvic LN metastatic deposits <10 mm (short axis) and LN metastatic deposits 
≥10 mm (short axis). 
5.4 
Safety Evaluations 
In all patients, safety evaluations will include AE monitoring and reporting from the time of 
informed consent throughout the study.  


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Vital sign assessments will also be conducted at screening and pre- and post-IP 
administration on the day of rhPSMA-7.3 (18F) injection. 
In addition, a focused physical examination will be performed at screening and at the safety 
follow-up visit within 1 to 3 days post-IP administration, and a 12-lead ECG will be 
performed pre-IP administration on the day of rhPSMA-7.3 (18F) injection and at the safety 
follow-up visit within 1 to 3 days post-IP administration. Baseline blood safety laboratory 
tests, including hematology (full blood count), biochemistry (urea and electrolytes, liver 
function tests) and coagulation will be performed pre-IP administration on the day of 
rhPSMA-7.3 (18F) injection and repeated at the safety follow-up visit within 1 to 3 days 
post-IP administration. 
Note: due to the COVID-19 pandemic, the safety follow-up (laboratory and ECG assessments 
and focused physical examination) may be conducted within 1 to 5 days post-IP 
administration to ensure the safety of enrolled patients. 


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6 
PATIENT SELECTION 
6.1 
Study Population 
Treatment naïve patients with a diagnosis of unfavorable intermediate-, high-risk or very 
high-risk PCa (per NCCN Guidelines Version 1.2020; PROS-2), scheduled to receive 
standard of care surgical treatment for PCa, including a PLND, who meet all of the inclusion 
and none of the exclusion criteria will be eligible for participation in this study.  
In order to have inclusion of sufficient numbers of histopathologically positive and negative 
cases, an interim look will be allowed to ensure a distribution of pN1 disease as would be 
anticipated in this patient population. After the inclusion of approximately 150 patients, the 
percentages of pN0 and pN1 will be monitored. If the percentage of pN1 exceeds 35%, 
inclusion of very high-risk and/or high-risk patients will be suspended. If the percentage of 
pN1 is less than 15%, the inclusion of intermediate-risk patients will be suspendedInclusion 
Criteria 
1. Patient willing to provide signed informed consent and willing to comply with all 
required study schedule events, where safe and feasible. 
2. Patient is male and aged >18 years old. 
3. Histologically confirmed adenocarcinoma of the prostate. 
4. Candidate for RP with PLND and scheduled to undergo the surgical procedure. 
5. Patient with either: 
a) Unfavorable intermediate-risk disease, defined as:  
− 
Any Gleason Grade Grouping [GGG] 3, or  
− 
GGG 2 with ≥50% of biopsy cores positive for PCa and/or >1 Intermediate 
Risk Factor [T2b; T2c; PSA 10-20] 
or  
b) High-risk or very high-risk disease (per NCCN Guidelines Version 1.2020; 
PROS-2). 
6.2 
Exclusion Criteria 
1. Patients with any medical condition or circumstance (including receiving an IP) that the 
investigator believes may compromise the data collected or lead to a failure to fulfil the 
study requirements. 
2. Patients who are planned to have an x-ray contrast agent or other PET radiotracer 
<24 hours prior to the PET scan. 
3. Patients currently receiving, or with a prior history of, androgen deprivation therapy 
(ADT; defined as surgical orchidectomy; luteinizing hormone-releasing hormone 
[LHRH] agonist alone [continuous or intermittent]; LHRH antagonist alone [continuous 
or intermittent]; administration or use of a first generation or second generation 
anti-androgen alone or in combination with an LHRH agonist/antagonist). 
4. Patients participating in an interventional clinical trial within 30 days and having 
received an IP within five biological half-lives prior to administration of rhPSMA-7.3 
(18F). 
5. Patients with known hypersensitivity to the active substance or to any of the excipients of 
the IP. 


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7 
CONCURRENT MEDICATIONS 
As medically feasible, all patients should be maintained on the same medications without 
change throughout the entire study period. 
Concomitant medications will be recorded at screening and any changes in administration 
will be noted. 
7.1 
Prohibited Medications 
The following medications are prohibited during the study and administration will be 
considered a protocol violation: 
• X-ray contrast agent <24 hours prior to the rhPSMA-7.3 (18F) PET scan. 
• 
Any other PET imaging agent within 24 hours prior to the rhPSMA-7.3 (18F) PET scan. 
• 
The initiation of any therapy should not occur until after definitive pathology or imaging 
results are obtained satisfying the Standard of Truth (SoT) assessment. 


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8 
STUDY TREATMENTS 
As manufacturing and supply of IP will be site-specific, the Study Pharmacy Manual 
provides additional information for the IP (rhPSMA-7.3 [18F] injection).  
8.1 
Method of Assigning Patients to Treatment Groups 
Not applicable. This is a single-arm study. 
8.2 
Blinding 
Not applicable. This is an open-label study. 
8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
The IP – rhPSMA-7.3 (18F) – is a PET imaging radiopharmaceutical formulated as a solution 
for injection. It is designed to target the extracellular epitope of the PSMA molecule and is 
administered as a single IV bolus microdose (i.e. the mass dose administered is less than 
100 µg/patient). 
The molecular structure of the drug substance comprises a PSMA binding motif, a peptide 
spacer, an 18F-radiolabeled silicon fluoride acceptor moiety and a gallium chelator complex 
(Figure 2, Section 1). 
Company Code: 
rhPSMA-7.3 (18F) 
Chemical Name: 
Gallium 2,2',2''-(10-((3S,7S,12R,26R,34S)-1,3,7,12,26,34-
hexacarboxy-29-((4-(di-tert-
buty-[18F]fluorosilyl)benzamido)methyl)-5,10,17,20,28,31-
hexaoxo-4,6,11,16,21,27,30-heptaazatetratriacontan-34-yl)-
1,4,6,10-tetraazacyclododecane-1,4,7-triyl)triacetate 
Molecular Formula: 
C63H9618FGaN12O25Si 
8.3.2 
Formulation of Control Product 
Not applicable. This is a single-arm study. 
8.3.3 
Packaging and Labeling 
rhPSMA-7.3 (18F) is supplied as a sterile, aqueous solution for IV administration. The product 
is supplied either in a multi-dose vial sealed with a synthetic rubber closure and aluminum 
overseal or in a single unit dose syringe depending on the manufacturing location. The product 
label will be region-specific and will include the following information: batch number, product 
expiry date/time, total product volume (dispensed), radioactive concentration and/or total 
radioactivity (activity in mCi and/or MBq) and calibration date and time. 
8.4 
Supply of IP at the Site 
Each vial or syringe is transported in a lead or tungsten shield. The quality control analysis of a 
sample of the drug product may be performed in parallel with transportation of the drug 


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product to the study site. The investigator (or nominated deputy) will receive release 
information for the drug product. Only product for which confirmation of release has been 
received shall be used. Where the product is transported as a single patient dose, the dose will 
be measured in a radionuclide dose calibrator before administration. Where the product is 
transported in its original container the volume of injection for each patient is calculated and 
withdrawn into a shielded syringe immediately before injection. The calculation is based on the 
radioactive content, the half-life of 18F (109.8 mins), the reference date and time, the prescribed 
dose and the time of injection. 
8.4.1 
Dispensing 
When the study site receives the dose and prior to administration, the activity in the syringe 
will be measured in a dose calibrator. Should the activity be less than 6.4 mCi (236 MBq), the 
volume required exceed 10 mL (US sites) or 6 mL (European sites) undiluted material or the 
IP be past the expiry date and time, the scan should not be performed. The dose can be 
diluted in the syringe to a maximum volume of 10 mL with 0.9% saline (as required). After 
administration, residual radioactivity in the injection device shall be measured using a 
radionuclide dose calibrator.  
8.4.2 
Administration Instructions 
Patients will receive a dose with an administered activity of 8 mCi (296 MBq) ± 20% of 
rhPSMA-7.3 (18F), delivered as an IV bolus injection with a 10 mL fast 0.9% sodium chloride 
flush, followed by PET imaging. Full details are provided in the Study Imaging Manual. 
8.4.3 
Storage 
The shelf-life of rhPSMA-7.3 (18F) injection is up to 10 hours from the end of synthesis and the 
product must not be used beyond this limit. rhPSMA-7.3 (18F) injection should be stored at 
room temperature in a shielded container. 
All non-radioactive containers (shielding, transport cans) must be returned to the manufacturing 
site. Containers that are radioactive or that contained radioactive products must be disposed of 
at either the study site or another designated facility, with prior approval from the Sponsor, 
after the study and after overall drug accountability has been completed by the Sponsor or its 
representative. 
Waste must be disposed of according to Federal, State and local regulations for radioactive 
material. Imaging sites must comply with all applicable regulations. 
Precautions for the safe handling of radioactive materials should be observed. 
8.5 
IP Accountability 
An accurate and current accounting of the dispensing and return/disposal of IP for each 
patient will be recorded on the IP Accountability Record. The study monitor will verify this 
document throughout the course of the study.  
8.6 
Measures of Treatment Compliance 
Participants will receive the rhPSMA-7.3 (18F) injection under direct supervision of study 
personnel. Each administration volume and total radioactivity injected will be checked. The 
batch number and activity per administration (determined by the radioactivity in the injection 


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device before and after administration, with measurement date and time) will be recorded in 
each patient’s electronic case report form (eCRF)/source document.  
8.7 
End of Trial 
The end of the trial will be when the last blinded image evaluation has been completed and 
the database is locked. The end of patient participation is defined as when the last patient has 
completed all the study procedures and the results of the histology or confirmatory imaging 
are available in order to satisfy the SoT. 


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9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is summarized in Appendix 1. 
Written informed consent will be obtained prior to conducting any study-related activities 
(see Section 18.3). Patients will provide written informed consent and be assessed for 
eligibility for study participation at screening (performed within 28 days before IP 
administration [or up to 45 days due to the COVID-19 pandemic]). 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at screening, with 
any changes in concomitant medication during the study recorded on the eCRF. The dose, 
route, unit frequency of administration, and indication for administration and dates of 
medication will be captured. 
9.1.2 
Demographics  
Demographic information (full/partial date of birth/age, gender, ethnicity/race, sex, height, 
weight, as permitted by local regulations) will be recorded at screening. Weight will also be 
recorded pre-IP administration on the day of the rhPSMA-7.3 (18F) injection. 
9.1.3 
Medical History 
Relevant medical history, including history of current disease, concomitant disease record, 
information regarding underlying diseases will be recorded at screening. Histological 
confirmation of adenocarcinoma of the prostate must be provided at screening. 
If not already performed within 60 days prior to screening, conventional imaging as part of 
routine 
clinical 
practice, 
which 
may 
include 
bone 
scan 
(99mtechnetium-
hydroxydiphosphate [99mTc-HDP], 
99mtechnetium-methyldiphosphonate [99mTc-MDP]), 
abdominal/pelvic CT or MRI, and chest CT as per local practice) will be performed. 
Conventional imaging that has been performed at non-participating institutions will be 
accepted provided the scans are retrievable and reviewed by the participating institution. 
Note: baseline conventional imaging performed as part of routine clinical practice should be 
performed at least 24 hours prior to the investigational rhPSMA-7.3 (18F) PET scan. 
9.1.4 
Physical Examination 
A focused physical examination will be performed by an appropriately licensed and 
credentialed clinician at screening and at the safety follow-up visit within 1 to 3 days post-IP 
administration (may occur within 1 to 5 days post-IP administration due to the COVID-19 
pandemic). New abnormal physical exam findings must be documented on the eCRF. Any 
clinically significant changes (as determined by the site investigator) in physical examination 
findings should be reported as an AE.  


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9.1.5 
Vital Signs 
Vital signs (body temperature, blood pressure, pulse and respiration rates) will be recorded 
after resting for 5 minutes at screening and pre- and post-IP administration on the day of 
rhPSMA-7.3 (18F) injection.  
In addition, a 12-lead ECG will be performed pre-IP administration on the day of 
rhPSMA-7.3 (18F) injection and at the safety follow-up visit within 1 to 3 days post-IP 
administration (may occur within 1 to 5 days post-IP administration due to the COVID-19 
pandemic). 
Any clinically significant changes in vital sign measurements (as determined by the site 
investigator) should be reported as an AE.  
9.1.6 
Diagnostic Imaging 
All patients will receive an IV bolus of rhPSMA-7.3 (18F) injection and undergo a PET scan 
as described in the Study Imaging Manual. 
For each patient, the PET imaging results will be reported to the responsible physician prior 
to the planned RP. Within 1 to 3 days post-IP administration, the patient must return to the 
clinic for safety follow-up (may occur within 1 to 5 days post-IP administration due to the 
COVID-19 pandemic). Clinical review of imaging results and discussion of further 
procedures/treatments with the patient should also take place at this visit if feasible. In cases 
where the rhPSMA-7.3 (18F) PET imaging results are not available at the safety follow-up 
visit, imaging results and further procedures/treatment plan should be discussed with the 
patient within 7 days after rhPSMA-7.3 (18F) imaging (this may be conducted by telephone at 
the clinician’s discretion).  
Within 45 days post-IP administration (may be extended up to 60 days due to the COVID-19 
pandemic), the patient will receive treatment: 
• 
Standard of care surgical treatment of PCa, including a PLND; or 
• 
If the rhPSMA-7.3 (18F) PET scan detects M1 lesion(s): 
o 
A biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required 
prior to initiation of treatment. 
Image Interpretation 
Results of local rhPSMA-7.3 (18F) PET interpretation will be used to guide 
biopsy/confirmatory procedures, if indicated, as well as for the physician to discuss further 
procedures/treatments with the patient. 
For the evaluation of the co-primary endpoints, rhPSMA-7.3 (18F) PET image data will be 
appropriately blinded, randomized, and read by 3 trained, independent central PET readers. 
9.1.7 
Biopsy/Surgery 
If the rhPSMA-7.3 (18F) PET shows M1 metastatic disease, the patient will be asked to 
undergo a biopsy or confirmatory imaging of the PET-positive lesion(s) to confirm the 
presence of a metastasis. If a surgical intervention of this lesion is carried out as part of the 
treatment, this may substitute for a biopsy. If the patient has proven M1 metastatic disease, 
the treatment decision may be altered, based on the responsible physician’s clinical 
judgement. This change will be documented on the eCRF.  


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If rhPSMA-7.3 (18F) PET does not detect M1 disease, the patient will undergo the scheduled 
RP and PLND. In patients without M1 lesions identified and in whom the patient and 
physician believe, after obtaining the results of the rhPSMA-7.3 (18F) PET, that EBRT would 
be a better therapeutic option than surgery, the patient may proceed to EBRT and the 
rationale for this change of management will be documented on the eCRF. 
The regional PLND must be performed by a suitably qualified surgeon and should include, at 
minimum, resection of lymphatic tissue for histological analysis from the following nodal 
groups: 1) hypogastric (internal iliac), 2) external iliac, and 3) obturator LNs. Extended LN 
dissection may be performed if clinically appropriate and the anatomical regions 
(e.g. pre-sacral, common iliac, peri-rectal) with left/right designations, should be recorded on 
the eCRF (when collected, pre-sacral lymph nodes should be placed in a separate packet from 
all other specimens and labeled “pre-sacral” prior to pathology assessment). Surgical 
procedures can be performed open, robotically, or laparoscopically. The location of the 
dissected material shall be marked in order to allow matching with their anatomical origin 
(left and right pelvis); the left and the right side of the specimen shall be clearly marked. The 
dissected LNs will be sectioned and analyzed by a pathologist for the presence or absence of 
PCa according to standard of care at the clinical site. The anatomical origin of these pelvic 
LN samples will be correlated to rhPSMA-7.3 (18F) PET BIE to determine the sensitivity and 
specificity of rhPSMA-7.3 (18F) PET for detecting pelvic LN metastases. 
At least one positive pelvic LN on PET (N1) and one positive LN as determined by 
histopathology (pN1) on the same side of the pelvis (left or right), as depicted in Table 2, will 
be deemed a TP on a patient level. A detailed description of patient level categorizations for 
patients who have no TP regions (left or right) is provided in Section 16.4. 
Table 2: 
Hemipelvis Region Categorization Method 
 
At Least One Pathology-positive 
LN in the Region 
No Pathology-positive LN in the 
Region 
At Least One PET-Positive LN 
in the Region 
True Positive (TP) region 
False Positive (FP) region 
No PET-positive LN in the 
Region 
False Negative (FN) region 
True Negative (TN) region 
LN=lymph node; PET=positron emission tomography. 
Any confirmatory procedure for suspected M1 disease should be performed prior to initiation 
of treatment. 
9.1.8 
Standard of Truth 
Histology or confirmatory imaging will be used as the SoT, as defined below. 
1. Histology 
a. Histology of surgically removed pelvic LNs; 
b. Histology obtained by biopsy of M1 lesion. 
2. Confirmatory Imaging 


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a. In patients without available histopathology, conventional imaging is acceptable as 
proof of M1 disease in case of unequivocal findings (e.g. sclerotic bone lesions on 
CT, positive bone lesions on bone scan, evidently enlarged LNs radiologically 
considered metastases, lesions in the liver representing metastases as determined by 
ultrasound, CT or MRI, multiple pulmonary nodules on CT). 
b. Confirmatory imaging for proof of M1 disease will be read centrally. Three central 
reviewers will review all submitted imaging and reach consensus on the nature of 
the target lesion. Reads of the confirmatory imaging as SoT will be directed by 
rhPSMA-7.3 (18F) PET findings (for confirmation of lesion location only). A brief 
summary of clinical information will be available to the readers (e.g. 67-year-old 
male with newly diagnosed, localized prostate cancer prior to rhPSMA-7.3 (18F) 
scan). Readers will be blinded to all other information. Further details are given in 
the study Independent Review Charter. 
9.1.9 
Adverse Events 
AEs will be captured for all patients throughout the study. AEs will be monitored and 
recorded from the time of informed consent until the last study visit. Duration (start and stop 
dates and times), severity/grade, outcome, treatment and relationship to IP will be recorded 
on the eCRF. Patients who experience an SAE (or an AE which developed within 3 days of 
IP administration and that persists at the final visit) will be followed until resolution or 
stabilization of these events is recorded.  
9.2 
Clinical Laboratory Measurements 
Blood safety laboratory tests, including hematology (full blood count), biochemistry (urea 
and electrolytes, liver function tests) and coagulation, will be performed at baseline (pre-IP 
administration on the day of rhPSMA-7.3 (18F) injection) and repeated at the safety follow-up 
visit within 1 to 3 days post-IP administration (may occur within 1 to 5 days post-IP 
administration due to the COVID-19 pandemic). Further details are provided in the Study 
Laboratory Manual.  
Any clinically significant changes (as determined by the site investigator) in clinical 
laboratory measurements should be reported as an AE.  
9.2.1 
Hematology 
Blood will be obtained and sent to a central laboratory (Eurofins) for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count determinations) for assessment of systemic evidence for 
infection and/or inflammation.  
9.2.2 
Biochemistry 
Blood will be obtained and sent to central laboratory (Eurofins) for determination of serum 
sodium, potassium, chloride, bicarbonate, random glucose, blood urea nitrogen, creatinine, 
aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, 
direct bilirubin, gamma-glutamyl transferase, albumin and lactate dehydrogenase. 
9.2.3 
Coagulation 
Blood will be obtained and sent to central laboratory (Eurofins) for determination of 
prothrombin time, activated partial thromboplastin time and international normalized ratio. 


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10 
EVALUATIONS BY VISIT 
10.1 
Visit 1 (Screening; Day -28 [Within 28 Days before IP Administration]) 
1. Review the study with the patient and obtain written informed consent and Health 
Insurance Portability and Accountability Act (HIPAA) authorization (or equivalent, as 
required), if appropriate. 
2. Assign the patient a unique screening number. 
3. Review eligibility criteria and confirm patient suitability for enrollment. 
4. Record demographics data. 
5. Record medical history and concomitant disease record, including a history of PCa, 
diagnosis date and prior PCa treatments, as well as histological confirmation of 
adenocarcinoma of the prostate. 
6. Record concomitant medications. 
7. Perform and record vital signs (omit if Visit 1 and Visit 2 are combined; see 
Section 10.3). 
8. Commence AE monitoring. 
9. If not already done within 60 days prior to screening, perform and record conventional 
imaging as part of routine clinical practice, which may include bone scan (99mTc-HDP, 
99mTc-MDP), abdominal/pelvic CT or MRI, and chest CT as per local practice. Note: 
Conventional imaging that has been performed at non-participating institutions will be 
accepted provided the scans are reviewed by the participating institution. Note: baseline 
conventional imaging performed as part of routine clinical practice should be performed 
at least 24 hours prior to the investigational rhPSMA-7.3 (18F) PET scan. 
10. Perform a focused physical examination. 
11. Schedule patient for Visit 2 within 28 days of consent. 
Note: Due to the COVID-19 pandemic, for patients who already have baseline 
conventional imaging, the screening/eligibility evaluation may take place on the day of 
rhPSMA-7.3 (18F) administration (with prior pre-screening via telephone) if necessary to 
ensure the safety of enrolled patients (see Visit 1 and Visit 2 combined; Section 10.3). 
Alternatively, the time from Visit 1 (initial screening) to Visit 2 (rhPSMA-7.3 (18F) PET 
scan) may be extended up to 45 days due to the COVID-19 pandemic.  
10.2 
Visit 2 (Day 1; IP Administration) 
1. Record any changes in concomitant medication since screening (omit if Visit 1 and 
Visit 2 are combined; see Section 10.3). 
2. Perform and record pre-IP administration vital signs. 
3. Record patient’s body weight pre-IP administration. 
4. Perform 12-lead ECG pre-IP administration. 
5. Perform baseline blood safety laboratory tests as outlined in Section 9.2. 
6. Ask about and record any AEs since screening (omit if Visit 1 and Visit 2 are combined; 
see Section 10.3). 
7. IP administration (IV bolus rhPSMA-7.3 (18F) injection). 
8. PET scan as described in the Study Imaging Manual. 


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9. Record any AEs occurring during the scan process. 
10. Perform and record post-IP administration vital signs. 
11. Schedule patient for Visit 3 within 1 to 3 days post-IP administration. 
Note: pre-IP administration ECG and blood safety laboratory tests may be performed at 
Visit 1 if: a) not feasible at the Visit 2 imaging center and b) collected up to 48 hours 
before IP administration where Visit 1 and Visit 2 are not combined.  
10.3 
Visit 1 and Visit 2 combined (Day 1; IP Administration) 
Due to the COVID-19 pandemic, for patients who already have baseline conventional 
imaging, Visit 1 and Visit 2 may be combined (named “Visit 1 and Visit 2 combined”) if 
judged by the investigator to be necessary to decrease potential exposure to severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) for patients. 
If Visit 1 and Visit 2 are combined, please complete all the procedures listed under Visit 1 
and Visit 2 (Sections 10.1 and 10.2, respectively) after obtaining written informed consent. 
Omit those procedures identified as not being required if combining visits.  
Notes: Visit 1 and Visit 2 combined requires pre-screening via telephone contact prior to 
Day 1 to review the study eligibility criteria, obtain initial consent (remote consent is 
acceptable if permitted under local regulations and approvals), to promote study visit 
compliance and to ensure patient understanding of the combined study visit and planned IP 
administration, as well as ask about baseline conventional imaging that may already have 
been performed or needs to be scheduled (note the specified requirement regarding bone 
scans [Section 10.1]). 
At sites where IP is not manufactured on-site, IP should be ordered prospectively at least 
5 days in advance in accordance with the IP Supply Manual.  
For sites with on-site manufacturing, the visits may be combined if mutually agreed by the 
Radiopharmacy and investigator even post-COVID-19 pandemic restrictions.  
10.4 
Visit 3 (Day 2 to 4; Follow-up Visit) 
1. Perform clinical review of imaging results and discussion of further 
procedures/treatments with the patient.  
2. Record any AEs and changes in concomitant medication since Visit 2. 
3. Perform a focused physical examination. 
4. Perform repeat blood safety laboratory tests as outlined in Section 9.2. 
5. Perform 12-lead ECG. 
6. Schedule patient to receive treatment within 45 days post-IP administration. 
Notes:  
a. 
in cases where the rhPSMA-7.3 (18F) PET imaging results are not available at this 
visit, the imaging results and further procedures/treatment plan should be reviewed 
with the patient within 7 days after rhPSMA-7.3 (18F) imaging (this may be 
conducted by telephone at the clinician’s discretion). 
b. to ensure patient safety due to the COVID-19 pandemic, the post-IP safety follow-up 
(laboratory and ECG assessments and focused physical examination) may be 
conducted within 1 to 5 days post-IP administration. 


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Patients will remain in the study until the results of the histology or confirmatory imaging are 
obtained in order to satisfy the SoT. 
10.5 
Follow-up Procedures (Within 45 Days after IP Administration]) 
Within 45 days post-IP administration patient should receive: 
• 
Standard of care surgical treatment for PCa, including a PLND; or 
• 
If the rhPSMA-7.3 (18F) PET scan detects M1 lesion(s): 
o 
A biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required 
prior to initiation of treatment. 
Note: due to the COVID-19 pandemic, follow-up procedures including standard of care 
surgical treatment for PCa, biopsy/surgery and/or additional imaging to confirm M1 
lesion(s) may be extended up to 60 days post-IP administration. 
10.6 
Early Withdrawal 
Patient participation in the study is entirely voluntary and patients may refuse to participate or 
withdraw from the trial, at any time, without prejudice to their future care. 
Although patients are not obliged to give a reason(s) for premature withdrawal, the 
investigator should make a reasonable effort to ascertain the reason(s), while fully respecting 
the patient’s rights. 
All withdrawals and dropouts of enrolled patients from the study should be reported and 
explained on the eCRF. 
Enrollment will continue until at least 75 positive cases and 225 negative cases have 
completed all study procedures; therefore, dropouts who fail to complete all study procedures 
necessary for the primary efficacy analysis, for reasons other than due to adverse 
reactions/AEs deemed related to IP, will be withdrawn from the study and replaced. No more 
than 15% of patients enrolled, who did not have M1 disease or EBRT, will be replaced (see 
Section 13.2). 


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11 
IMAGING PROTOCOL 
11.1 
PET Scanner 
A dedicated hybrid PET scanner (e.g. PET/CT) is mandatory. The selected PET scanner must 
be qualified by the study management team. Full details are in the Study Imaging Manual (also 
referred to as the Technical Operations Manual). 
11.2 
rhPSMA-7.3 (18F) Injection Administration 
As rhPSMA-7.3 (18F) represents approximately 39% of rhPSMA-7 (18F), clinical data obtained 
with rhPSMA-7 (18F) are relevant to the understanding of rhPSMA-7.3 (18F). These clinical 
data are available from a retrospective study of 1189 patients who underwent rhPSMA-7 (18F) 
PET scans. Based on these data, it was concluded that use of moderate activities >8 to 
10 mCi (297 to 370 MBq) at an early imaging time point (50 to 70 minutes) is likely 
preferable for rhPSMA-7 (18F) in general use (see rhPSMA-7.3 (18F) IB). 
A venous cannula will be inserted and the patient will receive an administered activity not 
expected to exceed 8 mCi (296 MBq) ± 20% of rhPSMA-7.3 (18F) injection diluted up to 
10 mL. The administration will be injected via the cannula with arms down, as an IV bolus 
injection followed by 10 mL flush with normal saline solution. The participant will then be 
positioned supine in the scanner, with the arms above the head (if possible), and will be 
scanned as described in the Study Imaging Manual. The time from the end of injection of 
rhPSMA-7 (18F) to the start of imaging will be between 50 to 70 minutes.  
Full details are in the Study Imaging Manual. 
11.3 
rhPSMA-7.3 (18F) PET Acquisition 
For the PET acquisition, patients will be imaged for approximately 20 minutes. For the CT 
acquisition (if acquired on a PET/CT scanner), an unenhanced (no IV contrast) CT will be 
employed. Further details on the PET acquisition are given in the Study Imaging Manual. 
11.4 
Image Transfer 
Following the completion of PET imaging at the study site, the scan data will be sent to the 
Invicro Imaging Core Lab (Invicro, LLC) using either the iPACS software or on physical 
media by courier. Full details are in the Study Imaging Manual. 
11.5 
rhPSMA-7.3 (18F) Image Reads 
All local and central readers will undergo training in interpretation of rhPSMA-7 (18F) PET 
scans, and will have a training set available for reference. Primary evaluation and reporting of 
the PET scan will be based on the site-based local read (as per standard of care). 


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12 
ADVERSE EVENT REPORTING AND DOCUMENTATION 
12.1 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the administration of an IP, whether or not related to that IP. An unexpected AE is one of a 
type not identified in nature, severity, or frequency in the current rhPSMA-7.3 (18F) IB or of 
greater severity or frequency than expected based on the information in the rhPSMA-7.3 (18F) 
IB. 
The investigator will probe, via discussion with the patient, for the occurrence of AEs during 
each visit and record the information in the site’s source documents. Adverse events will be 
recorded in the patient eCRF. Adverse events will be described by duration (start and stop 
dates and times), severity/grade, outcome, treatment and relationship to IP, or if unrelated, the 
cause. 
12.1.1 
Severity of Adverse Events 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5 (2017) will be used to assess and grade event severity, including laboratory 
abnormalities judged to be clinically significant. The severity grading is provided below 
(Table 3).  
Table 3: 
CTCAE (V5) AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
ADL=activities of daily living; AE=adverse event; CTCAE=Common Terminology Criteria for Adverse Events. 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
** Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
If the experience is not covered in the CTCAE criteria, the guidelines shown in Table 4 
below will be used to grade severity. It should be pointed out that the term “severe” is a 
measure of intensity and that a severe event is not necessarily serious. 


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Table 4: 
AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical intervention 
or therapy required. The patient may be aware of the sign or symptom but 
tolerates it reasonably well. 
Moderate (2) 
Mild 
to 
moderate 
limitation 
in 
activity, 
no 
or 
minimal 
medical 
intervention/therapy required. 
Severe (3) 
Marked 
limitation 
in activity, 
medical 
intervention/therapy 
required, 
hospitalizations possible. 
Life-threatening (4) 
The patient is at risk of death due to the adverse experience as it occurred. This 
does not refer to an experience that hypothetically might have caused death if it 
were more severe. 
Death (5) 
Death related to AE 
AE=adverse event. 
12.1.2 
Relationship of Adverse Events to IP 
The relationship of an AE to IP will be assessed using the guidelines outlined in Table 5. 
Table 5: 
Relationship of AEs to IP 
Relationship to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the patient’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined to have no reasonable probability to have 
relationship to the IP. 
AE=adverse event; IP=investigational product. 
12.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect 


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Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the patient or require intervention to prevent one of the 
outcomes listed above.  
12.2.1 
Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to IP) on an SAE 
Report Form. The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed. 
All SAEs must be reported immediately (as soon as possible after the investigator becomes 
aware of the event but no later than 24 hours) by sending the completed SAE Report Form by 
email to: 
For study sites in the United States: adverse.events@diag.bracco.com 
For study sites in Europe: braccodsu@bracco.com  
Additional and further requested information (follow-up or corrections to the original event) 
will be detailed on a new SAE Report Form and emailed to the same address. 
12.3 
Urgent Safety Measures 
An urgent safety measure is an action that the Sponsor and/or investigator may take in order 
to protect study participants against an immediate hazard to their health or safety (e.g., it is 
identified that there is a significant higher incidence of death at one investigator site and as a 
result recruitment is suspended at that site as an urgent safety measure). 
An urgent safety measure taken by the investigator must be immediately notified to the 
Sponsor. For all urgent safety measures, the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and Regulatory Agency/Competent Authority will be notified in 
accordance with International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) and applicable regulations. 
Initial notification may be followed by submission of a protocol amendment (see 
Section 18.2), notification of early termination of the trial within 15 days (if applicable) and 
notification of AEs and serious adverse reactions (if applicable). 
12.4 
Medical Monitoring 
Matthew Cooney, MD (Parexel) should be contacted directly at the following number to 
report medical concerns or questions regarding safety. 
Phone: +1 216 374 8221 


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13 
DISCONTINUATION AND REPLACEMENT OF PATIENTS 
13.1 
Discontinuation of IP 
Not applicable. rhPSMA-7.3 (18F) is administered as a single IV injection. 
13.2 
Discontinuation/Withdrawal from the Study 
Patients are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice. 
An investigator may discontinue or withdraw a patient for any of the following reasons:  
• 
Significant non-compliance/protocol violation requiring discontinuation from the study. 
• 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interests of the 
patient. 
• 
If the patient meets any of the exclusion criteria (either newly developed or not 
previously recognized) that precludes further study participation. 
• 
Lost to follow-up (see Section 13.4). 
• 
Sponsor request for early termination of study. 
The reason for patient discontinuation or withdrawal from the study will be recorded in the 
patient’s source documents and on the eCRF. 
Enrollment will continue until at least 75 positive cases and 225 negative cases have 
completed all study procedures; therefore, dropouts who fail to complete all study 
procedures, for reasons other than due to adverse reactions/AEs deemed related to IP, will be 
withdrawn and replaced. No more than 15% of patients enrolled, who did not have M1 
disease or EBRT, will be replaced. 
Note: Any patients who withdraw/are withdrawn due to adverse reactions to rhPSMA-7.3 
(18F) PET or AEs due to study procedures involved in rhPSMA-7.3 (18F) PET, will not be 
replaced. 
13.3 
Replacement of Patients 
Patients who sign the informed consent form but do not receive the IP may be replaced. 
Patients who sign the informed consent form and who receive the IP, but subsequently 
withdraw (or are withdrawn or discontinued from the study) will also be replaced except for 
patients who withdraw/are withdrawn due to adverse reactions to rhPSMA-7.3 (18F) PET or 
AEs due to study procedures involved in rhPSMA-7.3 (18F) PET (see Section 13.2). 
13.4 
Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for the follow-up visit 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study assessment: 


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• 
The site will attempt to contact the participant three times to reschedule a missed visit, 
and will counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
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, three 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.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
13.5 
Study Discontinuation or Termination 
Patient enrolment may be temporarily halted or stopped if any of the following occur: 
• 
SAE of severe acute hypersensitivity reaction attributed to the IP. 
• 
SAE of death attributed to the IP. 
• 
A new potential safety signal, e.g. multiple severe AEs which are new to the current 
rhPSMA-7.3 (18F) risk profile. 
• 
Data from other clinical trials which greatly and negatively influence the current 
rhPSMA-7.3 (18F) benefit/risk assessment. 


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14 
PROTOCOL DEVIATIONS 
A protocol deviation occurs when the patient, investigator, or Sponsor fails to adhere to 
significant protocol requirements or where there is a significant non-compliance to ICH-GCP, 
affecting patient safety or the scientific value of the trial. 
Any non-compliance with the protocol or GCP which is likely to effect to a significant degree 
the safety or physical or mental integrity of the study patients or the scientific value of the 
trial should be notified to the Sponsor within one working day. 
Protocol deviations for this study include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria (see Sections 0 and 6.2). 
• 
Use of a prohibited concomitant medication (see Section 7.1). 
• 
IP administration but no subsequent PET scan. 
The Sponsor will determine if a protocol deviation will result in withdrawal of a patient. 
Major protocol deviations will be defined and documented in the Statistical Analysis Plan 
(SAP), which will be written and approved before database lock.  


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15 
DATA SAFETY MONITORING 
Not applicable. 


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16 
STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed SAP will be written and approved 
describing all analyses that will be performed. The SAP will contain any modifications to the 
analysis plan described below.  
16.1 
Data Sets Analyzed 
All enrolled patients: all patients who signed the informed consent form. 
Full Analysis Set (FAS): all patients who were scheduled to receive the rhPSMA-7.3 (18F) 
injection by meeting the inclusion/exclusion criteria.  
Full Safety Population (FSP): all patients who received the rhPSMA-7.3 (18F) injection. 
Efficacy Analysis Population (EAP): all patients who received rhPSMA-7.3 (18F) injection 
with a PET scan and who got through RP and PLND. 
Per Protocol Population (PP): All evaluable patients in the EAP population.  
The primary analysis will be based on the EAP. The FSP will be used for all safety 
summaries. 
16.2 
Accountability of Patients and Imaging 
The completion status of all patients will be summarized. Further, availability of results of 
patient disease assessments, completion of visits, and information on image assessments 
performed will be reported. 
16.3 
Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: full/partial date of 
birth/age, gender, ethnicity/race, sex and height. Weight at screening and on Day 1 will be 
summarized. 
Relevant medical history (including history of current disease, concomitant disease record, 
information regarding underlying diseases) at screening will be also be summarized. 
16.4 
Analysis of Primary Endpoint(s) 
The co-primary endpoints for the study are based on the sensitivity and specificity of 
rhPSMA-7.3 (18F) PET (by central BIE) in detecting N1 disease compared to histopathology 
of pelvic LNs. The primary analysis involves a joint assessment of sensitivity and specificity 
against individual performance goals: 
H0: Sensitivity ≤ Se0 or Specificity ≤ Sp0 versus H1: Sensitivity > Se0 and Specificity 
> Sp0 
Where Se0 and Sp0 are performance goals for sensitivity and specificity, respectively. 
Performance goals of 22.5% (Se0) for sensitivity and 82.5% (Sp0) for specificity were 
selected based on the low sensitivity but high specificity of other PSMA ligands used for LN 
staging. The analyses for sensitivity and specificity will be performed using one-sided 0.025 
exact binomial tests. In addition to the rates, exact two-sided 95% confidence intervals (CIs) 
will also be provided. If the predefined sensitivity and specificity goals are met by the same 
two of three readers (both tests reach statistical significance for the same two readers), the 


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study will be considered to have successfully demonstrated the effectiveness of the 
rhPSMA-7.3 (18F) in detecting N1 disease. 
The TP, FP, TN and FN regions will be categorized according to Table 2 
(Section 9.1.7) using a right and left hemipelvis regional classification method. For the 
primary analysis, patients who have one TP region will be categorized as a TP patient. 
For patients who have no TP regions, Table 6a and Table 6b depict the method for assigning 
patient level categorizations based on by-region results (i.e. for the different possible 
hemipelvis combinations of TN, FN and FP regions).  
Two analyses will be performed based on the classification of patients with one TP region 
and one TN region. The primary analysis will include patients as FN if they only had one 
positive region by histopathology and it was missed by PET. Full diagnostic statistics will be 
provided for both patient level classifications.  
Table 6: 
Translation of Region Level to Patient Level Categorizations in Patients 
with No TP Regions 
a)  
Patient Level Categorization 
At Least one True 
Negative (TN) 
Region 
At Least one False 
Negative (FN) Region 
At Least one False 
Positive (FP) Region 
True Negative (TN) 
Yes 
No 
No 
False Negative (FN) 
Yes 
Yes 
No 
False Negative (FN) 
No 
Yes 
No 
False Positive (FP) 
Yes 
No 
Yes 
False Positive (FP) 
No 
No 
Yes 
False Negative (FN) for Primary 
Analysis; False Positive (FP) for 
Secondary Analysis* 
No 
Yes 
Yes 
PPV=positive predictive value.  
* 
Patient contributes to the primary efficacy analysis for Sensitivity (False Negative categorization) and a secondary 
analysis of PPV (False Positive categorization). 
b)  
Histopathology 
PET Patient Level Classification 
True Positive 
(TP) 
False Negative (FN) 
False Positive (FP) 
True Negative 
(TN) 
Two Positive 
Regions  
1 or 2 positive 
regions on PET 
Both regions negative on 
PET 
NA 
NA 
One Positive 
Region; One 
Negative 
Region 
PET is correct 
on positive 
region 
Primary analysis: PET is 
negative on the positive 
region 
Primary analysis: NA 
NA 
Secondary analysis: PET 
is negative on both 
regions only 
Secondary analysis: PET is 
negative on True Positive 
(TP) region and PET is 
positive on True Negative 
(TN) region 
Two Negative 
Regions 
NA 
NA 
PET-positive on one or two 
regions 
PET is negative 
on both regions 
NA=cell classification is not applicable; PET=positron emission tomography. 


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Analysis of subgroups will be included in the SAP. 
16.5 
Analysis of Secondary and Exploratory Endpoint(s) 
Secondary and exploratory endpoints will be summarized descriptively, with the exception of 
consistency of rhPSMA-7.3 (18F) scan interpretation by blinded independent readers which 
will be presented utilizing Kappa statistics. Two-sided 95% CIs will be presented, where 
applicable. 
Further details will be provided in the SAP. 
16.6 
Analysis of Safety Endpoint(s) 
Safety data will be summarized descriptively. For AEs and SAEs, the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and Preferred Terms will be used to 
code the reported events. The number of events, number of patients with one or more event, 
and percentage of patients with one or more event will be provided for all AEs, related AEs, 
SAEs, and all related SAEs. For blood safety laboratory tests, vital signs and 12-lead ECG 
results, the change from baseline results will also be summarized. Focused physical 
examination findings will be summarized. 
16.7 
Planned Interim Analysis 
No formal interim analysis is planned. As described in Section 16.8, in order to have 
inclusion of sufficient numbers of histologically positive and negative N1 cases to power the 
co-primary endpoints, an interim look will be allowed to ensure a distribution of pN1 disease 
as would be anticipated in this patient population.  
16.8 
Sample Size and Randomization 
A total sample size of approximately 375 patients is planned in order to obtain 300 evaluable 
patients for analysis of the primary endpoint. Assuming a sensitivity of 40% of PSMA 
ligands for detecting N1 disease (based on the previous OSPREY study [NCT02981368]), a 
sample size of 75 positive cases provides 90% power to reject the performance goal of 
22.5%. Assuming a specificity of 90% for rhPSMA-7.3 (18F) PET, a sample size of 
225 negative cases provides 90% power to reject the performance goal of 82.5%. Assuming 
the true prevalence rate of N1 disease is 25% (Klevečka, 2008; MSKCC, Nomogram; 
Internal Report: PSMA: TUM Data Report), a sample size of 300 evaluable patients is 
expected to provide 75 positive cases and 225 negative cases.  
Up to approximately 375 patients with unfavorable intermediate-, high- and very high-risk 
PCa will be enrolled into the study. Since some patients will have M1 disease and some 
patients will receive EBRT instead of RP following the PET scan, enrollment of up to 
approximately 375 patients will ensure inclusion of at least 300 evaluable patients undergoing 
RP and PLND. 
In order to have inclusion of sufficient numbers of histologically positive and negative cases, 
an interim look will be allowed to ensure a distribution of pN1 disease as would be 
anticipated in this patient population. After the inclusion of approximately 150 patients, the 
percentages of pN0 and pN1 will be monitored. If the percentage of pN1 exceeds 35%, 
inclusion of very high-risk and/or high-risk patients will be suspended. If the percentage of 
pN1 is less than 15%, the inclusion of intermediate-risk patients will be suspended.  


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17  
DATA COLLECTION, RETENTION AND MONITORING 
17.1 
Data Collection Instruments 
The investigator will prepare and maintain adequate and accurate study records and source 
documents designed to record all observations and other pertinent data on each of the site’s 
study patients. Particular care should be taken to ensure all data points are recorded in source 
documentation, especially those which are not part of standard practice. Source data should 
be attributable, legible, contemporaneous, original, accurate and complete. Changes to source 
data should be traceable, should not obscure the original entry, and should be explained if 
necessary.  
Study personnel at each site will enter data from source documents corresponding to a 
patient’s visit into the protocol-specific eCRF when the information corresponding to that 
visit is available.  
Patients will not be identified by name in the study database or on any study documents to be 
collected by the Sponsor (or designee), but will be identified by a site number, patient 
number and, where possible, patient initials. Data are pseudo-anonymized as the patient can 
be identified and as such data remains personal data and within the scope of US, European 
and UK law (US HIPAA 1996; European Union [EU] General Data Protection Regulation 
[GDPR] 2018; UK Data Protection Act 2018). 
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and creates an electronic audit trail.  
The investigator is responsible for all information collected on patients enrolled in this study. 
All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the investigator. A copy of the eCRF will remain at the 
investigator’s site at the completion of the study. 
17.2 
Data Management Procedures 
The data will be entered into a validated database. The Data Management group at Parexel 
will be responsible for data processing, in accordance with procedural documentation. 
Database lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting the Food and Drug Administration (FDA) guidelines for the handling and 
analysis of data for clinical trials. 
17.3 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. Queries 
are entered, tracked, and resolved through the electronic data capture (EDC) system directly. 
The study database will be updated in accordance with the resolved queries. All changes to 
the study database will be documented. 
17.4 
Archive of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. 


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Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), data 
for analysis is locked and cleaned per established procedures. 
The end of study electronic trial master file (eTMF) will be archived according to Blue Earth 
Diagnostics Standard Operating Procedures. 
17.5 
Availability and Retention of Investigational Records 
The investigator/institution should maintain the study documents as specified in Section 8 of 
ICH-GCP E6 (R2) and as required by the applicable regulatory requirement(s). The 
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
investigator/institution must make available for direct access all requested study-related 
records. 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations (e.g. 25 years per 
Clinical Trial regulations 536/2014/EC). No records will be destroyed without the written 
consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to inform the 
investigator when these documents no longer need to be retained. 
17.6 
Monitoring and Auditing 
Monitoring visits will be conducted by representatives of the Sponsor according to ICH-GCP 
and relevant regulations. By signing this protocol, the investigator grants permission to the 
Sponsor’s and designee’s monitors and auditors, as well as the IRB/IEC and regulatory 
authorities to conduct on-site monitoring and/or auditing and provide direct access to all 
requested study-related records. If on-site monitoring is not permitted due to restrictions 
imposed to maintain social distancing due to the COVID-19 pandemic, then the investigator 
will work remotely with the Sponsor and designee’s monitor to facilitate management of the 
study including review of study-related records. 
17.7 
Patient Confidentiality 
In order to maintain patient confidentiality, only a site number, patient number and, where 
possible, patient initials will identify all study patients on eCRFs and other documentation 
submitted to the Sponsor. Additional patient confidentiality issues (if applicable) are covered 
in the Clinical Study Agreement. 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only. All study records will be 
retained for 25 years in a locked file cabinet and code sheets linking a patient’s name to a 
patient identification number will be stored separately in another locked file cabinet.  
Clinical information will not be released without written permission of the patient, except as 
necessary for monitoring by Regulatory Authorities. The investigator must also comply with 


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all applicable privacy regulations (e.g., US HIPAA 1996; EU GDPR 2018; UK Data 
Protection Act 2018). 


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18 
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS 
The study will be conducted in accordance with ICH-GCP and all applicable regulations. The 
Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Sponsor and documented approval from the relevant 
regulatory authority (if applicable) and IRB/IEC, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study must have completed ICH-GCP training, relevant to their role. 
18.1 
Institutional Review Boards and Independent Ethics Committees 
Any documents that the IRB/IEC may need to fulfil its responsibilities (such as protocol, 
protocol amendments, IB, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC. 
The IRB/IECs written unconditional approval/favorable opinion of the study, and any 
additional local approvals (e.g., hospital management, Administration of Radioactive 
Substances Advisory Committee etc.), must be obtained prior to shipment of IP to the site 
and prior to any patients undergoing study-specific procedures. The investigator will obtain 
assurance of IRB/IEC compliance with regulations. 
Note: Regulatory authority approvals may also be required. 
The IRB/IEC’s SOPs and policies will be followed for the submission of SAEs and progress 
reports during the conduct of the study. 
An end of study notification will be submitted as determined by each countries regulatory 
requirements. 
18.2 
Amendments 
Any decision to amend the clinical trial application and/or associated documents 
(e.g. protocol, informed consent form, eCRF, IB etc.) will be made by the Sponsor. 
The relevant regulations will be followed to determine what approvals from regulatory, 
IRB/IEC or local bodies are required. All required approvals will be obtained prior to 
implementation of the amendment, except as necessary to eliminate immediate safety hazards 
to patients (see Section 12.3, Urgent Safety Measures), such as amendments made due to the 
COVID-19 pandemic to ensure patient safety by minimizing potential exposure to 
SARS-CoV-2. The Contract Research Organization will notify each participating investigator 
site when the amendment can be implemented. 
All changes to the consent form will be IRB/IEC approved; a determination will be made 
regarding whether a new consent needs to be obtained from patients who provided consent, 
using a previously approved consent form. 
18.3 
Patient Information and Consent 
In obtaining and documenting patient informed consent, the investigator must comply with 
the applicable regulatory requirement(s), ICH-GCP and the ethical principles that have their 
origin in the Declaration of Helsinki. 


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Patient information and consent forms, and any other written material provided to the patient, 
must be approved by the relevant IRB/IEC (and by any other body as required by national 
regulations) prior to the start of the study at each study site. 
The investigator (or an appropriately qualified designee) will explain the study to the patient 
or, if the patient is unable to provide informed consent, the patient’s legally acceptable 
representative, and answer any questions that arise. A verbal explanation will be provided in 
terms suited to the patient’s, or patient’s legally acceptable representatives, comprehension, 
of the purposes, procedures, and potential risks of the study and the rights of research 
participants. Patients (and the patient’s legally acceptable representative) will have the 
opportunity to carefully review the written information and consent form, to discuss the study 
with their family or surrogates, and be given ample time to think about the study and ask 
questions before agreeing to participate. 
Patients (and the patient’s legally acceptable representative) must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. The rights and welfare of the patients will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
Prior to the patient undergoing any study-specific procedures, the written informed consent 
form must be signed and personally dated by the patient, or their legally acceptable 
representative, and by the person who conducted the informed consent discussion. The 
informed consent process will also be documented in the source document (including the 
date/time consent was obtained). 
If a patient is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. The 
patient, or patient’s legally acceptable representative, may orally consent to the patient’s 
participation, if the patient, or patient’s legally acceptable representative, is not capable of 
providing of signing and personally dating the consent form. Once the patient, or patient’s 
legally acceptable representative, has provided consent, the witness should also sign and 
personally date the consent form. By signing the consent form the witness attests that the 
information sheet/consent form/any other written information was accurately explained to, 
and apparently understood by, the patient, or patient’s legally acceptable representative, and 
that informed consent was freely given by the patient, or patient’s legally acceptable 
representative. 
The distribution of the signed information sheet/consent form will be as required by any 
applicable local regulations. Otherwise a copy of the signed informed consent document will 
be given to the patient and the original maintained with the patient’s records.  
The patient, or patient’s legally acceptable representative, will be informed in a timely 
manner if new information becomes available that may be relevant to the patient’s 
willingness to continue participation in the study. The communication of this information will 
be documented in the source documentation. The written patient information/consent form 
and any other written information provided to the patients should be revised whenever 
important new information becomes available that may be relevant to the patient’s consent. 
Any revised written patient information and consent form should receive IRB/IEC 
approval/favorable opinion prior to use. The patient, or patient’s legally acceptable 
representative, should sign and personally date any revised consent form and receive a copy 
(or original, if required by applicable regulations). 


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18.4 
Post-trial Care 
rhPSMA-7.3 (18F) is a single-use diagnostic agent. Therefore, no additional care for trial 
participants is planned once their participation in the study has ended. All patients will 
receive standard of care treatment in line with their medical condition as determined by their 
physician. 
18.5 
Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions. The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the US 
HIPAA 1996 and the EU GDPR 2018.  


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19 
REFERENCES  
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rhPSMA-7.3 (18F) Investigator’s Brochure. Version 1. Blue Earth Diagnostics. 
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18F-DCFPyL positron emission tomography/computerized tomography for the preoperative 
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Urol 2018;199(1):126-32. 
Guberina N, Forsting M, Ringelstein A, et al. Radiation exposure during CT-guided biopsies: 
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Practice. 
November 
2016. 
Available 
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https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R
2__Step_4_2016_1109.pdf [Accessed 16 August 2019].  
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radionuclides. Oxford: Pergamon; 1992. 
Internal Report: PSMA: TUM Data Report. Version 2. Blue Earth Diagnostics. 
Israeli RS, Powell CT, Corr JG, et al. Expression of the prostate-specific membrane antigen. 
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Ito Y, Kikuchi E, Maeda T, et al. Bone scan in patients with newly diagnosed prostate cancer; 
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patients. J Urol 2013;189(Suppl 4S):e901, Abstract 2197. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 
2011;61(2):69-90. 
Klevečka V, Musch M, Roggenbuck U, et al. The incidence of lymph node metastases in 
prostate carcinoma depends not only on tumor characteristics but also on surgical 
performance and extent of pelvic lymphadenectomy. Medicina (Kaunas) 2008;44(8):601-8. 


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Kozikowski AP, Nan F, Conti P, et al. Design of remarkably simple, yet potent urea-based 
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of 
glutamate 
carboxypeptidase 
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APPENDIX 1. STUDY SCHEDULE 
 
VISIT 1 
Screening 
(Day -28)* 
VISIT 2 
(Day 1)* 
VISIT 3 
Follow-up 
(Day 2-4)** 
Follow-up Procedures 
(up to Day 45)*** 
Informed Consent  
X 
 
 
 
Review of Inclusion/Exclusion Criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History  
Xa 
 
 
 
Focused Physical Examination 
X 
 
X 
 
Height  
X 
 
 
 
Weight 
X 
Xb 
 
 
Vital Signs (blood pressure, pulse, respiration rate, temperature) 
X 
Xc 
 
 
12-lead ECG 
 
Xd 
X 
 
Conventional Imaging 
Xe 
 
 
 
Hematology 
 
Xf 
X 
 
Biochemistry 
 
Xf 
X 
 
Coagulation 
 
Xf 
X 
 
Record Adverse Eventsg 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
 
Administration of IP 
 
X 
 
 
Drug Accountability 
 
X 
 
 
Post-IP PET scan 
 
Xh 
 
 
Imaging findings/results for rhPSMA-7.3 (18F) 
 
 
X 
 


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VISIT 1 
Screening 
(Day -28)* 
VISIT 2 
(Day 1)* 
VISIT 3 
Follow-up 
(Day 2-4)** 
Follow-up Procedures 
(up to Day 45)*** 
Clinical reviewi 
 
 
X 
 
Planned treatment/change in planned treatmentj,k 
 
 
 
X 
Biopsy/surgery and/or additional imagingj 
 
 
 
X 
AE=adverse event; COVID-19=Corona Virus Disease-19; CT=computed tomography; EBRT=external beam radiation therapy; ECG=electrocardiogram; eCRF=electronic case report form; 
18F=fluorine-18; IP=investigational medicinal product; MRI=magnetic resonance imaging; PCa=prostate cancer; PET=positron emission tomography; PLND=pelvic lymph node dissection; 
rhPSMA=radiohybrid prostate-specific membrane antigen; RP=radical prostatectomy; SARS-CoV-2=severe acute respiratory syndrome coronavirus; SoT=Standard of Truth; 
99mTc-HDP=99mtechnetium-hydroxydiphosphonate; 99mTc-MDP=99mtechnetium-methyldiphosphonate. 
* 
Due to the COVID-19 pandemic, for patients who already have baseline conventional imaging, Visit 1 and Visit 2 may be combined (named “Visit 1 and Visit 2 combined”) if judged by 
the investigator to be necessary to decrease potential exposure to SARS-CoV-2 for patients. For all patients enrolled through the Visit 1 and Visit 2 combined pathway, pre-screening via 
telephone contact with the patient is required prior to Day 1 to review the study eligibility criteria, obtain initial consent (remote consent is acceptable if permitted under local regulations 
and approvals), to promote study visit compliance and to ensure patient understanding of the combined study visit and planned IP administration, as well as ask about baseline 
conventional imaging that may already have been performed or needs to be scheduled. Full written informed consent will be taken on Day 1 (Visit 1 and Visit 2 combined). For sites with 
on-site manufacturing, the visits may be combined if mutually agreed by the Radiopharmacy and investigator even post-COVID-19 pandemic restrictions.  
Alternatively, the time from Visit 1 (initial screening) to Visit 2 (rhPSMA-7.3 (18F) PET scan) may be extended up to 45 days due to the COVID-19 pandemic. 
** 
Visit 3 Follow-up should be performed within 1 to 3 days post-IP administration. At this visit, the patient must return to the clinic for safety follow-up including ECG, blood safety 
laboratory tests and focused physical examination. Clinical review of imaging results and discussion of further procedures/treatments with the patient should also take place at this visit, if 
feasible. In cases where the rhPSMA-7.3 (18F) PET imaging results are not available at this visit, imaging results and further procedures/treatment plan should be discussed with the patient 
within 7 days after rhPSMA-7.3 (18F) imaging (this may be conducted by telephone at the clinician’s discretion). Patients will remain in the study until the results of the histology or 
confirmatory imaging are obtained in order to satisfy the SoT. 
Note: Due to the COVID-19 pandemic, the post-IP safety follow-up (laboratory and ECG assessments and focused physical examination) may be conducted within 1 to 5 days post-IP 
administration to ensure the safety of enrolled patients. 
*** The patient should receive treatment within 45 days (may be extended up to 60 days due to the COVID-19 pandemic) post-IP administration, with treatment decision based on 
rhPSMA-7.3 (18F) PET imaging and conventional imaging (see k below). 
a  
To include medical history and concomitant disease record, including a history of PCa, diagnosis date and prior PCa treatments, as well as histological confirmation of adenocarcinoma of 
the prostate. 
b  
Pre-IP administration. 
c  
Vital signs to be recorded pre-IP administration and post-IP administration.  
d  
To be performed pre-IP administration. 
e  
If not already performed within 60 days prior to screening, conventional imaging will be performed as part of routine clinical practice, which may include bone scan (99mTc-HDP, 
99mTc-MDP), abdominal/pelvic CT or MRI, and chest CT as per local practice). Note: Conventional imaging that has been performed at non-participating institutions will be accepted 
provided the scans are retrievable and reviewed by the participating institution. Note: baseline conventional imaging performed as part of routine clinical practice should be performed at 
least 24 hours prior to the investigational rhPSMA-7.3 (18F) PET scan. 
f  
Baseline blood safety laboratory tests, including hematology (full blood count), biochemistry (urea and electrolytes, liver function tests) and coagulation to be performed pre-IP 
administration. 
g 
AEs will be monitored and recorded from the time of informed consent until the last study visit. 
h 
For full details see the Study Imaging Manual. 


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i 
To discuss imaging results and further procedures/treatments with the patient (all patients). 
j 
If rhPSMA-7.3 (18F) PET does not detect M1 disease, the patient will undergo the scheduled RP and PLND. In patients without M1 lesions identified and in whom the patient and physician 
believe, after obtaining the results of the rhPSMA-7.3 (18F) PET, that EBRT would be a better therapeutic option than RP, the patient may proceed to EBRT and the rationale for this change 
of management will be documented on the eCRF. 
Patients in whom the rhPSMA-7.3 (18F) PET shows M1 metastatic disease will be asked to undergo a biopsy or confirmatory imaging of the PET-positive lesion(s) to confirm the presence 
of a metastasis. If a surgical intervention of this lesion is carried out as part of the treatment, this may substitute for a biopsy. If the patient has proven M1 metastatic disease, the treatment 
decision may be altered, based on the responsible physician’s clinical judgement. This change will be documented on the eCRF.  
k 
Any confirmatory procedure for suspected M1 disease, as described above, should be performed prior to initiation of treatment.