Conditions: Prostatic Neoplasms Prostate Cancer
Keywords: [18F]CTT1057 Positron Emission Tomography/Computerized Tomography PET/CT Radioligand Imaging Primary Staging PS Standard of Truth SoT Prostate Cancer PCa
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 195
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the diagnostic performance of \[18F\]CTT1057 as a PET imaging agent for detection and localization of PSMA positive tumors using histopathology as Standard of Truth (SoT). Tissue specimens from both the primary tumor and pelvic lymph nodes dissected during surgery from patients with newly-diagnosed high-risk prostate cancer (PCa) were used for the histopathology assessments.

Detailed description:
This was a multi-center, single-arm, open-label prospective study to evaluate the diagnostic performance of vidoflufolastat (18F) as a positron emission tomography (PET) imaging agent for detection and localization of prostate specific membrane antigen (PSMA) positive tumors, using histopathology as standard of truth (SoT). in newly diagnosed high-risk prostate cancer (PCa) patients.

A total of 195 participants were enrolled to ensure that at least 156 participants were evaluable for the co-primary endpoints. Surgery was performed after vidoflufolastat (18F) positron emission tomography/computerized tomography (PET/CT) scan.

The co-primary endpoints of patient-level sensitivity and region-level specificity were assessed by comparing the central reading results of the vidoflufolastat (18F) PET/CT scan to the local histopathology results in the dissected tissue specimens, i.e. both the primary tumor and the dissected Pelvic Lymph Nodes (PLNs).

Arms:
arm 1: All eligible participants will be enrolled to receive \[18F\]CTT1057 imaging agent on Day 1 and have PET/CT scan

Interventions: intervention 1: [18F]CTT1057
Intervention descriptions: intervention 1: PET/CT imaging with \[18F\]CTT1057

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-003958-67 
Version number: 
01 (Amended Protocol Clean) 
Clinical Trial Phase: 
II/III 
Release date: 
20-Dec-2021 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 
Novartis Research and Development
AAA405
             Clinical Trial Protocol CAAA405A12302 / NCT04838626
Phase II/III study for evaluation of the diagnostic 
performance of [18F]CTT1057
 
PET imaging for the detection
 
 
of PSMA positive tumors using histopathology as a
standard of truth (GuideView)


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Protocol Amendment 01 (20-Dec- 2021) .......................................................................... 13 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 22 
Background ............................................................................................................ 22 
Purpose .................................................................................................................. 24 
2 
Objectives and endpoints ................................................................................................... 24 
Primary estimands ................................................................................................. 26 
Secondary estimands ............................................................................................. 27 
3 
Study design ...................................................................................................................... 27 
4 
Rationale ............................................................................................................................ 29 
Rationale for study design ..................................................................................... 29 
Rationale for dose/regimen and duration of treatment .......................................... 31 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 31 
Purpose and timing of interim analyses/design adaptations .................................. 31 
Risks and benefits .................................................................................................. 31 
Rationale for Public Health Emergency mitigation procedures ............................ 32 
5 
Study Population ............................................................................................................... 32 
Inclusion criteria .................................................................................................... 33 
Exclusion criteria ................................................................................................... 33 
6 
Treatment ........................................................................................................................... 33 
Study treatment ...................................................................................................... 33 
Investigational and control drugs .......................................................... 34 
Additional study treatments .................................................................. 34 
Supply of study treatment ..................................................................... 34 
Treatment duration ................................................................................ 34 
Other treatment(s) .................................................................................................. 34 
Concomitant therapy ............................................................................. 34 
Prohibited medication ........................................................................... 35 
Participant numbering, treatment assignment, randomization .............................. 35 


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Participant numbering ........................................................................... 35 
 
Treatment assignment, randomization .................................................. 35 
 
Treatment blinding ................................................................................................ 35 
 
Dose escalation and dose modification.................................................................. 36 
 
Follow-up for toxicities ......................................................................... 36 
 
Additional treatment guidance ............................................................................... 36 
 
Treatment compliance ........................................................................... 36 
 
Preparation and dispensation ................................................................................. 36 
 
Handling of study treatment and additional treatment .......................... 36 
 
Instruction for preparing and administering study treatment ................ 37 
7 
Informed consent procedures ............................................................................................ 38 
8 
Visit schedule and assessments ......................................................................................... 39 
 
Screening ............................................................................................................... 44 
 
Eligibility screening .............................................................................. 44 
 
Information to be collected on screening failures ................................. 44 
 
Participant demographics/other baseline characteristics ....................................... 44 
 
Efficacy .................................................................................................................. 45 
 
Imaging for tumor assessment .............................................................. 45 
 
Histopathology assessments .................................................................. 46 
 
Appropriateness of efficacy assessments .............................................. 47 
 
Safety ..................................................................................................................... 47 
 
Laboratory evaluations .......................................................................... 48 
 
Electrocardiogram (ECG) ..................................................................... 49 
 
Pregnancy and contraception ................................................................ 50 
 
Appropriateness of safety measurements .............................................. 50 
 
Additional assessments .......................................................................................... 51 
 
Pharmacokinetics .................................................................................. 51 
 53 
9 
Study discontinuation and completion .............................................................................. 53 
 
Discontinuation from study treatment and study  .................................................. 53 
 
Discontinuation from Study treatment  ................................................. 53 
 
Discontinuation from study ................................................................... 53 
 
Lost to follow-up ................................................................................... 54 
 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 55 
 
Early study termination by the sponsor ................................................................. 55 
 
Study completion and post-study treatment .......................................................... 56 


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10 Safety monitoring and reporting ........................................................................................ 56 
Definition of adverse events and reporting requirements ...................................... 56 
Adverse events ...................................................................................... 56 
Serious adverse events .......................................................................... 58 
SAE reporting........................................................................................ 59 
Pregnancy reporting .............................................................................. 59 
Reporting of study treatment errors including misuse .......................... 59 
Additional Safety Monitoring ................................................................................ 60 
Steering Committee ............................................................................... 60 
11 Data Collection and Database management ...................................................................... 60 
Data collection ....................................................................................................... 60 
Database management and quality control ............................................................ 60 
Site monitoring ...................................................................................................... 61 
12 Data analysis and statistical methods ................................................................................ 61 
Analysis sets .......................................................................................................... 62 
Participant demographics and other baseline characteristics ................................. 62 
Treatments ............................................................................................................. 62 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 63 
Definition of primary endpoint(s)/estimand(s) ..................................... 63 
Statistical model, hypothesis, and method of analysis .......................... 63 
Handling of remaining intercurrent events of primary estimand .......... 63 
Handling of missing values not related to intercurrent event ............... 63 
Sensitivity analyses for primary endpoint/estimand ............................. 64 
Supplementary analysis ......................................................................... 64 
Analysis of secondary endpoints/estimands .......................................................... 64 
Efficacy endpoint(s) .............................................................................. 64 
Safety endpoints .................................................................................... 65 
Pharmacokinetics .................................................................................. 68 
 69 
Interim analyses ..................................................................................................... 69 
Sample size calculation.......................................................................................... 69 
Primary endpoint(s) ............................................................................... 69 
13 Ethical considerations and administrative procedures ...................................................... 71 
Regulatory and ethical compliance ........................................................................ 71 
Responsibilities of the investigator and IRB/IEC .................................................. 71 
Publication of study protocol and results............................................................... 71 


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Quality Control and Quality Assurance ................................................................. 72 
14 Protocol adherence ............................................................................................................ 72 
 
Protocol amendments............................................................................................. 72 
15 References ......................................................................................................................... 74 
16 Appendices ........................................................................................................................ 80 
 
Appendix 1: Common Terminology Criteria for Adverse Events......................... 80 
 
Appendix 2: European Association of Urology Guidelines of Prostate cancer ..... 81 
 
Appendix 3: Anatomic template specification for histopathology assessment ..... 82 
 83 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
Table 6-1 
Investigational drug ............................................................................... 34 
Table 8-1 
Assessment Schedule ............................................................................ 40 
Table 8-2 
Assessments and Specifications ............................................................ 47 
Table 8-3 
ECOG Performance status .................................................................... 48 
Table 8-4 
Laboratory assessments ......................................................................... 49 
Table 8-5 
ECG collection plan .............................................................................. 50 
Table 8-6 
Pharmacokinetic blood collection log (PK patient subset only) ........... 51 
 
 52 
Table 10-1 
Guidance for capturing the study treatment errors including misuse ... 60 
Table 12-1 
Non-compartmental pharmacokinetic parameters ................................ 68 


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List of figures 
Figure 3-1 
Study Design ......................................................................................... 28 
 


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List of abbreviations 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration-time curve 
BCR 
Biochemical recurrence 
BUN 
Blood Urea Nitrogen 
C 
Code of Federal Regulations 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CL 
Clearance 
CMO&PS  
Chief Medical Office and Patient Safety 
CO 
Country Organization 
COVID-19 
Coronavirus disease 2019 
CPM 
counts per minute 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
EANM 
European Association of Nuclear Medicine  
EAU 
European Association of Urology 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report/Record Form 
ED 
Effective Dose 
EDC 
Electronic Data Capture 
EFF 
Efficacy Analysis Set 
EMA 
European Medicines Agency  
EOS 
Study completion 
ePLND 
extended Pelvic Lymph Node Dissection 
eSAE 
Electronic Serious Adverse Event 
EU 
European Union 
FAS 
Full Analysis Set 
FDG 
Fluorodeoxyglucose 
FN 
False Negative 
FP 
False Positive 


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GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HPLC 
High-Performance Liquid Chromatography 
HR  
Heart Rate 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LHRH 
Luteinizing Hormone-Releasing Hormone 
LLOQ 
Lower Limit of Quantification 
LN 
Lymph Node(s) 
MBq 
Mega-Becquerel 
MCH 
Mean Corpuscular Hemoglobin 
mCRPC 
metastatic-Castration Resistant Prostate Cancer 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
MR 
Magnetic Resonance 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
PAS 
Pharmacokinetic Analysis Set 
PCa 
Prostate Cancer 
PD 
Pharmacodynamic(s) 
PET 
Positron Emission Tomography 
PK 
Pharmacokinetic(s) 
PLN 
Pelvic Lymph Node 
PPV 
Positive Predictive Value 
PS 
Primary Staging 
PSA 
Prostate Specific Antigen 
PSMA 
Prostate Specific Membrane Antigen 
QC 
Quality Control 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RDC 
Remote Data Capture 


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RECIST 
Response Evaluation Criteria In Solid Tumors 
RP 
Radical Prostatectomy 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee  
SD 
standard deviation 
SMQ 
Standardized MedDRA Query 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
SoT 
Standard of Truth 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tc 
Calibration time 
TEAE 
Treatment Emergent Adverse Event 
TN  
True Negative 
TP 
True Positive 
US 
United States 
USPI 
US Prescribing Information  
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant  
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of 
all clinical trial activities. Examples of team members include the Study 
Lead, Medical Monitor, Trial Statistician etc. 
Coded Data  
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Discontinuation from 
study 
 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or 
data 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the 
use of their samples or data 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from  source data/documents  used at the point 
of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant 
or at a later point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description 
of the treatment effect reflecting the clinical question posed by the trial 
objective. It summarizes at a population-level what the outcomes would be 
in the same patients under different treatment conditions being compared. 
Attributes of an estimand include the population, variable (or endpoint) and 
treatment of interest, as well as the specification of how the remaining 
intercurrent events are addressed and a population-level summary for the 
variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 


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Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in participants with established 
disease and in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient).  
"Subject" is used in data collection 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant 
and should be used to identify the participant throughout the study for all 
data collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and 
will be used in clinical trial database setup and eventually in analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and biological 
samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he can be invited once for a new Screening visit after medical 
judgment and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper  
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs   or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 


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Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a 
complex sequence of interventions. This is the treatment of interest used 
in describing the related clinical question of interest, which might or might 
not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the variable 
might include whether the participant experiences an intercurrent event. 
Withdrawal of study 
consent (WoC)/ 
Opposition to use of 
data /biological 
samples 
Withdrawal of consent from the study occurs  when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes to 
receive study treatment, AND  does not want agree to  further   protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. Opposition to 
use data/biological samples occurs in the countries where collection and 
processing of personal data is justified by a different legal reason than 
consent. 


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Protocol Amendment 01 (20-Dec-2021) 
Amendment Rationale 
As of the date of release of this protocol amendment, 14 subjects have been enrolled in the study (9 
dosed).  
The main purpose of the amendment is to update the inclusion criterion on definition of high risk prostate 
cancer per D'Amico classification to also include patients with clinical stage T2c or higher at initial 
diagnosis (instead of T2c only) as those are considered high risk as well per D’Amico classification. 
Other clarifications and corrections of discrepancies or errors have been implemented across the 
protocol. All changes implemented are detailed below with their justification.  
The changes described in this amended protocol require IRB/IEC approval prior to implementation.  
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 
The changes herein do not affect the Informed Consent. 
  
 
Main changes implemented in the protocol amendment 
Section 
Change 
Description and rationale 
Protocol summary 
Section 5.1 
Section 2.1 
Section 8.2 
Update of Inclusion 
criterion #1 
  
Modified inclusion criterion (numbered 1a) to 
include patients with clinical stages T2c and 
higher for prostate cancer as D’Amico 
classification is also considering such 
patients as high risk. 
Protocol summary  
Section 5.2  
Section 6.2.2 
Removal of exclusion 
criterion #6 and update 
of exclusion criterion 
#5 and clarification that 
LHRH analogues 
include LHRH agonists 
or antagonists 
Exclusion criterion #6 is removed as the 
targeted population for this study is subjects 
who are newly diagnosed with prostate 
cancer and did not receive any prior 
androgen-deprivation therapy (ADT). 
Exclusion criterion #5 was updated 
accordingly (numbered 5a) to exclude any 
prior ADT including LHRH analogues 
(agonists or antagonists). Section 6.2.2 was 
also updated to clarify that LHRH analogues 
include LHRH agonists or antagonists. 
Protocol summary 
Section 2.1 
Section 3 
Section 8.3.2 
Update of Surgery 
timing  
Updated to mention that surgery will be 
performed up to 6 weeks after but not sooner 
than 48 hours after the completion of 
the [18F]CTT1057 PET/CT scan. This change 
ensures all patients will go at least through a 
2-day period to check their safety after PET 
scan without being confounded by the effects 
of surgery.    
Section 5 
Section 12.1 
Section 12.8 
Update of definition for 
efficacy analysis set 
Update to take into account patients who will 
be evaluable for co-primary endpoints, i.e. 
patients who have both an evaluable PET/CT 
scan and histopathology assessment and 
have not received any prohibited systemic 
antineoplastic therapy before the completion 
of PET/CT and surgery. 
Section 6.2.1 
Clarification of use of 
diuretics  
Clarification that the use of diuretics (e.g. 
furosemide) to help subject to void before 


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PET/CT scan imaging acquisition is allowed 
in case of need, upon the criteria of the 
investigator. 
Section 6.2.2 
Clarification of use of 
LHRH analogues and 
anti- androgens 
Clarification that use of any ADT including 
LHRH analogues (agonists or antagonists) as 
well as anti-androgens (both first and second 
generation compounds) and 5-alpha 
reductase inhibitors is prohibited prior to 
completing both PET imaging scans and 
surgery, to ensure that the same lesions are 
assessed on PET/CT scans and surgery 
without potential reduction in lesion size and 
therefore detectability due to administration of 
antineoplastic medications. 
Table 8-1 
(footnote#11) 
Section 8.4 
Update on safety follow-
up visit assessments 
timing 
For participants undergoing surgery prior to 
planned safety visit, safety follow-up 
assessments will need to be performed 
before the surgery and not sooner than 48 
hours after the PET scan. This change 
ensures all patients will go at least through a 
2-day period to check their safety after PET 
scan without being confounded by the effects 
of surgery.  
Section 10.1.3 
Reporting period for 
SAE 
Update to correct reporting period for any 
SAE to 14 days after the last dose of study 
treatment (instead of last study visit) for 
alignment with the definition of on-treatment 
period provided in Section 12.5.2. 
Other changes implemented in the protocol amendment 
Section 
Change 
Description and rationale, 
Table of Contents 
List of tables 
List of figures 
Updates 
Modified to reflect changes made in protocol 
body 
Glossary of terms 
Updates and 
clarification 
Addition of definitions and clarifications of 
some definitions. 
Table 2-1 
 
Alignment between 
Objectives and 
Endpoints wording 
Correction of discrepancies between name of 
the objectives and definition of the 
corresponding endpoints.  For the patient-
level primary and secondary objectives, 
“evaluated for all patients” was removed as 
efficacy endpoints will be evaluated in the 
efficacy set. For region level specificity and 
accuracy primary and secondary objectives, 
“evaluated for all regions” was removed as 
only pelvic lymph node (PLN) region will be 
evaluated for those endpoints considering 
that histopathology will be not be available as 
standard of truth for extra-PLN. 
Table 2-1 
Section 12.5.1 
Correction and 
Clarification in 
definition of distant 
metastases for the 
secondary objective 
Correction in definition of distant metastases 
for the secondary objective of detection of 
distant metastasis in PS patients was made 
as distant metastatic lesions for prostate 
cancer are defined in clinical practice as 
metastasis in extra-PLN or in any visceral or 


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skeletal location. Lesions in PLN are 
considered local metastases. It was also 
clarified in the definition of this endpoint that it 
will be assessed in all patients with an 
evaluable [18F]CTT1057 PET/CT scan.  
Table 2-1 
Update of Incidence of 
AEs  
Update to remove that incidence of AEs will 
be described after each PET tracer injection, 
after each PET/CT scans and at 24-72 h after 
each PET/CT scan. Indeed, the incidence of 
AEs will be summarized for AEs occurring 
during each treatment period (i.e. within 14 
days after each PET tracer administration) as 
described in Section 12.5.2. 
Section 3 
Screening assessments 
update 
Update to remove imaging assessments from 
screening period paragraph as imaging 
procedures to be performed in the study do 
not belong to screening assessments. 
Section 4.1 
Update in regions 
definition 
Update to mention the different regions 
considered for this study for the 
[18F]CTT1057 PET/CT evaluation: prostate 
region (comprising prostate bed/prostate 
gland and any local invasion of the urinary 
bladder, rectum or seminal vesicles), PLN 
region, extra-PLN region, skeletal region and 
visceral region). The statement that all 
regions will be assessed for other endpoints 
is incorrect and was removed as some 
region-level endpoints are only evaluating the 
PLN region, while others consider all regions, 
as detailed in Section 12. 
Section 6.3.2 
Update on timelines for 
ordering 
Update to remove timelines for ordering in the 
protocol and reference to pharmacy manual 
was added. 
Section 8 
Clarification on 
assessment 
requirements for 
discontinuation from 
study 
Update to add that safety follow-up visit is to 
be performed in case of discontinuation from 
study. 
Table 8-1 (footnote*) 
Addition of footnote* 
Addition of footnote* to clarify that all 
screening assessments to confirm eligibility 
must be done prior enrollment. 
Table 8-1 
Clarification of 
screening period timing  
The table is updated to clarify that enrollment 
in IRT can occur any time between Day -28 
and Day -14 provided all results are available 
for assessment of subject’s eligibility. Day 1 
should occur maximum 14 days after 
enrollment.  
Table 8-1 
Update of Day 1 visit 
window 
The table is updated to allow a visit window of 
7 days since the enrollment could occur 
earlier than 14 days prior Day 1. 
Table 8-1 (footnote #7) 
Update on ordering 
requirements 
Update to clarify that order is to be placed 
after enrollment and based on drug 
availability local timelines (refer to Pharmacy 


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Manual) in order to perform PET imaging Day 
1 no more than 14 days after enrollment. 
Table 8-1 
Clarification of 
urinalysis requirements 
Update for urinalysis as urinalysis results will 
be documented in source and not captured in 
the eCRF. Any clinically significant finding for 
urinalysis testing should be reported in the 
eCRF as AE.  
Section 8.3.1 
Table 8-1 
(Footnote #9) 
Terminology update for 
CT scan 
Update to remove the “low dose” terminology 
which is no longer used in clinical practice for 
the CT portion of PET/CT (transmission 
scan). 
Section 8.3.1 
Addition of Cross-
reference for PET 
positivity 
Update to add a cross-reference to Section 
4.1 for the criteria to be applied for PET 
positivity for easier reference for local 
imaging readers. 
Table 8-2 
Correction of misplaced 
information on 
collection of vital signs 
Update to remove vital signs from the 
physical examination and include all details in 
the part of the table already describing vital 
signs. 
Section 8.4.1 
Clarification on lab test 
results at screening 
Updated to remove the statement that only 
central laboratory results will be used for 
assessment of participants’ eligibility to the 
study as eligibility can be based on local 
laboratory results. 
Table 8-4 
Clarification of lab tests  Updated for clarification that phosphorus 
laboratory parameter is phosphate (inorganic 
phosphorus) and that glucose is non-fasting 
glucose. 
Section 8.4.2.1 
Clarification on ECG 
assessments 
Clarified to confirm that the ECGs should be 
locally collected and evaluated 
Section 8.4.2.2 
Table 8-1 (footnote #2) 
Clarification in 
collection of 
blood/urine samples for 
PK 
Updated to clarify that the collection of blood 
and urine samples for PK subset applies for 
the patients who consent for the PK sample 
collection.  
Section 9.1 
Section 9.1.1 
Clarification in the 
discontinuation 
definition and wording 
Update to separate discontinuation from 
study treatment (not applicable for this study) 
and discontinuation from study.  
Section 9.1.2 
Addition of section 
Update to separate discontinuation from 
study treatment (not applicable for this study) 
and discontinuation from study.  
Section 9.1.3 
Addition of section 
Update to move the section “lost to follow-up” 
from “withdrawal of consent” section 9.2, 
added in the discontinuation study section. 
Section 9.2 
Clarification and 
addition of new concept 
Update to add the concept of “opposition to 
use data/biological samples” which can occur 
on top of withdrawal of consent. 
Section 9.3 
Clarification on 
definition and 
requirements 
Update to add specific actions to be 
performed prior early discontinuation of the 
study. 
Section 10.1.3 
Section 10.1.5 
Clarification on SAE 
reporting 
Update to emphasize reporting timelines 
requirements and all related documentation. 
Section 10.1.5 
Update of study 
treatment error section 
Update to remove the concept of “abuse” of 
study treatment since not applicable to this 


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study (only a single dose administered at 
clinical site). 
Section 10.1.5 
Table 10-1 
Clarification on study 
treatment errors/misuse 
Updated to clarify that all study treatment 
errors/misuse should be reported to the 
Sponsor. A reference to Table 10-1 was 
added for guidance on recording of study 
treatment errors or misuse on the relevant 
CRF and Table 10-1 was updated to clarify 
that cases of misuse must be recorded in AE 
eCRF even if not associated with an AE. 
Section 10.1.5 
Table 10-1 
Terminology “abuse” 
not relevant removed 
Updated to remove the terminology of abuse 
as this is not relevant for the PET imaging 
tracers used in this study, which are 
administered to patients on site by qualified 
site staff and not self-administered.  
Section 12 
Clarification of cut-off 
for final analysis 
Updated to clarify that the cut-off for the final 
analysis will be the last visit for last subject in 
the study. 
Section 12.5.2 
  
Update in stats 
presentation for some 
data. 
Updated to indicate that clinically notable 
values or changes in vital signs will be 
flagged in listings, the ECG result at 
screening will be summarized as number (%) 
of subjects with normal or abnormal (clinically 
significant) ECG and will be provided as 
listing. ECG timepoints for the patients in the 
PK subset have been added for reference. 
Section 12.4.6 
Update the 
supplementary analysis 
description  
Updated to remove PPV from primary 
endpoint as it is part of secondary endpoint.  
Section 12.5.1 
Update of sub-section 
title  
Updated as Pharmacodynamic is not 
applicable for the study. 
Section 12.5.1 
Update and clarification 
of definitions 
 Alignment with the updated Table 2-1 for 
endpoints wording. 
Section 12.5.3 
Update 
Pharmacokinetics 
section 
Update to remove redundancy. 
Section 12.8 
Clarification on analysis 
set for co-primary 
endpoints 
Alignment with the updated EFF definition. 
All sections 
Minor updates 
Minor typographical corrections, removal of 
duplicated wording and minor rewording were 
implemented across the document. 


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Protocol summary 
Protocol number 
CAAA405A12302 
Full Title 
Phase II/III study for evaluation of the diagnostic performance of 
[18F]CTT1057 PET imaging for the detection of PSMA positive tumors using 
histopathology as a standard of truth (GuideView) 
Brief title 
Study of diagnostic performance of [18F]CTT1057 for PSMA-positive tumors 
detection  
Sponsor and 
Clinical Phase 
Novartis Phase II/III 
Investigation type 
Radiopharmaceutical  
Study type 
Interventional 
Purpose and 
rationale 
[18F]CTT1057 is a promising novel Prostate Specific Membrane Antigen 
(PSMA)-targeting [18F]-labeled Positron Emission Tomography (PET) imaging 
agent. Unlike other PSMA agents which share a urea backbone, 
[18F]CTT1057 is based on a phosphoramidate scaffold that 
 binds 
to PSMA with high nanomolar affinity, which may account for a higher and 
prolonged tumor uptake. Together with the higher resolution of 
PET/Computerized Tomography (CT) images when using a [18F]-labelled PET 
agent, it would therefore favor the identification of smaller lesions, and 
consequently, also at earlier stages of the disease. A [18F]CTT1057 Phase-I 
study has shown an acceptable safety profile without any radiotracer-related 
adverse reactions, and has provided preliminary evidence of diagnostic 
performance of [18F]CTT1057 PET in detecting and localizing PSMA-positive 
tumors using pathology as standard of truth (SoT).  
The purpose of this study is to evaluate the diagnostic performance of 
[18F]CTT1057 as a PET imaging agent for detection and localization of PSMA 
positive tumors using histopathology as SoT. Tissue specimens from both the 
primary tumor and PLN dissected during surgery from patients with newly-
diagnosed high-risk prostate cancer (PCa) will be used for the histopathology 
assessments.  
Primary 
Objective(s)  
The co-primary objectives of this study are  
• 
to evaluate the patient-level sensitivity of [18F]CTT1057  
• 
to evaluate the region-level specificity of [18F]CTT1057  
The primary clinical question of interest is: Does [18F]CTT1057 target 
PSMA expressing PCa cells, allowing to obtain adequate [18F]CTT1057 
PET/CT images to detect and localize PSMA positivity using histopathology 
as SoT? 
Secondary 
Objectives 
• 
To evaluate the patient-level specificity of [18F]CTT1057  
• 
To evaluate the patient-level positive predictive value of [18F]CTT1057  
• 
To evaluate the patient-level negative predictive value of [18F]CTT1057  
• 
To evaluate the patient-level accuracy of [18F]CTT1057  
• 
To evaluate the region-level sensitivity of [18F]CTT1057 for patients 
excluding micro-metastasis  
• 
To evaluate the region-level sensitivity of [18F]CTT1057  
• 
To evaluate the region-level positive predictive value of [18F]CTT1057  
• 
To evaluate the region-level negative predictive value of [18F]CTT1057  
• 
To evaluate the region-level accuracy of [18F]CTT1057  
• 
Detection of distant metastasis in PS patients  


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• 
To characterize the safety and tolerability of [18F]CTT1057  
• 
[18F]CTT1057 scan inter-reader variability  
• 
[18F]CTT1057 scan intra-reader variability  
• 
To further assess [18F]CTT1057 pharmacokinetics in humans in subset of 
approximately 10 patients 
Study design 
This is a multi-center, single-arm, open-label prospective study to evaluate 
the diagnostic performance of [18F]CTT1057 as a PET imaging agent for 
detection and localization of PSMA positive tumors, using histopathology as 
SoT. Tissue specimens from both the primary tumor and PLN dissected 
during surgery from patients with newly-diagnosed high-risk PCa will be used 
for the histopathology assessments.  
All participants will receive [18F]CTT1057 for PET/CT scan imaging, and 
surgery will be performed up to 6 weeks after but not sooner than 48 hours 
after the completion of the [18F]CTT1057 PET/CT scan [18F]CTT1057 PET/CT  
for pathology assessment of the tissue specimens.  
The co-primary endpoints of patient-level sensitivity and region-level 
specificity will be assessed by comparing the central reading results of the 
[18F]CTT1057 PET scan to the histopathology results in the dissected tissue 
specimens, i.e. both the primary tumor and the dissected PLN.  
Pathology will be assessed by the local pathologists as per Standard of Care 
(SoC), who will be blinded to the PET data. 
Study population 
Male participants ≥ 18 years of age, with newly diagnosed high-risk PCa who 
are candidates for radical prostatectomy (RP) and extended lymph node 
resection as per SoC.  
Approximately 195 participants will be enrolled to ensure that at least 156 
participants are evaluable (i.e. have both an evaluable PET/CT scan and 
histopathology assessment and have not received any prohibited systemic 
antineoplastic therapy before the completion of PET/CT and surgery), which 
will be required for the calculation of the co-primary endpoints.  
Inclusion criteria 
• 
Signed informed consent must be obtained prior to participation in the 
study 
• 
Untreated high risk biopsy-proven PCa patients according to D’Amico 
classification (Stage ≥ T2c or Prostate Specific Antigen (PSA) level 
>20ng/ml or Gleason score ≥8) 
• 
Scheduled or planned radical prostatectomy and extended pelvic lymph 
node resection up to 6 weeks after the investigational PET/CT scan 
followed by histopathology assessment 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 
• 
Participants must be adults ≥ 18 years of age 
Exclusion criteria 
• 
Inability to complete the needed investigational and standard-of-care 
imaging examinations due to any reasons (severe claustrophobia, inability 
to lie still for the entire imaging time, etc.) 
• 
Any additional medical condition, serious intercurrent illness, concomitant 
cancer or other extenuating circumstance that, in the opinion of the 
Investigator, would indicate a significant risk to safety or impair study 
participation, including, but not limited to, current severe urinary 
incontinence, hydronephrosis, severe voiding dysfunction, need of 
indwelling/condom catheters, New York Heart Association class III or IV 
congestive heart failure, history of congenital prolonged QT syndrome, 


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uncontrolled infection, active hepatitis B or C, and Coronavirus Disease 
2019 (COVID-19) 
• 
Known allergy, hypersensitivity, or intolerance to [18F]CTT1057 
• 
Prior and current use of PSMA targeted therapies 
• 
Prior and current treatment with any Androgen Deprivation Therapy (ADT) 
(first or second generation), including Luteinizing Hormone-Releasing 
Hormone (LHRH) analogues (agonists or antagonists) 
• 
Any 5-alpha reductase inhibitors within 30 days before screening 
• 
Patients with small cell or neuroendocrine PCa in more than 50% of 
biopsy tissue 
• 
Patients with incidental PCa after transurethral resection 
• 
Use of other investigational drugs within 30 days before screening 
Study treatment 
The term “Study Treatment” indicates the administration 
of [18F]CTT1057 whether the PET/CT scan was acquired or not.  
Treatment of 
interest 
In this study, the investigational imaging agent of interest [18F]CTT1057, 
injected as a single intravenous dose of approximately 370 Mega-
Becquerel (MBq) and subsequent PET/CT scan. 
Efficacy 
assessments 
Efficacy assessments in this study include local histopathology assessments 
(primary tumor and PLN) and central reads of PET/CT images using a 
[18F]CTT1057 agent.  
Pharmacokinetic 
assessments 
Summary statistics of [18F]CTT1057 pharmacokinetic parameters (i.e. Cmax, 
Tmax, Area under the plasma concentration-time curve (AUC)last, AUCinf, 
T1/2, Vz and clearance (CL) from blood radioactivity data 
Quantification of urinary excretion of [18F]CTT1057 from urine data 
Key safety 
assessments 
• 
Adverse Events (AEs) 
• 
Serious Adverse Events (SAEs) 
• 
Vital signs, physical examinations 
• 
Electrocardiograms (ECGs) 
• 
Laboratory parameters including hematology, clinical chemistry, urinalysis 
• 
Concomitant medications and/or therapies 
Data analysis 
The following data analyses are planned for the study: 
The co-primary endpoints of the study are patient-level sensitivity and region-
level specificity.  
• 
Patient-level sensitivity is defined as the proportion of PSMA true positive 
(TP) patients among PSMA TP patients and PSMA false negative (FN) 
patients.   
• 
PSMA TP patients are those who show at least one pathological 
[18F]CTT1057 uptake either in the primary tumor and/or metastatic 
PLN with anatomically localized correspondence with the SoT.  
• 
PSMA FN patients are those who do not show any pathological 
[18F]CTT1057 uptake either in the primary tumor or metastatic PLN 
but will be confirmed having primary tumor or metastatic PLN with 
the SoT. 


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Patient-level sensitivity and its 95% confidence interval (CI) will be calculated 
based on the binomial distribution. The lower bound of the 95% CI for patient-
level sensitivity should be greater than 0.5 to attain the first co-primary 
endpoint. 
• 
Region-level specificity is defined as the proportion of PSMA true 
negative (TN) regions among PSMA TN regions and PSMA false positive 
(FP) regions.   
• 
PSMA TN regions are regions that test negative for PLN on 
[18F]CTT1057 and confirmed negative on the SoT.   
• 
PSMA FP regions are regions that test positive for PLN on 
[18F]CTT1057 but verified negative on the SoT.  
Region-level specificity and its 95% CI will be calculated based on the 
binomial distribution. 
The lower bound of the 95% CI for specificity should be greater than 0.70 for 
the study to attain the second co-primary endpoint. 
Analyses for co-primary endpoints will be based on the efficacy analysis 
set. Other secondary endpoints including patient-level specificity of 
[18F]CTT1057, patient-level positive predictive value, patient-level negative 
predictive value,  patient-level accuracy, region-level sensitivity excluding 
micro-metastasis, region-level sensitivity including micro-metastasis, region-
level positive predictive value, region-level negative predictive value, region-
level accuracy, incidence of AEs, inter-reader agreement, Intra-reader 
agreement, Pharmacokinetic (PK) parameters will also be analyzed. Detailed 
statistical methodology for these analyses will be provided in the statistical 
analysis plan. 
Key words 
[18F]CTT1057, PET/CT, Radioligand, Imaging, Primary Staging (PS), SoT, 
PCa 
 
 


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1 
Introduction 
 
Background 
Prostate-specific membrane antigen (PSMA) and prostate cancer 
Prostate-specific membrane antigen (PSMA) is a transmembrane protein, also known as folate 
hydrolase or glutamate carboxypeptidase II. PSMA is highly overexpressed in the tumor cells 
of prostate adenocarcinomas (Mannweiler et al 2009, Hupe et al 2018, Bravaccini et al 2018) 
and has also been reported to be overexpressed in tumor cells and tumor-vasculature of 
endometrial and ovarian cancer (Wernicke et al 2017), and mainly in tumor-vasculature of a 
variety of other cancer types such are breast (Tolkach et al 2018), colorectal, gastric (Haffner 
et al 2009), glioblastoma (Wernicke et al 2011, Tanjore Ramanathan et al 2020), kidney (Spatz 
et al 2018), liver (Tolkach et al 2019), lung (Wang et al 2015, Schmidt et al 2017) and 
pancreatic cancer (Stock et al 2017). PSMA has restricted and several hundred-fold lower 
expression than PCa cells in some normal tissues such as the duodenal mucosa, proximal renal 
tubules, and salivary glands (Bostwick et al 1998, Ghosh and Heston 2004). 
From all the above named PSMA-overexpressing tumors, PCa is the one in which the role of 
PSMA has been more extensively studied. PCa remains the cancer with the second highest 
mortality in the United States (US), and the third leading cause of cancer-related death in 
Europe in men (Siegel et al 2017, Malvezzi et al 2019). It also remains the most diagnosed 
cancer with an estimated increase of 9,960 new cases with a total of 164,690 in 2018 
(Siegel et al 2018) to174,650 in 2019 ( Siegel et al 2019). Most of the diagnosed cases are in 
more developed regions due to the use of PSA testing, but there is only modest variation in 
mortality rates globally which is driven by metastatic, and often castration-resistant disease 
(Bray et al 2013). Subsequent treatment is multifaceted and may involve observation, surgery 
(prostatectomy), radiation therapy (external beam or brachytherapy), hormonal therapy, 
chemotherapy, and in the near future, radioligand therapy (Roscigno et al 2005, Jani 2006). 
PSMA overexpression correlates with advanced, high-grade, metastatic, androgen-independent 
disease (Ross et al 2003). The differential expression of PSMA from tumor to non-tumor tissue 
has resulted in numerous targeted strategies involving both disease localization using PSMA-
PET imaging as well as therapeutic intervention. Correct identification of disease location and 
extent determines treatment decisions for patients with PCa. Identification of distant metastatic 
disease at the initial diagnosis of PCa is important in planning PCa management. There is 
increasing evidence that primary landing sites for PCa lie outside the template of an extended 
pelvic lymph node dissection (ePLND). Primary lymph node landing sites outside an ePLND 
have been reported in 47.7% of men with suspected node-positive disease on [68Ga]Ga-PSMA 
PET/CT (Yaxley et al 2019a). This is very important, as the morbidity of an ePLND could be 
avoided, given the change in expectation of management from one of curative intent, to 
management that will require a multimodality approach after treatment of the prostate primary 
(Yaxley et al 2018, Yaxley et al 2019b). It is relevant, therefore, to detect smaller lesions as 
early as possible. With the emergence of PSMA-targeted radioligand therapy, in addition to 
early diagnosis accurate PSMA-positivity detection is needed to determine the future use of 
radioligand therapy. 


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 Positron Emission Tomography (PET) imaging in PCa 
The usual diagnostic tools for PCa include PSA testing, digital rectal palpation, transrectal 
ultrasound, prostate biopsy, and histopathologic examination (Schwarzenböck et al 2012, 
Smith et al 2016, Prasad et al 2016). Additionally, further imaging techniques such as 
Magnetic Resonance Imaging (MRI), bone scintigraphy, CT, and [18F]Fluorodeoxyglucose 
(FDG), [18F]Choline, [11C]Choline and the most recently approved [18F]-fluciclovine 
(Nanni et al 2016, Odewole et al 2016) PET/CT are used for staging primary PCa and restaging 
biochemical recurrences (Schwarzenböck et al 2012). CT and MRI are the standard of care 
imaging procedures for measuring tumors at baseline and lesions selected for response 
assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria 
1.1(Eisenhauer et al 2009). However, these imaging modalities have shown limited yielding in 
the staging of PLN in patients with PCa. A meta-analysis showed pooled sensitivities of 0.42 
(95% CI 0.26-0.56) for CT, and of 0.39 (95% CI 0.22-0.56) for MRI (Hövels et al 2008). 
Therefore, more sensitive and accurate imaging tests than the currently available Standard of 
Care (SoC) examinations are needed (Hricak et al 1987, Shinohara et al 1989, 
Scheidleret al 1999, Blomqvist et al 2014 ). Novel PET radiotracers promise to overcome this 
limitation. PET imaging is an enticing choice as it offers the potential to both stage patients and 
provide insight into tumor biology. Among the various PET probes available, 68Ga-labeled 
ligands of the PSMA were associated with unprecedented accuracy and effect on treatment in 
several meta-analyses of retrospective studies (Perera et al 2016, Han et al 2018, Von Eyben et 
al 2018). Recent studies reported that 68Ga-labeled PSMA PET/CT has excellent detection rates 
for lymph node metastases, skeletal metastases, local relapses, and soft-tissue metastases 
compared with other PET tracers such as 18F- and 11C-labeled choline derivatives 
(Afshar-Oromieh et al 2013, Afshar-Oromieh et al 2014, Ceci et al 2015, Eiber et al 2015, 
Budäus et al 2016). Since its introduction in 2012, [68Ga]Ga-PSMA-11 is the most studied 
PSMA PET agent to date. It has been widely used in clinical practice on a compassionate use 
basis and reported in prospective studies and numerous retrospective case series 
(Afshar-Oromieh et al 2015, Eiber et al 2015, Morigi et al 2015, Meredith et al 2016, 
Sachpekidis et al 2016, Afshar-Oromieh et al 2017, Berliner et al 2017, Gupta et al 2017, Hope 
et al 2017, Sanli et al 2017, Schmuck et al 2017, Derlin et al 2018, Grubmüller et al 2018, 
Kranzbühler et al 2018, Lengana et al 2018, Rauscher et al 2018, Fendler et al 2019), and it has 
been recently approved in the USA (December 2020) as a radioactive diagnostic PET imaging 
agent in men with PCa with suspected metastasis who are candidates for initial definitive 
therapy, 
or 
with 
suspected 
recurrence 
based 
on 
elevated 
serum 
PSA 
level 
([15Ga]Ga-PSMA-11 USPI).  However, despite the diagnostic accuracy of [68Ga]Ga-PSMA-
11, its practical use at scale is limited by the short half-life of 68Ga, which requires radiolabeling 
in close proximity to the point of care. Moreover, the yield of currently available 68Ga 
generators limits the manufacturing of the number of doses required to address the growing 
population of PCa patients. This gap between the unmet need and availability is expected to 
widen as radio-ligand therapy options are available for treatment. While solid targetry using 
cyclotrons (currently unapproved for clinical use) can generate greater quantities of 68Ga, and 
thereby more doses, the geographical reach of the few cyclotrons coupled with the short half-
life of 68Ga would still leave this need unaddressed. 
[18F]CTT1057: A promising investigational PSMA-PET radiotracer 


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Most experts in the field agree, the future of PSMA-based PET imaging will be with 18F-labeled 
tracers because of the practical advances: 18F has a longer half-life than 68Ga, which enables the 
tracers to be distributed to PET centers without a cyclotron and to be easily handled in clinical 
routine. In addition, the higher positron decay branching of 18F (96.9%) versus 68Ga (87.7%), 
together with the shorter positron range of 18F, account to the higher PET imaging resolution 
achieved with 18F-labeled radiopharmaceuticals (Conti and Eriksson 2016). [18F]CTT1057 is a 
promising novel PSMA-targeting 18F-labeled PET imaging agent. Unlike most other PSMA 
agents labelled with either 68Ga or 18F (e.g. [68Ga]Ga-PSMA-11, [18F]PSMA1007, 
[18F]DCFPyL) which share a urea backbone, [18F]CTT1057 is based on a phosphoramidate 
scaffold that 
 binds to PSMA with high nanomolar affinity, which may account for 
a higher and prolonged tumor uptake (Behr et al 2019). Together with the higher resolution of 
PET/CT images when using a 18F-labelled PSMA agent, it would therefore favor the 
identification of smaller lesions, and consequently, also at earlier stages of the disease. 
A Phase-I study in 20 PCa patients (n=5 primary staging, n=15 metastatic-castration resistant 
prostate cancer (mCRPC)) (Behr et al 2019) has shown an acceptable safety profile, without 
any radiotracer-related adverse reactions. The biodistribution of [18F]CTT1057 in humans is 
similar to that of other PSMA-targeted agents, and exposure rates of [18F]CTT1057 are also 
similar to those of the urea-based PET compounds, with the advantageous exception of lower 
exposure to kidneys and salivary glands. Preliminary evidence of diagnostic performance of 
[18F]CTT1057 PET in detecting and localizing PSMA-positive tumors was provided from the 
n=5 primary staging patients using pathology as SoT. Abnormal [18F]CTT1057 PET uptake 
corresponding to the pathology-proven cancer was shown in 4 of the 5 subjects. The only 
subject who did not show PET uptake in the primary tumor had the lowest PSA in the 
cohort.  The Phase-I study also demonstrated that metastatic lesions are detected with higher 
sensitivity on [18F]CTT1057 imaging than on conventional imaging (Behr et al 2019). Another 
smaller study showed that the image quality on [18F]CTT1057 PET imaging was qualitatively 
similar to that obtained on [68Ga]Ga-PSMA-11 PET (Behr et al 2017).  
Further details on [18F]CTT1057 can be found in the Investigator's Brochure (IB). 
 
Purpose 
The purpose of this study is to evaluate the diagnostic performance of [18F]CTT1057 as a 
PET imaging agent for detection and localization of PSMA positive tumors using 
histopathology as SoT. Tissue specimens from both the primary tumor and PLN dissected 
during surgery from patients with newly-diagnosed high-risk PCa will be used for the 
histopathology assessments. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Evaluate the patient-level 
sensitivity of [18F]CTT1057  
• 
Sensitivity of [18F]CTT1057 PET imaging, considering PSMA 
positive patients as those who show at least one pathological 


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Objective(s) 
Endpoint(s) 
[18F]CTT1057 uptake either in the primary tumor and/or 
metastatic PLN regions, with anatomically localized 
correspondence with the SoT. See Section 2.1 for Primary 
Estimand. 
• 
Evaluate the region-level 
specificity of [18F]CTT1057  
• 
Specificity of [18F]CTT1057 PET imaging, defined as 
proportion of PLN regions that test negative for lymph nodes 
on [18F]CTT1057 among those that are lymph node negative 
on the SoT. See Section 2.1 for Primary Estimand. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Evaluate the patient-level 
specificity of [18F]CTT1057  
• 
Specificity of [18F]CTT1057 PET imaging, considering PSMA 
negative patients as those who do not show any 
pathological [18F]CTT1057 uptake either in the primary tumor 
or PLNs and will be confirmed not having primary tumor or 
metastatic PLNs with the SoT 
• 
Evaluate the patient-level 
positive predictive value of 
[18F]CTT1057  
• 
Proportion of patients who are both [18F]CTT1057 and SoT 
positive (true positives (TP) among those who test positive 
on [18F]CTT1057 (TP+ false positives(FP)) 
• 
Evaluate the patient-level 
negative predictive value of 
[18F]CTT1057  
• 
Proportion of patients who are both [18F]CTT1057 and SoT 
negative (true negatives (TN)) among those who test 
negative on [18F]CTT1057 (TN+ false negatives (FN)) 
• 
Evaluate the patient-level 
accuracy of [18F]CTT1057  
• 
Proportion of patients that are SoT and [18F]CTT1057 
positive (TP) and negative (TN) among all patients in EFF 
(TP+TN+FP+FN) 
• 
Evaluate the region-level 
sensitivity of [18F]CTT1057 
for patients excluding 
micro-metastasis 
• 
Sensitivity of [18F]CTT1057 PET imaging in the PLN region, 
excluding from the analysis those lymph nodes showing 
metastasis <2mm (micro-metastasis)  
• 
Evaluate the region-level 
sensitivity of [18F]CTT1057  
• 
Proportion of PLN regions that test positive on both 
[18F]CTT1057 and SoT (TP) among those that are SoT 
positive (TP+FN) 
• 
Evaluate the region-level 
positive predictive value of 
[18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
positive (TP) among those regions that test positive on 
[18F]CTT1057 (TP+FP) 
• 
Evaluate the region-level 
negative predictive value of 
[18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
negative (TN) among those regions that test negative on 
[18F]CTT1057 (TN+FN) 
• 
Evaluate the region-level 
accuracy of [18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
positive (TP) and negative (TN) among all PLN regions 
assessed [18F]CTT1057 (TP+TN+FP+FN) 
• 
Detection of distant 
metastasis in PS patients  
• 
Number of distant metastasis (extra-PLN, visceral or skeletal) 
identified at PET/CT scan per patient, and percentage of 
patients with at least one distant metastatic lesion identified 
by PET/CT scan 
• 
Characterize the safety and 
tolerability of [18F]CTT1057 
• 
Incidence of AEs. Treatment emergent adverse event 
(TEAE) rate within 14 days of administration 
• 
[18F]CTT1057 scan inter-
reader variability 
• 
Inter-reader agreement of [18F]CTT1057 images 


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Objective(s) 
Endpoint(s) 
• 
[18F]CTT1057 scan intra-
reader variability 
• 
Intra-reader agreement of [18F]CTT1057 images 
• 
To further assess 
[18F]CTT1057 
pharmacokinetics in 
humans in subset of 
approximately 10 patients 
• 
Summary statistics of [18F]CTT1057 pharmacokinetic 
parameters (i.e. Cmax, Tmax, AUClast, AUCinf, T1/2, Vz and 
CL from blood radioactivity data; quantification of urinary 
excretion of [18F]CTT1057 from urine data) 
 
Primary estimands 
The primary clinical question of interest is: Does [18F]CTT1057 target PSMA expressing PCa 
cells, allowing to obtain adequate [18F]CTT1057 PET/CT images to detect and localize 
PSMA positivity using histopathology as SoT? 
The justification for the primary estimand is that we wish to assess the diagnostic performance 
of [18F]CTT1057 PET in detecting and localizing PSMA positivity. For this reason, newly-
diagnosed high risk PCa patients will undergo a [18F]CTT1057 PET/CT scan within 6 weeks 
before surgery (but not sooner than 48 hours after the completion of the [18F]CTT1057 PET/CT 
scan), and  results of the [18F]CTT1057 PET/CT scans will be compared against the 
histopathology results (SoT) in the dissected tissue specimens (primary tumor and PLN), both 
at a patient and region level.  
The primary estimands are described by the following attributes: 
Primary estimand 1: 
1. Population: Untreated high risk PCa patients according to D’Amico classification (Stage ≥ 
T2c or PSA level >20ng/ml or Gleason score ≥8) (D'Amico et al 1998), who are scheduled 
or planned RP and lymph node resection. Further details about the population are provided 
in Section 5. 
2. Variables: Proportion of patients that test positive on both [18F]CTT1057 and SoT (TP) 
among those that are SoT positive ( TP + FN), considering PSMA positive patients are 
those who show at least one pathological [18F]CTT1057 uptake either in the primary 
tumor and/or metastatic PLN, with anatomically localized correspondence with the SoT.  


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3. Treatment (investigational imaging agent) of interest: [18F]CTT1057 injected as a single 
intravenous dose of approximately 370 MBq and subsequent PET/CT scan. Further details 
about the investigational imaging agent are provided in Section 6. 
4. Handling of remaining intercurrent events:   
• Patients who received the investigational imaging agent [18F]CTT1057 but did not 
undergo/complete the PET/CT scan for any reasons (e.g. consent withdrawal, PET 
camera failures, etc.), will be excluded from the primary analysis. Details on how to 
handle intercurrent events are provided in Section 12.4.3. 
5. Summary measure: Estimate of  proportion of patients that test positive on 
both [18F]CTT1057 and SoT (TP) among those that are SoT positive (TP + FN), 
considering PSMA positive patients are those who show at least one pathological 
[18F]CTT1057 uptake either in the primary tumor and/or metastatic PLN, with 
anatomically localized correspondence with the SoT, along with its 95% CI Further details 
on how the summary measure will be tested are provided in Section 12.4.2. 
Primary estimand 2: 
1. Population: the same as the primary estimand 1 
2. Variables: Proportion of PLN regions that test negative on both [18F]CTT1057 and SoT 
(TN) among those PLN region that test negative on the SoT (TN + FP), considering 
PSMA negative PLN regions those that do not show any pathological [18F]CTT1057 
uptake within the region. 
3. Treatment (investigational imaging agent) of interest: the same as the primary estimand 1 
4. Handling of remaining of intercurrent events: the same as the primary estimand 1 
5. Summary measure: Estimate of the proportion of PLN regions that test negative on both 
[18F]CTT1057 and SoT (TN) among those PLN region that test negative on the SoT (TN + 
FP), considering PSMA PLN negative regions those that do not show any 
pathological [18F]CTT1057 uptake within the region, along with its 95% CI. Further 
details on how the summary measure will be tested are provided in Section 12.4.2. 
 
Secondary estimands 
Not applicable 
3 
Study design 
This is a multi-center, single-arm, open-label prospective study to evaluate the diagnostic 
performance of [18F]CTT1057 as a PET imaging agent for detection and localization of PSMA 
positive tumors, using histopathology as SoT. Tissue specimens from both the primary tumor 
and PLN dissected during surgery from patients with newly-diagnosed high-risk PCa will be 
used for the histopathology assessments. 
Approximately 195 participants will be enrolled to ensure that at least 156 participants are 
evaluable for co-primary endpoints. Surgery will be performed up to 6 weeks after 
[18F]CTT1057 PET/CT but not sooner than 48 hours after the completion of the [18F]CTT1057 
PET/CT scan (in order to limit the potential confounding factors related to the effects of surgery 


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for the assessment of [18F]CTT1057 PET/CT safety) for pathology assessment of the tissue 
specimens.  
The co-primary endpoints of patient-level sensitivity and region-level specificity will be 
assessed by comparing the central reading results of the [18F]CTT1057 PET/CT scan (see 
Section 4.1 and Section 8.3.1 for central read details and Section 6.4 for blinding details) to the 
histopathology results in the dissected tissue specimens, i.e. both the primary tumor and the 
dissected PLN (Maurer et al 2016, Woythal et al 2018, Kuten et al 2020). 
Pathology will be assessed by the local pathologists as per SoC. Pathologists will be blinded to 
the PET data. For anatomical localization, a sextant anatomic template for the prostate and a 
left/right template for the PLN will be used (see appendix Section 16.2). Pathology results 
should be available within 2 weeks after surgery. 
 
 
 
 
 
 
 
 
 
 
 
 See Figure 3-1 for study design schema. 
Figure 3-1 
Study Design 
 
Screening Period 
Written informed consent form (ICF) must be obtained prior to any screening procedures. The 
participant must be registered in the Interactive Response Technology (IRT) for screening 
and [18F]CTT1057 requested. All procedures described in the Assessment Schedule as per 
Table 8-1 must be carried out, prioritizing laboratory assessments to allow time to obtain the 
results at least 14 days prior the planned PET imaging day (Day 1). The participants will be 


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assessed for eligibility before they will undergo a [18F]CTT1057 PET/CT scan. Eligibility must 
then be confirmed at the latest on Day -14. The screening period should last up to 28 days. 
[18F]CTT1057 PET imaging day: 
[18F]CTT1057 PET imaging will be performed using a standard integrated PET/CT system. The 
following steps to take place during this day are described in Section 8.3.1. 
In the PK subset  of approximately 10 participants at the same site, several blood and urine 
samples as well as additional ECG assessments for safety will be done at the pre-specified time 
points on PET imaging day. 
Safety Check 
All treated participants will be contacted by phone within 24 to 72 hours following the scan in 
order to capture potential occurring Adverse Events. 
Safety Follow-up  
Participants will come back to the hospital 14 days after the PET/CT scan day, for a safety visit 
including vital signs, lab and urine analysis. For participants undergoing surgery prior to 
planned safety visit, these safety follow-up assessments will need to be performed before the 
surgery but not sooner than 48 hours after the PET/CT scan. 
Additional Follow-up 
Surgery (RP/ePLND) will be scheduled for all participants as planned per SoC on a date that 
must  not be sooner than 48 hours after the completion of the [18F]CTT1057 PET/CT scan, and 
no later than 6 weeks after completion of the [18F]CTT1057 PET/CT scan. Final histopathology 
results have to be obtained within 2 weeks after surgery. 
4 
Rationale 
 
Rationale for study design 
In this study, a single-dose of the investigational PET imaging radiopharmaceutical 
[18F]CTT1057 will be administered intravenously, in an open-label single-arm design. 
The most commonly used measures for evaluating the diagnostic performance of a new imaging 
modality are sensitivity and specificity. Histopathology of the tumor samples is considered as 
the SoT to assess the diagnostic performance of PET tracers targeting PSMA 
(Maurer et al 2016, Woythal et al 2018, Kuten et al 2020). In PS patients, both the primary 
tumor and the metastatic lymph nodes (LN) are expressing PSMA, which is the target for 
[18F]CTT1057 binding. Within a period of up to 6 weeks after completion of the [18F]CTT1057 
PET/CT scan, patients will undergo surgery as per their standard of care treatment plan, 
consisting of RP and ePLND, as per the European Association of Urology (EAU) guidelines 
for Prostate Cancer 2020 (refer to Section 16.1). 
In addition to the prostate dissection, a minimum of 12 PLN per patient will be dissected in 
order to have enough numbers of PLN in total for the calculation of the co-primary endpoints 
and the diagnostic performance yielding secondary endpoints.  


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Local pathologists with experience in PCa who will be blinded to the [18F]CTT1057 PET/CT 
results will then assess the tissue specimens as per SoC. For the anatomical correspondence 
with PET/CT images, a sextant template will be used for the prostate (Kuten et al 2020). For 
the PLN, an anatomical side approach left/right will be used, since the borders of dissection are 
not usually very clear neither for the surgeon nor for the pathologist. 
A central read of the PET/CT scan will be performed at a Contract Research Organization 
(CRO) by a total of three independent nuclear medicine physicians or radiologists experienced 
in reading oncology PET, who will be blinded to patient data, including the clinical condition 
of the patient, results of histopathology/biopsy, and results of conventional imaging. Patients 
and regions will be graded on a two-point scale by each reader (0 = negative; 1 = positive). The 
results from each of the 3 readers will be individually compared to the SoT to generate per-
reader performance. An individual PET reader will be considered successful if he/she meets 
predefined thresholds for both co-primary endpoints, and at least two of three readers should be 
successful for overall study positive. PET results will be compared to histopathology results, 
and anatomically localized positive lesions in both PET and histopathology will be considered 
“TP” for sensitivity and specificity calculations as the primary endpoints of the study. 
Regions defined for this study are prostate region (comprising prostate bed/prostate gland and 
any local invasion of the urinary bladder, rectum or seminal vesicles), PLN region, extra-PLN 
region, skeletal region and visceral region. 
The criteria to be applied for PET positivity is the following: 
• A patient will be judged as positive if at least one lesion in any region is visually positive.  
• A region will be judged as positive if at least one lesion in the region is visually positive.  
• Visually PET positive lymph nodes will be considered greater than blood pool (adjacent or 
mediastinal blood pool). 
• PET positive bone lesions will be considered greater than physiologic bone marrow. 
• PET positive prostate, prostate bed and visceral lesions will be considered greater than 
physiologic background activity of the involvement organ or anatomic site, as previously 
described (Ceci et al 2015, Eiber et al 2015, Fendler et al 2019).  
Only prostate region and PLN will be used as regions for comparison to the SoT and co-primary 
endpoint calculations.  
Consistency of the PET/CT scan interpretation both between different readers and within 
readers is an important issue in medical imaging, as it affects portability of results between 
institutions and may affect patient care. The degree of inter- and intra-reader variability in the 
qualitative assessment of [18F]CTT1057 PET/CT images will be assessed as a secondary 
endpoint to ensure consistency of interpretation and hence reliable diagnosis, which has pivotal 
role in the patient management. 


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. Further details on the 
questionnaire and procedure are provided in Section 3. 
In order to reproduce as much as possible the real clinical context, this [18F]CTT1057 PET/CT 
scan will be read by a local nuclear medicine physician or radiologist with expertise in reading 
oncology PET/CT scans who will not be blinded to patient data. See also Section 6.4 and 
Section 8.3 for blinding and reading details.  
The co-primary endpoints will not be assessed in those patients who, as a consequence of a 
change in treatment will not be considered suitable for surgery. These patients will remain in 
the study for the assessment of some secondary 
  
 
Rationale for dose/regimen and duration of treatment 
For PET diagnostic radiopharmaceuticals, only a single administration is required, usually 
intravenously. The investigational PET radiopharmaceutical [18F]CTT1057 will be 
administered accordingly, as a single intravenous (i.v.) dose of approximately 370 MBq (266 – 
407 MBq). This dose was shown to be safe and well tolerated in the Phase I study 
(Behr et al 2019), and it is in line with the recommended dose of the commercial product 
[18F]FDG according to both the European Association of Nuclear Medicine (EANM) and 
Society of Nuclear Medicine guidelines (Delbeke et al 2006, Boellaard et al 2015). Human 
dosimetry was studied in the Phase I study. The effective dose (ED) was estimated at 
0.023±0.007 mSv/MBq, which is in line as well with the ED of the commercial product 
[18F]FDG (0.019 mSv/MBq)  according to the EANM guideline (Boellaard et al 2015) and in 
other publications (0.020-0.025 mSv/MBq) (Kaushik et al 2015), as well as the ED of other 
PSMA PET agents (Behr et al 2019). The radiation dose estimated from an i.v. administration 
of 370 MBq of [18F]CTT1057 is 8.51 mSV. Moreover, this dose allowed to obtain the optimal 
image quality, which was rated 76 ± 5.4 on a Visual Analog Scale (VAS) of 1 to 100 (1 = 
nondiagnostic, 100 = perfect study), by 2 experienced Nuclear Medicine physicians 
(Behr et al 2019). Further details on [18F]CTT1057 can be found in the IB. 
 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
 
Purpose and timing of interim analyses/design adaptations 
Not applicable 
 
Risks and benefits 
The use of PSMA-PET scanning of PCa participants has been ongoing since 2011, mostly with 
[68Ga]Ga-PSMA-11, to assess disease burden in the setting of both biochemical recurrence 
(BCR) and advanced/metastatic disease. Publications that report clinical use have demonstrated 
better sensitivity and specificity than choline-based PET imaging for PCa, with a very low rate 
of adverse events. [68Ga]Ga-PSMA-11 has been shown to be well tolerated with no adverse 
events following infusion in a retrospective analysis of 1007 participants (Afshar-Oromieh et 
al 2017).  Recently, [68Ga]Ga-PSMA-11 has been approved in the USA (December 2020) as a 


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radioactive diagnostic PET imaging agent in men with PCa with suspected metastasis who are 
candidates for initial definitive therapy, or with suspected recurrence based on elevated serum 
PSA level ([15Ga]Ga-PSMA-11 USPI). Subsequently, other PSMA-PET agents have been 
investigated and are under clinical development, all of them showing a good safety and 
tolerability profile. PCa patients diagnosed of localized disease, at primary staging, have been 
enrolled in studies requiring histopathology comparisons to determine diagnostic yield of the 
technique. A Phase-I study of [18F]CTT1057 in 20 PCa patients (n=5 primary staging, n=15 
mCRPC (NCT02916537) has shown an acceptable safety profile, without any radiotracer-
related adverse reactions. The biodistribution of [18F]CTT1057 in humans is similar to that of 
other PSMA-targeted agents, and exposure rates of [18F]CTT1057 are also similar to those of 
the urea-based PET compounds, with the advantageous exception of lower exposure to kidneys 
and salivary glands. Preclinical work, dosimetry studies, and clinical experience 
with [18F]CTT1057 suggest good imaging quality properties and a favorable safety profile 
(Behr et al 2019). 
As this is a study on the diagnostic performance of an investigational PET agent, patients 
enrolled are not expected to derive direct benefit. It is expected that distant disease will be 
identified in some patients as a consequence of this study and these patients may benefit from 
a more appropriated management plan, which will not be based on the investigational procedure 
alone, but confirmed by SoC diagnostic procedures. The risk-benefit ratio is expected to be 
favorable to the [18F]CTT1057 imaging agent. 
Any risk to participants in this trial is minimized by compliance with the eligibility criteria and 
study procedures, as well as close clinical monitoring. Appropriate eligibility criteria are 
included in this protocol. 
Additional details of the nonclinical and clinical experience with [18F]CTT1057 are provided in 
the Investigator's Brochure. 
 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
In this study, the participant population will consist of males ≥ 18 years of age, with newly 
diagnosed high-risk PCa who are candidates for RP and extended lymph node resection as per 
SoC. 
Approximately 195 participants will be enrolled to ensure that at least 156 participants are 
evaluable (i.e. have both an evaluable PET/CT scan and histopathology assessment and have 
not received any prohibited systemic antineoplastic therapy before the completion of PET/CT 
and surgery), which will be required for the calculation of the co-primary endpoints. Refer to 
Section 12.8.1 for sample size calculation. 


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Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1a. Untreated high risk biopsy-proven PCa patients according to D’Amico classification                            
(Stage ≥ T2c or PSA level >20ng/ml or Gleason score ≥8) (D'Amico et al 1998) 
2. Scheduled or planned radical prostatectomy and extended pelvic lymph node resection up 
to 6 weeks after the investigational PET/CT scan followed by histopathology assessment 
3. ECOG performance status 0-2 
4. Signed informed consent must be obtained prior to participation in the study 
5. Participants must be adults ≥ 18 years of age 
 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Inability to complete the needed investigational and standard-of-care imaging 
examinations due to any reason (severe claustrophobia, inability to lie still for the entire 
imaging time, etc.) 
2. Any additional medical condition, serious intercurrent illness, concomitant cancer or other 
extenuating circumstance that, in the opinion of the Investigator, would indicate a 
significant risk to safety or impair study participation, including, but not limited to, current 
severe urinary incontinence, hydronephrosis, severe voiding dysfunction, need of 
indwelling/condom catheters, New York Heart Association class III or IV congestive heart 
failure, history of congenital prolonged QT syndrome, uncontrolled infection, active 
hepatitis B or C, and COVID-19. 
3. Known allergy, hypersensitivity, or intolerance to [18F]CTT1057  
4. Prior and current use of PSMA targeted therapies 
5a. Prior and current treatment with any ADT (first or second generation), including LHRH   
analogues (agonists or antagonists) 
7. Any 5-alpha reductase inhibitors within 30 days before screening 
8. Patients with small cell or neuroendocrine PCa in more than 50% of biopsy tissue 
9. Patients with incidental PCa after transurethral resection 
10. Use of other investigational drugs within 30 days before screening 
6 
Treatment 
 
Study treatment 
In this study, the investigational imaging agent is the radioligand imaging compound 
[18F]CTT1057. Participants will be administered [18F]CTT1057 as an intravenous injection, 
single dose (Refer to Section 6.7 for study drug preparation and dispensation).  
All study participants will receive [18F]CTT1057 and the dose is listed in Table 6-1. 
[18F]CTT1057 will be provided by Novartis.  


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Investigational and control drugs 
Administration of [18F]CTT1057  
Study participants will be injected intravenously with approximately 370 MBq (range 266 – 
407 MBq) of [18F]CTT1057 (Refer to Section 6.7 for study drug preparation and dispensation). 
Table 6-1 
Investigational drug 
Investigation
al name 
Pharmaceuti
cal Dosage 
Form 
Route of 
Administratio
n 
Frequency 
Supply Type 
Sponsor 
(global or 
local) 
[18F]CTT1057 
(370 MBq/mL 
at calibration 
time (Tc)) 
Radiopharma
ceutical 
solution for 
injection  
Intravenous 
use 
Single 
administration 
Open label, 
vial/Syringe 
Sponsor 
(Global) 
 
Additional study treatments 
No other treatment beyond investigational imaging agent is included in this trial. 
 
Supply of study treatment 
[18F]CTT1057 will be provided as a single mono-dose in syringe (for US) or a single multidose 
vial (for European Union (EU)) ready to use radiopharmaceutical solution for injection, with a 
volumetric activity of 370  (±10%) MBq/mL at the reference date and time (calibration time 
(Tc)). The natural decay of the radionuclide leads to a continuous decrease of the specific 
activity, the total radioactivity and the radioactive concentration (volumetric activity) over the 
time. Therefore, the volume of the solution injected varies in order to provide the required 
amount of radioactivity at the date and time of injection. The exact expiry time based on shelf 
life of the product and the production activities is reported on the [18F]CTT1057 certificate of 
release as described in the Pharmacy Manual. 
 
Treatment duration 
Participants will receive a single injection intravenously of approximately 370 MBq (range 266 
– 407 MBq) of [18F]CTT1057 during the single imaging day. 
 
Other treatment(s) 
 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 


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Use of diuretics (e.g. furosemide) to help subject to void before PET/CT scan imaging 
acquisition is allowed in case of need, upon the discretion of the investigator. 
 
Prohibited medication 
Any medication that may interfere with PSMA PET imaging is not allowed. Prior to completing 
[18F]CTT1057 PET/CT imaging and surgery, any ADT including LHRH analogues (agonists 
or antagonists) as well as anti-androgens (both first and second generation compounds) and 5-
alpha reductase inhibitors are prohibited. Any therapy/procedure that could interfere with PET 
PSMA imaging is not allowed. 
 
Participant numbering, treatment assignment, randomization 
 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is entered for screening and is retained for the participant 
throughout his participation in the trial. A new Participant No. will be assigned at every 
subsequent study participation if the participant is re-screened. The Participant No. consists of 
the Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential participant number suffixed to it, so that each participant’s participation is numbered 
uniquely across the entire database. Upon signing the informed consent form, the participant is 
assigned to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
 
Treatment assignment, randomization 
All eligible participants will be enrolled via IRT. The investigator or his/her delegate will 
contact the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. 
The investigator or his/her delegate will order the [18F]CTT1057 dose  prior to the scheduled 
dosing date (refer to Pharmacy Manual). The administration will be tracked by the investigator 
or his/her delegate via IRT. Detailed instructions of Investigational Medicinal Product (IMP) 
ordering and IRT use will be provided in the Pharmacy Manual. 
 
Treatment blinding 
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the study team. The following blinding is applicable in this study: 
• [18F]CTT1057 PET/CT images will be submitted to a CRO for independent centralized 
review by 3 independent reviewers blinded to patient data collected in clinical database 
(such as medical history details or diagnostic test results). 
• Pathology assessments by the local pathologists will be performed as per SoC. 
Pathologists will be blinded to the [18F]CTT1057 PET/CT data, but not to other relevant 
patient data. 
• [18F]CTT1057 PET/CT images will be reviewed by a local nuclear medicine physician or 
radiologist with expertise in reading oncology PET/CT scans, who will not be blinded to 


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patient data and the results will be provided to the treating physician / Clinical Study 
 
 
Dose escalation and dose modification 
Investigational dose adjustments and/or interruptions are not applicable in this study in which 
the imaging agent is administered only once. 
 
Follow-up for toxicities 
Participants whose treatment is discontinued due to an adverse event or clinically significant 
laboratory value, must be followed up at least once a week (or more frequently if required by 
institutional practices, or if clinically indicated) for 4 weeks, and subsequently at approximately 
4-week intervals, until resolution or stabilization of the event, whichever comes first. 
Appropriate clinical experts should be consulted as deemed necessary. All participants must be 
followed up for adverse events as described in Table 8-1. 
 
Additional treatment guidance 
 
Treatment compliance 
All participants will have the study treatments administered during site visits as per schedule of 
events in Table 8-1. All study treatments must be recorded in the Drug Accountability Log and 
in the corresponding electronic case report form (eCRF) pages. 
 
Preparation and dispensation 
Each study site will be supplied with the study drug packaged as described under Section 6.1.1. 
 [18F]CTT1057 is a ready to use solution for injection therefore no preparation is needed. Please 
refer to procedure and instructions contained in the Pharmacy Manual. 
Immediately after administration to the participant, site personnel will complete the study 
treatments accountability logs for traceability purpose. For more detailed instructions, please 
refer to the Pharmacy Manual. 
 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the IB. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.  
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatments in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 


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[18F]CTT1057 
The packaging [18F]CTT1057 consists of a white glass multidose vial (For EU) or a mono-dose 
syringe (US) containing the sterile radioactive solution.  
[18F]CTT1057 solution should be handled by the user in a manner which satisfies both radiation 
safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be 
taken, complying with the requirements of Good Manufacturing Practice for pharmaceuticals. 
Since [18F]CTT1057 is a ready-to-use solution, no manipulation of the investigational product 
is intended at the clinical site, except the: 
• dispensation into mono-dose syringes, or the use of automatic dispenser and infusion 
system, according to local procedure, when applicable. 
• disposal which must be documented appropriately and a copy of the completed drug 
accountability log should be sent on a regular basis to the Novartis monitor or to 
the Novartis address provided in the investigator folder at each site. 
The radioactive [18F]CTT1057 will be locally discarded according to all disposal requirements 
and local regulations for radioactive materials. 
For [18F]CTT1057 solution storage conditions, quality control (QC), administration and 
disposal, clinical sites must follow instruction as describe in the [18F]CTT1057 Pharmacy 
Manual. 
These different steps in [18F]CTT1057 product management have to be documented as 
described in the Pharmacy Manual using forms/log provided in the investigator folder at each 
site in order to ensure traceability of the product at any time. 
[18F]CTT1057 labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions, batch number, expiry date. 
 
Instruction for preparing and administering study treatment 
[18F]CTT1057 
Preparation 
[18F]CTT1057 is a ready-to-use multi-dose vial (EU) or a mono-dose syringe (US).  
The instruction for cautionary notes, analytical controls and stability of the radiolabeled product 
will be provided to each site (please refer to the Pharmacy Manual). 
Administration 
Injection of [18F]CTT1057 must be performed in accordance with national and/or local 
radiation and safety requirements. 
Approximately 370 MBq (range 266 – 407 MBq) of [18F]CTT1057 will be injected 
intravenously then flushed by 10 mL of saline. 
The radioactive [18F]CTT1057 will be locally discarded according to all disposal requirements 
and local regulations for radioactive materials. 


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The total activity administered must be recorded (mCi or MBq) by measuring the residual 
radioactivity in the vial or in the syringe before and after administration with the dose calibrator 
(or activimeter). 
For clinical sites equipped with an automatic infusion system, apply the local procedure to 
register the exact amount of radioactivity injected. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent. 
If applicable, in cases where the participant’s representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his understanding. If the participant is capable of doing so, he must indicate 
agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, the Investigator 
may conduct the informed consent discussion remotely (e.g. telephone, videoconference), if 
allowable by a local Heath Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g. the presence of an 
impartial witness, sign/dating separate ICFs by trial participant and person obtaining informed 
consent, etc). 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonisation Good Clinical Practice (ICH 
GCP) E6 guidelines and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant during the study as needed. Any new information 
regarding the safety profile of the investigational drug that is identified between IB updates will 
be communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also includes:  
• a subsection that requires a separate signature for the Optional Consent for the PK 
analyses. The study includes optional additional assessments for PK analyses that 


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requires a separate signature if the patient agrees to participate. It is required as part of 
this protocol that the Investigator presents this option to patients, as permitted by local 
governing regulations. Declining to participate in these optional assessments for PK 
analyses will in no way affect the patient’s ability to participate in the main research 
study. 
• a subsection that requires a separate signature for the Optional Consent for Additional 
Research to allow future research on data/samples collected during this study. 
A copy of the approved version of all consent forms must be provided to Novartis/Sponsor after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants whodiscontinue from the study 
treatment are to return for the end of treatment visit as soon as possible, and attend the follow-
up visits as indicated in the Assessment Schedule. Participants who discontinue from the study 
or withdraw their consent/oppose the use of their data/biological samples should be scheduled 
for a final evaluation visit if they agree, as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all dispensed investigational 
product should be reconciled, and the adverse event and concomitant medications not 
previously reported must be recorded on the case report form (CRF). 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the investigator 
as the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name Screening 
Enrolment 
PET Imaging 
Safety 
Check 
Safety 
Follow-
up 
Additional 
Follow-up 
EOS1 
Days Day -28 to 
Day -14 
Day -28 to Day -14  
Day 1  
(+ 7) 
Day 2 to 
3 
Day 15 
(+3)11 
Up to 8 weeks 
after Day 1 
Day 15 to 
Follow-up end 
Time 
(post-
dose) 
- 
- 
Pre-
Injection 
Inject
ion 
Post-Injection/ 
Pre-imaging 
Imagi
ng 
Post-
Imaging/ 
EOT 
- 
- 
- 
- 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
IRT 
participant 
registration 
X 
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
Medical 
History & 
Demograp
hics 
X 
  
  
  
  
  
  
  
  
  
  
Electrocar
diogram 
(ECG) 
X 
  
X2 
  
X2 
  
X2 
  
X2 
  
  
ECOG 
Performan
ce Status 
X 
  
  
  
  
  
  
  
  
  
  
Physical 
Examinatio
n 
S (short) 
  
S (short) 
  
  
  
  
  
S (short) 
  
  


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Period 
Screening 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name Screening 
Enrolment 
PET Imaging 
Safety 
Check 
Safety 
Follow-
up 
Additional 
Follow-up 
EOS1 
Days Day -28 to 
Day -14 
Day -28 to Day -14  
Day 1  
(+ 7) 
Day 2 to 
3 
Day 15 
(+3)11 
Up to 8 weeks 
after Day 1 
Day 15 to 
Follow-up end 
Time 
(post-
dose) 
- 
- 
Pre-
Injection 
Inject
ion 
Post-Injection/ 
Pre-imaging 
Imagi
ng 
Post-
Imaging/ 
EOT 
- 
- 
- 
- 
Body 
Weight 
X 
  
X 
  
  
  
  
  
  
  
  
Body 
Height 
X 
  
  
  
  
  
  
  
  
  
  
Vital 
Signs3 
X 
  
X 
  
X 
  
X 
  
X 
  
  
Hematolog
y4 
X 
  
X 
  
  
  
  
  
X 
  
  
Clinical 
Chemistry4 
X 
  
X 
  
  
  
  
  
X 
  
  
PSA level 
X 
  
  
  
  
  
  
  
  
  
  
Urinalysis5 
S 
  
S 
  
  
  
  
  
S 
  
  
PK 
Sample 
Collection6 
  
  
For approximately 10 participants from the same clinical 
site only 
  
  
  
  
Adverse 
Events 
AEs to be collected throughout this period 
 
 
Concomita
nt 
medication
s 
Concomitant Medications to be collected throughout this period 
 
 
IRT 
enrollment 
  
X 
  
  
  
  
  
  
  
  
  


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Period 
Screening 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name Screening 
Enrolment 
PET Imaging 
Safety 
Check 
Safety 
Follow-
up 
Additional 
Follow-up 
EOS1 
Days Day -28 to 
Day -14 
Day -28 to Day -14  
Day 1  
(+ 7) 
Day 2 to 
3 
Day 15 
(+3)11 
Up to 8 weeks 
after Day 1 
Day 15 to 
Follow-up end 
Time 
(post-
dose) 
- 
- 
Pre-
Injection 
Inject
ion 
Post-Injection/ 
Pre-imaging 
Imagi
ng 
Post-
Imaging/ 
EOT 
- 
- 
- 
- 
[18F]CTT10
57 
ordering7 
  
X 
  
  
  
  
  
  
  
  
  
[18F]CTT10
57 
Administra
tion8 
  
  
  
X 
  
  
  
  
  
  
  
[18F]CTT10
57 PET/CT 
Imaging9 
  
  
  
  
  
X 
  
  
  
  
  
Safety 
Follow-up 
Call 
  
  
  
  
  
  
  
X 
  
  
X 
Histopatho
logy 
Assessme
nt10 
  
  
  
  
  
  
  
  
  
Up to 8 weeks 
after imaging 
Day1 
  
End of 
Phase 
Disposition 
X 
  
  
  
  
  
X 
  
  
  
X 


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Period 
Screening 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name Screening 
Enrolment 
PET Imaging 
Safety 
Check 
Safety 
Follow-
up 
Additional 
Follow-up 
EOS1 
Days Day -28 to 
Day -14 
Day -28 to Day -14  
Day 1  
(+ 7) 
Day 2 to 
3 
Day 15 
(+3)11 
Up to 8 weeks 
after Day 1 
Day 15 to 
Follow-up end 
Time 
(post-
dose) 
- 
- 
Pre-
Injection 
Inject
ion 
Post-Injection/ 
Pre-imaging 
Imagi
ng 
Post-
Imaging/ 
EOT 
- 
- 
- 
- 
* All Screening assessments to confirm eligibility into the study must be performed prior enrollment 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Phone call will be performed when histopathology results are available and recorded in CRF 
2 For a subset of approximately 10 participants from the same clinical site consenting for the PK sample collection  
3 Vital signs will be performed at screening, at PET imaging day (pre and post-injection and prior to discharge) and at Safety Follow-up visit 
4 Peripheral venous blood samples will be collected at screening and PET imaging day pre-injection and at Safety follow-up (Day 15) 
5 Urine samples will be collected at screening, at PET imaging day and Safety Follow-up and analyzed at the clinical site if dipstick results are abnormal 
6 For 10 participants from the same clinical site, blood and urine samples will be collected for PK analysis, refer to Section 8.5.1 of the protocol 
7 Order to be placed after enrollment and based on drug availability local timelines (refer to Pharmacy Manual) in order to perform PET imaging Day 1 no more than 14 
days after enrollment. 
8 Participant will be injected intravenously  approximately 370 MBq (range 266–407 MBq) of [18F]CTT1057, flushed with 10 mL saline 
9 
 after [18F]CTT1057 imaging agent injection, a CT will be obtained from vertex to mid-thighs, followed by static PET emission scan over same area starting 
from mid-thighs 
10 Histopathology results must be obtained within up to 2 weeks following RP with ePLND, which must be planned within up to 6 weeks after but not sooner than 48 
hours after PET Imaging Day 
11 For participants undergoing surgery prior to planned safety visit, these safety follow-up assessments will need to be performed before the surgery and not sooner than 
48 hours after the PET scan and in that case safety assessments are not to be repeated on Day15 


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Screening 
Written informed consent must be obtained prior to any screening procedures. Please refer to 
Section 7 for the Informed Consent procedures. After informed consent is collected, the 
participant must be registered in IRT.  
Laboratory assessments should be carried out as priority to allow the necessary time to obtain 
the results and to confirm participant eligibility prior to placing the [18F]CTT1057 order. All 
Screening assessments to confirm eligibility into the study should be performed between Day-
28 and Day-14 as per Visit Assessment Schedule Table 8-1. 
It is permissible to re-screen (only once) a participant if he fails the initial screening (screen 
failure); however, each case must be discussed and agreed with the Sponsor on a case-by-case 
basis. Re-screening should not be performed for avoiding the eligibility criteria, putting the 
participant at safety risk. Re-screened participants will need to be re-consented and a new 
Participant Number will be assigned. Re-screening tests should be repeated as per 
inclusion/exclusion requirements and re-screening should be documented in medical records.  
 
Eligibility screening 
Following registration in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system 
at IRT enrollment. Please refer and comply with detailed guidelines in the IRT manual. 
 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to enrollment will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
section for reporting details Section 10.1.3). If the participant fails to be enrolled, the IRT must 
be notified, within 2 days of the screen fail, that the participant was not enrolled. 
Participants who are enrolled and fail to start treatment, e.g. participants enrolled in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
 
Participant demographics/other baseline characteristics 
Country/Region specific regulations should be considered for the collection of demographic 
and baseline characteristics in alignment with eCRF. 
Participant demographic and baseline characteristic data are to be collected on all participants. 
Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. 


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Relevant medical history/current medical condition present before signing the informed consent 
will be recorded. Investigators will have the discretion to record abnormal test findings on the 
appropriate eCRF whenever in their judgment, the test abnormality occurred prior to the 
informed consent signature. 
Subject demographic and baseline characteristic data to be assessed on all subjects include: 
• Demographic information: age, gender, self-identified ethnicity and race 
• Vital signs: body temperature, blood pressure, heart rate (HR), respiratory rate (RR), 
• Weight, and height 
• ECOG  Performance status scale 
• Laboratory evaluations: hematology, chemistry, urinalysis test and PSA (see 
Section 8.4.1) 
Medical history:  
• Date of diagnosis of PCa (diagnostic criteria is to be reported also in the eCRF) ((Stage ≥ 
T2c or PSA level >20ng/ml or Gleason score ≥8) 
• Results of digital rectal examination (cT1c, cT2a, cT2b, cT2c, cT3) 
• Ongoing medical conditions, symptoms and diseases which are recorded on the Medical 
History eCRF should include the toxicity grade when applicable 
• Concomitant medications of the last 30 days prior to enrollment (dose, dates) 
• Other important medical, surgical, and allergic conditions that could have an impact on the 
participant's evaluation) / current medical conditions (e.g. all relevant current medical 
conditions which are present at the time of signing informed consent). 
Other data: 
• Date of planned RP and extended ePLND (up to 6 weeks after PET/CT scan) 
 
Efficacy 
Efficacy assessments in this study include histopathology assessments (primary tumor and 
PLN) and assessments of PET/CT images using a [18F]CTT1057 agent. Please refer to the 
schedule of assessments provided in Table 8-1. 
 
Imaging for tumor assessment 
Post-baseline [18F]CTT1057 PET imaging assessments 
[18F]CTT1057 PET imaging assessments as described in Table 8-1 should be performed at Day 
1. The following steps will take place on PET imaging day: 
1. Participant will be asked to drink 1-2 glasses of water before arrival at the clinic. 
2. Participant will be weighed and vital signs (body temperature, blood pressure, heart rate, 
respiratory rate) will be recorded prior injection. 
3. Participant will be injected i.v. with approximately 370 MBq (range 266 – 407 MBq) of 
[18F]CTT1057, flushed by 10 ml of saline. 
4. Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be recorded 
after the injection. 


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5. Participant will void immediately prior to the scan. If it is not possible for the participant 
to void, a urethral catheterization will be considered. 
6. [18F]CTT1057 PET/CT scan acquisition will preferably, 
 
 A CT 
(transmission scan) will be obtained from vertex to midthighs for anatomical reference 
and attenuation correction purposes. This will be followed by a static PET emission scan 
over the same area, starting from mid thighs. Refer to imaging charter and/or site imaging 
manual for details. 
7. If intense activity in the urinary bladder is seen in the PET/CT images that precludes 
appropriate assessment of the prostate bed and/or PLN regions, then the patient will be 
allowed to void again, and urethral catheterization and a new (1 bed) PET/CT image of the 
pelvis will be considered in case of need. This additional pelvic image can then be 
acquired within 
 
8. Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be recorded 
again at the completion of the study (prior to patient discharge). 
9. Participant will be discharged with the reminder of the safety follow-up as described in the 
ICF. 
[18F]CTT1057 PET/CT images will be submitted to the designated imaging CRO for 
independent central read. All reviewers have to be blinded to patient data (including clinical 
condition, histopathology and imaging results). Central read results will not be provided to 
site/Study Investigator. 
[18F]CTT1057 PET/CT images will also be read by an independent local nuclear medical 
physician or radiologist with expertise in reading oncology PET/CT scans, who will not be 
participating in the central read of images. The report from this local reader will be provided to 
the treating physician/ Clinical Study Investigator to complete 
 
 before the participant undergoes surgery. The criteria to be applied for PET 
positivity are detailed in Section 4.1. 
[18F]CTT1057 PET/CT imaging data to be documented in eCRF will include the outcome of 
the assessment, i.e. if negative or positive for PCa tumor or metastases, region(s) and location 
of the lesions as well as their characteristics. 
 
Histopathology assessments 
Within a period of  not sooner than 48 hours after the completion of the [18F]CTT1057 PET/CT 
scan and not later than the 6 weeks after the [18F]CTT1057 PET/CT scan, patients will undergo 
surgery as per their standard of care treatment plan, consisting of RP and ePLND, as per 
the EAU guidelines of Prostate Cancer 2020. (uroweb.org/guideline/prostate-cancer/) 
A minimum of 12 PLN per patient will be dissected in order to have enough number of positive 
(i.e. metastatic) and negative (i.e. normal) PLN in total. Refer to Section 16.2. 
The histopathology results are the only efficacy assessment as SoT, and will be compared to 
the [18F]CTT1057 PET/CT scan central read results for the calculation of the co-primary 
endpoints. 


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Pathology data to be documented in eCRF will include the outcome of the assessment, i.e. if 
negative or positive for adenocarcinoma, if other tumor histological types are present, size of 
the tumor or metastatic lesions within the tissue specimens, and location according to the 
anatomical templates described in Section 16.2. 
 
Appropriateness of efficacy assessments 
Histopathology of the tumor samples is considered as the SoT to assess the diagnostic 
performance of [18F]CTT1057 PET agent. After surgery, pathology of the primary tumor and 
the dissected PLN will be used as SoT. 
The assessment will be performed by the local pathologists with experience in PCa at each site, 
as per SoC, in order to mimic as much as possible the clinical situation. Pathologists will be 
blinded to the PET/CT scan results. 
 
Safety 
Safety assessments are specified below (Table 8-2) with the assessment schedule detailing when 
each assessment is to be performed. For participants undergoing surgery prior to planned safety 
visit, these safety follow-up assessments will need to be performed before the surgery and not 
sooner than 48 hours after the PET scan and in that case safety assessments are not to be 
repeated on Day15. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits 
regular phone or virtual calls will occur (as close as possible to the visits as per schedule) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again. If participants cannot visit the site for protocol specified safety 
lab assessments, an alternative lab (local) collection site may be used. 
For details on AE collection and reporting, refer to the AE section. 
Table 8-2 
Assessments and Specifications 
Assessment 
Specification 
Physical 
examination 
A short physical exam will include the examination of general appearance. A 
short physical exam will be at all visits starting from screening visit. 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be recorded on the appropriate CRF 
that captures medical history. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs include Systolic Blood Pressure (SBP) and Diastolic Blood 
Pressure (DBP) (supine position preferred when ECG is collected), HR, RR 
and body temperature. 
Weight and height 
Body weight (in indoor clothing, but without shoes) and height will be 
measured as specified in Table 8-1. 
Performance status: 
ECOG Performance status scale will be used as described in Table 8-3. 


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Table 8-3 
ECOG Performance status 
Score 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
Laboratory evaluations 
Central laboratory will be used for analysis of hematology, chemistry and PSA testing according 
to the schedule of assessments as described in Table 8-1. The samples need to be taken prior 
the administration of the Investigational Product. Details on the collections, shipment of the 
samples and reporting of results by the central laboratory are provided to investigators in the 
laboratory manual.  
Urine samples will be collected at screening, at imaging day and safety follow-up by dipstick 
and analyzed locally at the clinical site if dipstick results are abnormal. 
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 1) they induce clinical signs or symptoms, 2) they are considered 
clinically significant, or 3) they require concomitant therapy or procedures. Clinically 
significant abnormal laboratory values or test results should be identified through a review of 
values outside of normal ranges/clinically notable ranges, significant changes from screening 
or the previous visit. 
Unscheduled local laboratory assessments may be performed if medically indicated to assess a 
(potential) adverse event or when the treating physician cannot wait for central laboratory 
results for decision making (e.g. therapeutic intervention, interruption of study treatment). In 
this particular situation, if possible, the blood sample obtained at the same time point should be 
submitted to the central laboratory for analysis in parallel with local analysis. The results of the 
local laboratory will be recorded in the eCRF if any of the following criteria are met: 
• Local lab results document an adverse event not reported by the central lab, or 
• Local lab results document an adverse event severity is worse than the one reported by the 
central lab, or 
• There are no concomitant central results available 
At any time during the study, abnormal laboratory parameters which are clinically 
relevant, whether specifically requested in the protocol or not, will be recorded on the AE eCRF 


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page. Laboratory data will be summarized using the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5 (Section 16.1). Additional analyses are left to the discretion of the 
investigator. 
Novartis must be provided with a copy of the local laboratory’s certification (if applicable), and 
a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study must 
be reported via an updated tabulation indicating the date of revalidation.  
The investigator is responsible for reviewing all laboratory reports for participants in the study 
and evaluating any abnormalities for clinical significance. 
Table 8-4 
Laboratory assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH),  Platelets, Red 
blood cells, White blood cells, Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands) 
Chemistry 
Albumin, Alkaline phosphatase, Alanine Aminotransferase (ALT) , Aspartate 
Aminotransferase (AST) , Gamma-glutamyl transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium,Phosphate (inorganic 
phosphorus), Chloride, Sodium, Potassium, Creatinine, Creatine kinase (CK), 
Direct Bilirubin, Total Bilirubin, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
Amylase, Lipase, Glucose (non-fasting) 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
If needed, Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, 
Crystals, Bacteria, Epithelial cells) 
PSA 
PSA 
 
Electrocardiogram (ECG) 
8.4.2.1 
All participants 
A standard 12 lead ECGs will be performed at screening and should be recorded after 10 
minutes rest in the supine position to ensure a stable baseline. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, while patient is at rest, 
followed by vital signs, and blood sampling. ECGs will be locally collected and evaluated. 
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate eCRF. Clinically significant findings must be discussed with Novartis prior to 
enrolling the participant in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded as adverse events. 
The original ECG appropriately signed must be collected and archived at the study site. If heat 
sensitive paper is used, a certified copy on non-heat sensitive paper must be also collected and 
archived at the study site. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate eCRF. Each ECG tracing should be labeled with the study number, participant 


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initials (where regulations permit), participant number, date and time, and kept in the source 
documents at the study site.  
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. 
8.4.2.2 
PK subset of participants 
For a subset of approximately 10 participants from the same site consenting for PK sample 
collection, additional ECGs will be done to collect cardiac safety data in a representative sample 
of patients at timepoints at which PK characteristics are known. ECGs will be recorded as 
below. 
Standard triplicate 12 lead ECG recording will be performed at Day 1 as described in the Table 
8-5. The individual ECGs should be recorded approximately 2 minutes apart. Interpretation of 
the tracing must be made by a qualified physician and documented on the appropriate 
eCRF together with specified parameters (PR, QRS, QT, QT interval corrected by Fridericia’s 
formula (QTcF), and RR intervals).The mean value of each parameter for each time point will 
be calculated from the triplicate ECGs for each participant. 
A standard 12 lead ECGs will be performed at Safety follow-up Day 15. 
Table 8-5 
ECG collection plan 
Treatment Period or 
Cycle 
Day 
Scheduled 
Time Point 
ECG type 
  
Screening 
  
12 Lead 
1 
1 
Pre-Injection 
12 Lead, triplicate 
1 
1 
30 min- 1h Post- 
injection  
12 Lead, triplicate 
1 
1 
3h - 5h Post- injection 
12 Lead, triplicate 
  
15 
  
12 Lead 
 
Pregnancy and contraception 
Contraception measures are not required. However, due to potential radiation 
exposure/contamination to partners, it is recommended that study patients refrain from sexual 
activity/intercourse for 12 hours following the administration of [18F]CTT1057. 
 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 


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Additional assessments 
 
Pharmacokinetics 
Pharmacokinetic (PK) samples (blood / urine) will be collected at the visits defined in the 
assessment schedule (Table 8-6 and Table 8-7) from a subset of approximately 10 participants 
from the same, singular site. 
The number of samples/blood draws and total blood volume collected will not exceed those 
stated in the protocol. 
Blood and urine samples will be counted at the investigational site in an accurately calibrated 
gamma-counter (e.g. NaI spectrometer) with a suitable reference source of 18F of known activity 
counted in the same geometry as that of the biological samples (e.g. 1 mL in a vial). 
Information related to the administration of [18F]CTT1057, including but not limited to the 
activity of the dose at the time administration, date and time of dosing, date and time of dose 
preparation and specific activity at time of dose preparation, must be recorded in the appropriate 
eCRF page. All samples will be counted locally at the site and the counts per minute (CPM) 
value will be recorded in the appropriate blood or urine eCRF pages. Well/gamma counter 
calibration records will be collected from the participating site prior to patient enrollment. 
Calibrations related information such as date of calibration, calibration factor and background 
count must be recorded in a dedicated eCRF. 
8.5.1.1 
Pharmacokinetic Blood collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. At specified time points described in Table 8-6, 1-1.2 mL blood draws will be 
collected into tubes containing an anticoagulant and gently inverted several times to thoroughly 
mix the anticoagulant. 1 mL of blood will be transferred into a vial for radioactivity 
measurement in the well/gamma-counter. 
All data including but not limited to actual date and time of blood sampling, date and time of 
measurement by well/gamma-counter, exact volume of sample measured (including any 
dilutions if applicable) and activity counted by well/gamma counter must be recorded in the 
appropriate blood collection eCRF page. 
Table 8-6 
Pharmacokinetic blood collection log (PK patient subset only) 
Dose Reference 
ID 
Treatment 
Period or 
Cycle 
Day 
Scheduled Time 
(post-
dose/injection) 
PK Sample No 
1 
1 
1 
Pre-dose (before 
injection) 
101 


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Dose Reference 
ID 
Treatment 
Period or 
Cycle 
Day 
Scheduled Time 
(post-
dose/injection) 
PK Sample No 
1 
1 
1 
0-5 min 
102 
1 
1 
1 
15 min (± 5 min) 
103 
1 
1 
1 
30 min (± 5 min) 
104 
1 
1 
1 
1 h (± 15 min) 
105 
1 
1 
1 
2 h (± 30 min) 
106 
1 
1 
1 
3-4 h 
107 
1 
1 
1 
5 h (± 30 min)* 
108 
* This sample is optional but clinical logistics permitting effort should be taken to collect this sample 


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9 
Study discontinuation and completion 
 
Discontinuation from study treatment and study  
 
Discontinuation from Study treatment  
This is a single injection study of an investigational imaging agent and therefore treatment 
discontinuation is not applicable.  
 
 
Discontinuation from study  
Discontinuation from study is when the participant permanently stops receiving the study 
treatment (e.g. declines to receive the single injection or cannot receive it for any reason), and 
further protocol-required assessments or follow-up, for any reason. If the participant agrees, a 


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final evaluation at the time of the participant’s study discontinuation should be made as detailed 
in the assessment table (refer to Section 8). 
 
Discontinuation from study is required  under the following circumstances: 
• Unacceptable patient condition as assessed by Investigator  
• Participant non-compliance or voluntary withdrawal from study 
• Required use of a prohibited treatment for participant safety reasons 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• At the sponsor's or investigator's discretion 
The investigator should make a reasonable effort to understand the primary reason for the 
participant’s  discontinuation of study and record this information in the source and 
corresponding eCRF pages. The investigator must also contact the IRT to register the 
participant’s end of treatment. 
Participants who discontinue from the study can agree to return for the end of treatment and 
follow-up visits and any efficacy assessments as indicated in the assessment schedule (Table 8-
1).  
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After study discontinuation, at a minimum, the following data should be collected at clinic visits 
or via telephone/email contact: 
• New / concomitant treatments 
• Adverse events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
 


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Withdrawal of informed consent/Opposition to use 
data/biological samples 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/opposition to use data/biological samples occurs when a 
participant: 
• 
Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) and 
• No longer wishes to receive study treatment (e.g. declines to receive the single injection) 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.  
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his consent and/or 
for his opposition to use data/biological samples and record this information. 
Where consent to the use of personal and coded data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their personal data. 
Study treatment must not be administered and no further assessments conducted, and the data 
that would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. If the 
participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition to use data/biological 
samples. 
 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination  


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• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as  a participant who discontinued from study treatment: that the safety follow-up period must 
be completed if applicable and which visits to be performed. The investigator may be informed 
of additional procedures to be followed in order to ensure that adequate consideration is given 
to the protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes the last visit for the study or, 
in the event of an early study termination decision, the date of that decision.  
All treated participants should have a safety follow-up conducted approximately 14 days (+3 
days) after the imaging visit, followed by an additional follow-up prior the final call Study 
completion (EOS). Please refer to Table 8-1 for the required assessments at these visits. 
10 
Safety monitoring and reporting 
 
Definition of adverse events and reporting requirements 
 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 


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1. The Common Toxicity Criteria (CTC) AE grade version 5.0. Grade 1 to 5 will be used to 
characterize the severity of the Adverse Event. (Section 16.1) Information about any 
deaths (related to an Adverse Event or not) will also be collected through a Death form. 
2. Its relationship to the study investigational imaging agent [18F]CTT1057. If the event is 
due to progression of underlying illness (i.e. exacerbation of pre-existing conditions) the 
assessment of causality will usually be ‘Not suspected.’ The rationale for this guidance is 
that the symptoms of progression of underlying illness are not caused by the trial drug, 
they happen in spite of its administration and progression of underlying disease can only 
be evaluated meaningfully by an analysis of cohorts, not on a single participant. 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding the study treatment. 
6. Its outcome. 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 14 days following the last dose of 
[18F]CTT1057. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms. 
• they are considered clinically significant. 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 


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Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH E2D (2004) Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study  and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH 
E2D (2004) Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse of the product are also considered serious adverse event 
irrespective if a clinical event has occurred.  


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SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 14 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, under no 
circumstances later than within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the eSAE eCRFs 
(with paper Serious Adverse Event Report Form back-up); all applicable sections of the 
eCRFs/form must be completed in order to provide a clinically thorough report. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety 
(CMO&PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 14-day period after the last dose of study treatment should only 
be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment. 
 
Pregnancy reporting 
Not applicable 
 
Reporting of study treatment errors including misuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition). 
Misuse refers to situations where the investigational product is intentionally and inappropriately 
used not in accordance with the protocol. 
Study product injection errors and uses outside of what is foreseen in the protocol will be 
reported irrespective of whether or not associated with an AE/SAE (please refer to Table 10-1 
for guidance on recording on the appropriate CRF) and reported to Safety only if associated 
with an SAE. Misuse will be collected and reported in the safety database irrespective of it 
being associated with an AE/SAE immediately, without undue delay, under no circumstances 
later than within 24 hours of Investigator’s awareness. 


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Table 10-1 
Guidance for capturing the study treatment errors including misuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse 
Yes 
Yes, even if not 
associated with an AE 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
 
Additional Safety Monitoring 
 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial and other experts. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulations (CFR) Part 11 requirements, Investigator site staff will not be 
given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.  
 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 


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investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, imaging, screen failures and study completion, and data about all study 
drug dispensed to the participant will be tracked using an Interactive Response Technology 
(IRT). The system will be supplied by Novartis, who will also manage the database. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after the lock, can only 
be made after written agreement by Novartis development management. 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Primary efficacy and safety analyses will be conducted at the time of final analysis on the 
final locked clinical database, for the efficacy analysis set (EFF) and safety set (SAF) 
respectively. Cut-off for the final analysis will be the last visit for last subject in the study. 


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Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
 
Analysis sets 
The Full Analysis Set (FAS) includes all enrolled participants. 
The Efficacy Analysis Set (EFF) includes all enrolled participants who receive study drug, and 
have both an evaluable PET/CT scan and histopathology assessment and have not received any 
prohibited systemic antineoplastic therapy before the completion of PET/CT and surgery. 
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one 
evaluable PK concentration. A profile is considered evaluable if all of the following conditions 
are satisfied: patient receives the investigational treatment (i.e. [18F]CTT1057) and provides at 
least on primary PK parameter. The PAS will be used for all PK analyses. 
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. Specific time points might be 
removed from the analysis set if technical issues with sample are reported (e.g. sampling issues, 
missing information) or if Lower Limit of Quantification (LLOQ) sample is observed between 
measurable concentrations. These patients and concentration data points will be identified at 
the time of analysis. 
The Safety Set (SAF) includes all participants who received the investigational treatment (i.e. 
[18F]CTT1057). 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all participants for the FAS and EFF. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized  by 
system organ class and preferred term for the FAS and EFF. 
Treatments 
Actual received [18F]CTT1057 dose and time interval from injection to [18F]CTT1057 PET/CT 
scan acquisition start will be summarized by means of descriptive statistics using the SAF. 
Categorical data will be summarized as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for the FAS. 


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Analysis of the primary endpoint(s)/estimand(s) 
The primary objective of the study is described in Table 2-1. Efficacy analysis will use the EFF. 
 
Definition of primary endpoint(s)/estimand(s) 
The co-primary endpoints of the study are patient-level sensitivity and region-level specificity. 
•
Patient-level sensitivity is defined as the proportion of PSMA TP patients among PSMA
TP patients and PSMA FN patients.
•
PSMA TP patients are those who show at least one pathological [18F]CTT1057 uptake
either in the primary tumor and/or metastatic PLNs with anatomically localized
correspondence with the SoT.
•
PSMA FN patients are those who do not show any pathological [18F]CTT1057 uptake
either in the primary tumor or metastatic PLNs but will be confirmed having primary
tumor or metastatic PLNs with the SoT.
•
Region-level specificity is defined as the proportion of PSMA TN PLN regions among
PSMA TN PLN regions and PSMA FP PLN regions.
•
PSMA TN PLN regions are regions that test negative for PLN on [18F]CTT1057 and
confirmed negative on the SoT.
•
PSMA FP PLN regions are regions that test positive for PLN on [18F]CTT1057 but
verified negative on the SoT.
 
Statistical model, hypothesis, and method of analysis 
To address the co-primary efficacy objectives: 
Patient-level sensitivity and its 95% CI will be calculated based on the binomial distribution. 
The lower bound of the 95% CI for patient-level sensitivity should be greater than 0.5 to attain 
the first co-primary endpoint. 
Region-level specificity and its 95% CI will be calculated based on the binomial distribution. 
The lower bound of the 95% CI for specificity should be greater than 0.70 for the study to attain 
the second co-primary endpoint. 
 
Handling of remaining intercurrent events of primary estimand 
The primary analysis will account for intercurrent events as explained in the following: 
•
Patients receive the investigational imaging agent [18F]CTT1057 but do not
undergo/complete the  [18F]CTT1057 PET/CT scan for any reasons (e.g. drop out, PET
camera failures, etc): they will not be used for the primary endpoint analysis, but safety
data will be collected after the administration of the investigational imaging agent.
Handling of missing values not related to intercurrent event 
This is a diagnostic study, primary endpoint is calculated on the basis of one-time imaging 
assessment, missing data not related to intercurrent events will not be imputed. 


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Sensitivity analyses for primary endpoint/estimand 
Not applicable 
Supplementary analysis 
As supplementary analyses performed in the EFF, the 95% CI for patient-level sensitivity and 
region-level specificity will be obtained from covariate adjusted logistic regression model. 
Important covariates will be specified in the Statistical Analysis Plan (SAP).  
If the primary endpoints of patient-level sensitivity and region-level specificity are met, other 
subgroup analyses to assess the homogeneity of the treatment effect across demographic and 
baseline disease characteristics will be performed. Other subgroups will be specified in the 
SAP. Further supplementary analyses will be specified in the SAP.  
Analysis of secondary endpoints/estimands 
The secondary objectives are described in Table 2-1. 
Efficacy endpoint(s) 
Patient-level specificity is defined as the proportion of TN patients among those who are TN 
or FP. 
Patient-level positive predictive value is defined as the proportion of TP patients among those 
who are TP or FP.  
Patient-level negative predictive value is defined as the proportion of TN patients among 
those who are TN or FN.   
Patient-level accuracy is defined as the proportion of TP and TN patients among all patients 
in EFF (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN patients are defined as follows: 
•
PSMA TP patients are those who show at least one pathological [18F]CTT1057 uptake
either in the primary tumor and/or metastatic PLNs with anatomically localized
correspondence with the SoT.
•
PSMA TN patients are those who do not show any pathological [18F]CTT1057 uptake
neither in the primary tumor nor metastatic PLNs and will be confirmed
NOT having primary tumor nor metastatic PLNs with the SoT.
•
PSMA FP patients are those who show at least one pathological [18F]CTT1057 uptake
either in the primary tumor and/or metastatic PLNs but will be verified NOT
having primary tumor nor metastatic PLNs with the SoT or none of the lesions is correctly
localized in anatomical location by the SoT.
•
PSMA FN patients are those who do not show any pathological [18F]CTT1057 uptake
neither in the primary tumor nor metastatic PLNs but will be confirmed having primary
tumor or metastatic PLNs with the SoT.
Number of TP, TN, FP, FN patients will be presented and used to calculate the diagnostic 
performance parameters.  


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95% CI for diagnostic performance parameters will be calculated based on the binomial 
distribution. 
[18F]CTT1057 scan inter-reader variability is defined as agreement rate among reader 
determinations and will be assessed by Fleiss' Kappa statistic. Further details will be specified 
in the SAP.  
[18F]CTT1057 scan intra-reader variability is defined as within-reader agreement rate and 
will be assessed by Cohen's Kappa statistic. Further details will be specified in the SAP. 
Detection number of distant metastasis is defined as number of distant metastasis (extra-
PLN, visceral or skeletal) identified at PET scan for each patient in all patients with an evaluable 
[18F]CTT1057 PET/CT scan. 
Detection rate of distant metastasis is defined as percentage of patients with at least one 
distant metastatic lesion (extra-PLN, visceral or skeletal)identified by PET scan in all patients 
with an evaluable [18F]CTT1057 PET/CT scan. 
Region-level sensitivity is defined as the proportion of TP PLN regions among those that are 
TP or FN. 
Region-level-sensitivity excluding from the analysis those PLN showing metastasis <2mm 
(micro-metastasis).  
Region-level positive predictive value is defined as the proportion of TP PLN regions among 
those that are TP or FP. 
Region-level negative predictive value is defined as the proportion of TN PLN regions among 
those that are TN or FN. 
Region-level accuracy is defined as the proportion of TP and TN PLN regions among those 
that are identified on [18F]CTT1057 (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN PLN regions are defined as follows: 
• PSMA TP regions are regions that test positive for PLN on [18F]CTT1057 and confirmed 
positive on the SoT  
• PSMA TN regions are regions that test negative for PLN on [18F]CTT1057 and confirmed 
negative on the SoT  
• PSMA FP regions are regions that test positive for PLN on [18F]CTT1057 but verified 
negative on the SoT 
• PSMA FN regions are regions that test negative for PLN on [18F]CTT1057 but verified 
positive on the SoT 
Number of TP, TN, FP, FN regions will be presented and used to calculate the diagnostic 
performance parameters.  
95% CI for diagnostic performance parameters will be calculated based on the binomial 
distribution. 
 
Safety endpoints 
For all safety analyses, the SAF will be used. 


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Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day and time 
before dosing of study medication. 
2. On-treatment period: from day of dosing of study medication to 14 days after dosing of 
study medication. 
3. Post-treatment period: starting 15 days after dosing of study medication. 
Adverse events 
All information obtained on adverse events will be displayed by participant. 
The number (and percentage) of participants with TEAE (events started after the first dose of 
study medication or events present prior to start of study treatment but increased in severity 
based on preferred term) will be summarized in the following ways: 
• primary system organ class and preferred term. 
• primary system organ class, preferred term and maximum severity. 
• Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, i.e. the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events during the on-treatment period will be 
tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
Vital signs 
All vital signs data will be listed by participant, and visit/time and clinically notable values 
or changes in vital signs  will be flagged. Summary statistics will be provided by visit/time. 


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12-lead ECG
For all participants:
The ECG result at screening will be summarized as number (%) of subjects with normal or 
abnormal (clinically significant) ECG and will be provided as listing.  
In addition for the 10 PK subset participants: 
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each
participant during the study on treatment day (Day 1) at pre-injection, post-injection/pre-
imaging, and post-imaging and at Safety follow-up Day 15. ECG data will be read and
interpreted (locally).
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from
baseline will be presented. In addition, a listing of these participants will be produced.
Clinical laboratory evaluations 
All laboratory data will be listed by participant, and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
•
Listing of all laboratory data with values flagged to show the corresponding CTCAE
version 5.0 grades if applicable and the classifications relative to the laboratory normal
ranges
For laboratory tests where grades are defined by CTCAE version 5.0: 
•
Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant
will be counted only once for the worst grade observed post-baseline.
•
Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-
treatment value
For laboratory tests where grades are not defined by CTCAE version 5.0: 
•
Shift tables using the low/normal/high/ (low and high) classification to compare baseline
to the worst on-treatment value.


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In addition to the above mentioned tables and listings, other 
, for example, 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan. 
 
Pharmacokinetics 
For all PK analyses, the PAS will be used. 
The [18F]CTT1057 pharmacokinetic analysis will be performed based on decay-corrected blood 
radioactivity concentration data converted to mass unit, obtained by measuring the blood 
samples drawn at pre-defined time points (Table 8-6) using a calibrated gamma-counting 
device. 
Blood radioactivity concentration and blood mass concentration data will be listed by patient 
and visit/sampling time point. Pharmacokinetic parameters will be listed by patient. Descriptive 
summary statistics will be provided by visit/sampling time point. Summary statistics will 
include mean (arithmetic and geometric), standard deviation (SD), coefficient of variation (CV) 
(arithmetic and geometric), median, minimum, and maximum. An exception to this is Tmax 
where only median, minimum, and maximum will be presented. 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin® (Version 8 or 
higher): Cmax, Tmax, AUClast, AUCinf, T1/2, Vz and CL (Table 12-1). 
Table 12-1 
Non-compartmental pharmacokinetic parameters 
AUC%Extrap1 
Area under the plasma concentration-time curve extrapolated from the time t to 
infinity as a percentage of total AUC (%) 
AUClast 
The AUC from time zero to the last measurable concentration sampling time 
(tlast) (mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
Clast2 
Last measurable concentration (mass x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi 
logarithmic concentration-time curve (time) 
Tlast2 
Last measurable concentration sampling (time) 
Rsqadj1 
Square of the correlation coefficient associated with lambda_z 
CL 
The total body clearance (CL) of drug from plasma, blood serum, or other body 
fluid drug concentration (volume x time-1) 
Vz 
The apparent volume of distribution during terminal phase (associated with λz) 
(volume) 
1 AUC%Extrap and Rsqadj will be used in the interpretation of the primary PK parameters and 
therefore will be included in the listings only.  
2 Clast and Tlast will only be listed but not summarized 
The elimination of the compound in urine will be evaluated based on decay-corrected urine 
radioactivity concentration data obtained by measuring the blood samples drawn a pre-defined 


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time points (Table 8-7) using a calibrated gamma-counting device. Urine elimination data will 
be expressed as percentage of injected activity (%ID) in each specified time interval and also 
as cumulative %ID excreted up to the end of each time interval. Urine elimination data will be 
listed by patients. Descriptive summary statistics will include mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum, and maximum. 
 
Interim analyses 
Not applicable. 
 
Sample size calculation 
The sample size calculation is based on the co-primary endpoints patient-level sensibility and 
region-level specificity. 
Overall, a total study sample size of approximately 195 participants will be enrolled in order to 
get at least 156 evaluable participants for co-primary endpoints (i.e. have both an evaluable 
PET/CT scan and histopathology assessment and have not received any prohibited systemic 
antineoplastic therapy before the completion of PET/CT and surgery). These calculations were 
made using the software PASS 11 and R 3.6.1. 
 
Primary endpoint(s) 
This study is planned to recruit approximately 195 patients. The primary objective is to evaluate 
the patient-level sensitivity of [18F]CTT1057 (evaluated for all patients including primary 
tumors and PLN) and the region-level specificity of [18F]CTT1057 (evaluated only for PLN 
regions). The sample size calculation is based on the co-primary endpoints of patient-level 
sensitivity and region-level specificity of [18F]CTT1057. 
The rationale for the choice of the co-primary endpoints is provided below: 


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In PS patients before surgery, both the primary tumor and the metastatic PLN are expressing 
PSMA, which is the target for [18F]CTT1057 binding. After surgery, pathology of both the 
primary tumor and the dissected pelvic LN will be used as a SoT. A patient-level analysis would 
allow to identify positive lesions in both regions. A region-level analysis for sensitivity is not 
considered appropriate for the primary endpoint as 156 positive PLN would be needed in order 
to determine sensitivity with a power of 90% on a regional level. Given the low prevalence and 
high variability of metastatic lymph nodes in the PS population (from 4-58%) 
(Petersen and Zacho 2020), approximately 520 patients would have to be injected with the 
radioactive investigational PET tracer to yield the 156 positive PLN. In order to limit the 
number of participants exposed to radiation for this purpose and given that both the primary 
tumor and affected PLN are [18F]CTT1057 targets, sensitivity is proposed to be analyzed on 
patient level. Region-level sensitivity is included as a secondary endpoint. On the other hand, 
specificity can be assessed on the regional level (at the PLN region) since enough number of 
negative PLN are expected to be obtained at pathology. 
The assumptions for sample size calculations are based on estimates available from prior studies 
as described below. 
A large variability in sensitivity of PSMA-PET in the primary staging setting has been reported. 
Two recent systematic reviews of [68Ga]PSMA PET /CT diagnostic accuracy focused on the 
PS population using pathology as SoT, sensitivity of 33–99% across studies has been reported 
(Corfield et al 2018), as well as pooled sensitivity and specificity ranges of 23-100% and 67-
100% respectively (Petersen and Zacho 2020). Recent preliminary data on the diagnostic 
efficacy of F-18-rhPSMA-7.3 PET imaging in PS patients compared to histopathology (n=56) 
reported a 95% CI low bound patient level sensitivity of 54.4% (81.3 (95% CI-54.4-96.0) 
(Maurer et al 2020). CT and MRI are the standard of care imaging procedures for measuring 
tumors at baseline and lesions selected for response assessment as per RECIST criteria 1.1 
(Eisenhauer et al 2009). A meta-analysis on the diagnostic accuracy of CT and MRI in the 
staging of pelvic lymph nodes in patients with PCa reported a pooled sensitivity of 0.42 (95% 
CI 0.26-0.56) for CT, and of 0.39 (95% CI 0.22-0.56) for MRI (Hövels et al 2008). A study 
evaluating the diagnostic value of [68Ga]PSMA PET versus CT and MRI for lymph node staging 
in 130 consecutive patients who got RP and PLN dissection after PET/Magnetic Resonance 
(MR) (n=95) and PET/CT (n=35) and who had tumor specimens available for reanalysis to 
correlate with PET reported a sensitivity of 43.9% (95% CI 28.5-60.3) and 85.4% specificity 
(95% CI 76.3-92.0) for morphological imaging alone (CT and MRI) (Maurer et al 2016).   
Taking all the above into consideration, an overall patient-level sensitivity of 50% and a region 
level specificity of 70% will be considered as unacceptably low. Hence, the sample size 
calculation will be performed based on the null and alternative hypotheses as follows.  
• Patient-level sensitivity  
For patient-level sensitivity, the null hypothesis H0: patient-level sensitivity p0 = 0.50 will be 
tested against the alternative hypothesis H1: p1>0.50, assuming a sensitivity of 0.63 under the 
alternative hypothesis, approximately 156 patients with primary tumor and/or metastatic lymph 
nodes would achieve 90% statistical power to detect a change in sensitivity of 0.13 using a one-
sided binomial test at a target significance level of 2.5%.  Taking into account 20% dropout 
rate, 195 patients can ensure the 90% statistical power. 


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• Region-level specificity 
For region-level specificity, the null hypothesis H0: region-level specificity p0 = 0.70 will be 
tested against the alternative hypothesis H1: p1 > 0.70. Assuming a specificity of 0.85 under 
the alternative hypothesis, approximately 123 patients (which includes 37 patients with PLN 
based on 30% prevalence) would achieve 90% statistical power to detect a change in specificity 
of 0.15 using a one-sided binomial test at a target significance level of 2.5 %. Taking into 
account 20% dropout rate, 154 patients can ensure the 90% statistical power. The lower bounds 
of the 95% CI for specificity should be greater than 0.70 to be considered success. 
The lower bound of the 95% CI for sensitivity should be greater than 0.50 and the lower bound 
of the 95% CI for specificity should be greater than 0.70 for the study to be considered a success. 
A total sample size of 195 patients can ensure 90% statistical power for patient-level sensitivity 
and 99% statistical power for region-level specificity resulting in an overall study statistical 
power of at least 89.1% (0.9 x 0.99). 
13 
Ethical considerations and administrative procedures 
 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis  processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 


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be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
[68Ga]Ga-PSMA-11 U.S Prescribing Information (USPI) FDA (Internet) Available from: 
accessdata.fda.gov/drugsatfda_docs/label/2020/212642s000lbl.pdf (Accessed December 
2020). 
Afshar-Oromieh A, Avtzi E, Giesel FL, et al (2015) The diagnostic value of PET/CT imaging 
with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate 
cancer. Eur. J. Nucl. Med. Mol. Imaging; 42:197-209. 
Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al (2017) Diagnostic performance of 68Ga-
PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 
patients. Eur J Nucl Med Mol Imaging; 44:1258-68. 
Afshar-Oromieh A, Malcher A, Eder M, et al (2013) PET imaging with a [68Ga]gallium-
labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first 
evaluation of tumour lesions. Eur J Nucl Med Mol Imaging; 40:486-95. 
Afshar-Oromieh A, Zechmann CM, Malcher A, et al (2014) Comparison of PET imaging with 
a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of 
recurrent prostate cancer. Eur J Nucl Med Mol Imaging; 41:11-20. 
Behr S, Aggarwal R, Flavell R, et al (2017) Comparison of a novel fluorine-18 labeled 
PSMA-targeting agent, CTT1057, to gallium-68 PSMA-11 in patients with prostate cancer 
[abstract]. J Nucl Med; 58 Suppl 1:733A. 
Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18F-
Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane 
Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6. 
Berliner C, Tienken M, Frenzel T, et al (2017) Detection rate of PET/CT in patients with 
biochemical relapse of prostate cancer using [68Ga]PSMA I&T and comparison with 
published data of [68Ga]PSMA HBED-CC. Eur J Nucl Med Mol Imaging; 44:670-7. 
Blomqvist L, Carlsson S, Gjertsson P, et al (2014) Limited evidence for the use of imaging to 
detect prostate cancer: a systematic review. Eur J Radiol; 83:1601-6. 
Boellaard R, Delgado-Bolton R, Oyen WJG, et al (2015) FDG PET/CT: EANM procedure 
guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging; 42:328-54. 
Bostwick DG, Pacelli A, Blute M, et al (1998) Prostate specific membrane antigen expression 
in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer; 
82(11):2256-61. 
Bravaccini S, Puccetti M, Bocchini M, et al (2018) PSMA expression: a potential ally for the 
pathologist in prostate cancer diagnosis. Sci Rep; 8:4254. 
Bray F, Ren JS, Masuyer E, et al (2013) Global estimates of cancer prevalence for 27 sites in 
the adult population in 2008. Int J Cancer; 132:1133-45. 


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Budäus L, Leyh-Bannurah SR, Salomon G, et al (2016) Initial Experience of (68)Ga-PSMA 
PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur 
Urol; 69:393-6. 
Ceci F, Uprimny C, Nilica B, et al (2015) (68)Ga-PSMA PET/CT for restaging recurrent 
prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med 
Mol Imaging; 42:1284-94. 
Conti M, Eriksson L (2016) Physics of pure and non-pure positron emitters for PET: a review 
and a discussion. EJNMMI Physics; 3(1):1-17. 
Corfield J, Perera M, Bolton D, et al (2018) 68Ga-prostate specific membrane antigen 
(PSMA) positron emission tomography (PET) for primary staging of high-risk prostate 
cancer: a systematic review. World J Urol; 36:519-27. 
D'Amico AV, Whittington R, Malkowicz SB, et al (1998) Biochemical outcome after radical 
prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically 
localized prostate cancer. JAMA; 280(11):969-74. 
Delbeke D, Coleman RE, Guiberteau MJ, et al (2006) Procedure guideline for tumor imaging 
with 18F-FDG PET/CT 1.0. J Nucl Med; 47(5):885-95. 
Derlin T, Schmuck S, Juhl C, et al (2018) PSA-stratified detection rates for [68Ga]THP-
PSMA, a novel probe for rapid kit-based 68Ga-labeling and PET imaging, in patients with 
biochemical recurrence after primary therapy for prostate cancer. Eur J Nucl Med Mol 
Imaging; 45:913-22. 
Eiber M, Maurer T, Souvatzoglou M, et al (2015) Evaluation of Hybrid ⁶⁸Ga-PSMA Ligand 
PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl 
Med; 56(5):668-74. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45:228-47. 
Fendler WP, Calais J, Eiber M, et al (2019) Assessment of 68Ga-PSMA-11 PET Accuracy in 
Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA 
Oncol; 5(6):856-63. 
Ghosh A, Heston WDW (2004) Tumor target prostate specific membrane antigen (PSMA) 
and its regulation in prostate cancer. J Cell Biochem; 91:528-39. 
Grubmüller B, Baltzer P, D'Andrea D, et al (2018) 68Ga-PSMA 11 ligand PET imaging in 
patients with biochemical recurrence after radical prostatectomy - diagnostic performance and 
impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging; 45:235-42. 
Gupta SK, Watson T, Denham J, et al (2017) Prostate-Specific Membrane Antigen Positron 
Emission Tomography-Computed Tomography for Prostate Cancer: Distribution of Disease 
and Implications for Radiation Therapy Planning. Int J Radiat Oncol Biol Phys; 99(3):701-9. 
Haffner MC, Kronberger IE, Ross JS, et al (2009) Prostate-specific membrane antigen 
expression in the neovasculature of gastric and colorectal cancers. Hum Pathol; 40:1754-61. 


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Han S, Woo S, Kim YJ, et al (2018) Impact of 68Ga-PSMA PET on the Management of 
Patients with Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol; 74:179-90. 
Hope TA, Aggarwal R, Chee B, et al (2017) Impact of 68Ga-PSMA-11 PET on Management 
in Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med; 58(12):1956-61. 
Hricak H, Dooms GC, Jeffrey RB, et al (1987) Prostatic carcinoma: staging by clinical 
assessment, CT, and MR imaging. Radiology; 162:331-6. 
Hupe MC, Philippi C, Roth D, et al (2018) Expression of Prostate-Specific Membrane 
Antigen (PSMA) on Biopsies Is an Independent Risk Stratifier of Prostate Cancer Patients at 
Time of Initial Diagnosis. Front Oncol; 8:623. 
Hövels AM, Heesakkers RAM, Adang EM, et al (2008) The diagnostic accuracy of CT and 
MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. 
Clin Radiol; 63:387-95. 
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting (Internet) Available from: 
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002807.p
df (Accessed 15 January 2021) 
Jani AB (2006) Management strategies for locally advanced prostate cancer. Drugs Aging; 
23(2):119-29. 
Kaushik A, Jaimini A, Tripathi M, et al (2015) Estimation of radiation dose to patients from 
(18) FDG whole body PET/CT investigations using dynamic PET scan protocol. Indian J Med 
Res; 142:721-31. 
Kranzbühler B, Nagel H, Becker AS, et al (2018) Clinical performance of 68Ga-PSMA-11 
PET/MRI for the detection of recurrent prostate cancer following radical prostatectomy. Eur J 
Nucl Med Mol Imaging; 45:20-30. 
Kuten J, Fahoum I, Savin Z, et al (2020) Head-to-Head Comparison of 68Ga-PSMA-11 with 
18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and 
Immunohistochemical Analysis as a Reference Standard. J Nucl Med; 61(4):527-32. 
Lengana T, van de Wiele C, Lawal I, et al (2018) 68Ga-PSMA-HBED-CC PET/CT imaging in 
Black versus White South African patients with prostate carcinoma presenting with a low 
volume, androgen-dependent biochemical recurrence: a prospective study. Nucl Med 
Commun; 39(2):179-85. 
Malvezzi M, Carioli G, Bertuccio P, et al (2019) European cancer mortality predictions for 
the year 2019 with focus on breast cancer. Ann Oncol; 30(5):781-7. 
Mannweiler S, Amersdorfer P, Trajanoski S, et al (2009) Heterogeneity of prostate-specific 
membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol. 
Oncol. Res.; 15:167-72. 
Maurer T, Gschwend JE, Rauscher I, et al (2016) Diagnostic Efficacy of (68)Gallium-PSMA 
Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging 


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of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol; 
195:1436-43. 
Maurer T, Langbein T, Kroenke M, et al (2020) Diagnostic efficacy of 18F-RHPSMA-7.3 
imaging for n-staging patients with high-risk prostate cancer [abstract]. J Urol; 203 Suppl 
4:e952A 
Meredith G, Wong D, Yaxley J, et al (2016) The use of 68 Ga-PSMA PET CT in men with 
biochemical recurrence after definitive treatment of acinar prostate cancer. BJU Int; 118 Suppl 
3:49-55. 
Morigi JJ, Stricker PD, van Leeuwen PJ, et al (2015) Prospective Comparison of 18F-
Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have 
Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J 
Nucl Med; 56(8):1185-90. 
Nanni C, Zanoni L, Pultrone C, et al (2016) (18)F-FACBC (anti1-amino-3-(18)F-
fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: 
results of a prospective trial. Eur J Nucl Med Mol Imaging; 43:1601-10. 
Odewole OA, Tade FI, Nieh PT, et al (2016) Recurrent prostate cancer detection with anti-3-
[(18)F]FACBC PET/CT: comparison with CT. Eur J Nucl Med Mol Imaging; 43:1773-83. 
Perera M, Papa N, Christidis D, et al (2016) Sensitivity, Specificity, and Predictors of Positive 
68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced 
Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol; 70:926-37. 
Petersen LJ, Zacho HD (2020) PSMA PET for primary lymph node staging of intermediate 
and high-risk prostate cancer: an expedited systematic review. Cancer Imaging; 20:10 
Prasad V, Steffen IG, Diederichs G, et al (2016) Biodistribution of [(68)Ga]PSMA-HBED-CC 
in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour 
Lesions. Mol Imaging Biol; 18:428-36. 
Rauscher I, Düwel C, Haller B, et al (2018) Efficacy, Predictive Factors, and Prediction 
Nomograms for 68Ga-labeled Prostate-specific Membrane Antigen-ligand Positron-emission 
Tomography/Computed Tomography in Early Biochemical Recurrent Prostate Cancer After 
Radical Prostatectomy. Eur Urol; 73:656-61. 
Roscigno M, Sangalli M, Mazzoccoli B, et al (2005) Medical therapy of prostate cancer. A 
review. Minerva Urol Nefrol; 57(2):71-84. 
Ross JS, Sheehan CE, Fisher HAG, et al (2003) Correlation of primary tumor prostate-
specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer 
Res; 9:6357-62. 
Sachpekidis C, Eder M, Kopka K, et al (2016) (68)Ga-PSMA-11 dynamic PET/CT imaging in 
biochemical relapse of prostate cancer. Eur J Nucl Med Mol Imaging; 43:1288-99. 
Sanli Y, Kuyumcu S, Sanli O, et al (2017) Relationships between serum PSA levels, Gleason 
scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer. Ann 
Nucl Med; 31:709-17. 


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Page 78 of 83 
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Scheidler J, Hricak H, Vigneron DB, et al (1999) Prostate cancer: localization with three-
dimensional proton MR spectroscopic imaging--clinicopathologic study. Radiology; 
213(2):473-80. 
Schmidt LH, Heitkötter B, Schulze AB, et al (2017) Prostate specific membrane antigen 
(PSMA) expression in non-small cell lung cancer. PLoS ONE; 12(10):e0186280. 
Schmuck S, Nordlohne S, von Klot CA, et al (2017) Comparison of standard and delayed 
imaging to improve the detection rate of [68Ga]PSMA I&T PET/CT in patients with 
biochemical recurrence or prostate-specific antigen persistence after primary therapy for 
prostate cancer. Eur J Nucl Med Mol Imaging; 44:960-8. 
Schwarzenböck S, Souvatzoglou M, Krause BJ (2012) Choline PET and PET/CT in Primary 
Diagnosis and Staging of Prostate Cancer. Theranostics; 2(3):318-30. 
Shinohara K, Wheeler TM, Scardino PT (1989) The appearance of prostate cancer on 
transrectal ultrasonography: correlation of imaging and pathological examinations. J Urol; 
142:76-82. 
Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin; 67(1):7-30. 
Siegel RL, Miller KD, Jemal A (2018) Cancer Statistics, 2018. CA Cancer J Clin; 68(1):7-30. 
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin; 69(1):7-34. 
Smith RA, Andrews K, Brooks D, et al (2016) Cancer screening in the United States, 2016: A 
review of current American Cancer Society guidelines and current issues in cancer screening. 
CA Cancer J Clin; 66(2):95-114. 
Spatz S, Tolkach Y, Jung K, et al (2018) Comprehensive Evaluation of Prostate Specific 
Membrane Antigen Expression in the Vasculature of Renal Tumors: Implications for Imaging 
Studies and Prognostic Role. J Urol; 199:370-7. 
Stock K, Steinestel K, Wiesch R, et al (2017) Neovascular Prostate-Specific Membrane 
Antigen Expression Is Associated with Improved Overall Survival under Palliative 
Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma. Biomed Res Int; 2847303. 
Tanjore Ramanathan J, Lehtipuro S, Sihto H, et al (2020) Prostate-specific membrane antigen 
expression in the vasculature of primary lung carcinomas associates with faster metastatic 
dissemination to the brain. J Cell Mol Med; 24:6916-27. 
Tolkach Y, Gevensleben H, Bundschuh R, et al (2018) Prostate-specific membrane antigen in 
breast cancer: a comprehensive evaluation of expression and a case report of radionuclide 
therapy. Breast Cancer Res Treat; 169:447-55. 
Tolkach Y, Goltz D, Kremer A, et al (2019) Prostate-specific membrane antigen expression in 
hepatocellular carcinoma: potential use for prognosis and diagnostic imaging. Oncotarget; 
10(41):4149-60. 
Von Eyben FE, Picchio M, von Eyben R, et al (2018) 68Ga-Labeled Prostate-specific 
Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography for 
Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus; 4:686-93. 


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Wang HL, Wang SS, Song WH, et al (2015) Expression of prostate-specific membrane 
antigen in lung cancer cells and tumor neovasculature endothelial cells and its clinical 
significance. PLoS ONE; 10(5):e0125924. 
Wernicke AG, Edgar MA, Lavi E, et al (2011) Prostate-specific membrane antigen as a 
potential novel vascular target for treatment of glioblastoma multiforme. Arch Pathol Lab 
Med; 135:1486-9. 
Wernicke AG, Kim S, Liu H, et al (2017) Prostate-specific Membrane Antigen (PSMA) 
Expression in the Neovasculature of Gynecologic Malignancies: Implications for PSMA-
targeted Therapy. Appl Immunohistochem Mol Morphol; 25(4):271-6. 
Woythal N, Arsenic R, Kempkensteffen C, et al (2018) Immunohistochemical Validation of 
PSMA Expression Measured by 68Ga-PSMA PET/CT in Primary Prostate Cancer. J Nucl 
Med; 59(2):238-43. 
Yaxley JW, Dagher J, Delahunt B, et al (2018) Reconsidering the role of pelvic lymph node 
dissection with radical prostatectomy for prostate cancer in an era of improving radiological 
staging techniques. World J Urol; 36:15-20. 
Yaxley JW, Raveenthiran S, Nouhaud FX, et al (2019a) Risk of metastatic disease on 
68gallium-prostate-specific membrane antigen positron emission tomography/computed 
tomography scan for primary staging of 1253 men at the diagnosis of prostate cancer. BJU 
Int; 124:401-7. 
Yaxley JW, Raveenthiran S, Nouhaud FX, et al (2019b) Outcomes of Primary Lymph Node 
Staging of Intermediate and High Risk Prostate Cancer with 68Ga-PSMA Positron Emission 
Tomography/Computerized Tomography Compared to Histological Correlation of Pelvic 
Lymph Node Pathology. J Urol; 201:815-20. 


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16 
Appendices 
 
Appendix 1: Common Terminology Criteria for Adverse Events 
The complete NCI CTCAE (version 5.0) can be found at the following site: 
[ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refe
rence_8.5x11.pdf]  


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Appendix 2: European Association of Urology Guidelines of 
Prostate cancer 
The latest EAU Guidelines for Prostate cancer can be found at the following site: 
uroweb.org/guideline/prostate-cancer/ 
Refer to Section 6.1.2.3.2 for the pelvic lymph node dissection guidelines. 


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Appendix 3: Anatomic template specification for histopathology 
assessment 
For the anatomical localization for prostate, a sextant anatomic template will be used (Kuten 
et al 2020).  
For the PLN, an anatomical side approach left/right will be used, since the borders of 
dissection are not usually very clear neither for the surgeon nor for the pathologist.  


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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Document type: 
SAP Documentation 
Document status: 
Final  
Release date: 
26-Dec-2023 
Number of pages: 
43 
Property of Novartis 
Confidential  
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 
 
Clinical Development
AAA405
         Clinical Trial Protocol CAAA405A12302 / NCT04838626
 
 
Phase II/III study for evaluation of the diagnostic performance of 
[18F]CTT1057 PET imaging for the detection of PSMA positive tumors
 
 
using histopathology as a
 
standard of truth (GuideView)
Statistical Analysis Plan (SAP)


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
12-
Oct -
2021 
Prior to DB 
lock 
Creation of 
final version 
N/A - First version 
NA 
30-
Sep-
2022 
After 
PA01, 
before 
original 
IND 
submission 
Incorporating 
changes 
made in the 
protocol 
amendment 
v01. 
1. Updated surgery timing to ensure that 
surgery will be performed up to 6 weeks 
after but not sooner than 48 hours after 
the completion of the [18F]CTT1057 
PET/CT scan. 
2. 
Updated 
safety 
follow-up 
visit 
assessments timing to ensure all patients 
will go through at least a 2-day period to 
check their safety after PET scan without 
being confounded by the effects of 
surgery. 
3. Aligned between objectives and 
endpoints wording, e.g. “evaluated for all 
regions” removed. 
4. Removed that incidence of AEs will be 
described after PET tracer injection, after 
PET/CT scans and at 24-72 h after 
PET/CT scan. 
5. Updated the definition of efficacy 
analysis set about patients who will be 
evaluable for co-primary endpoints. 
6. Alignment with the protocol added 
regarding the definition of overall study 
positivity. 
7. Clarification added to the definition of 
TP and FP patients. 
8. 
Clarification 
added 
regarding 
a 
secondary objective of detection of distant 
metastasis in PS patients that distant 
metastatic lesions for prostate cancer are 
defined in clinical practice as metastasis 
in extra-PLN or visceral or skeletal 
location. It was also clarified in the 
definition of this endpoint that it will be 
assessed in all patients with an evaluable 
[18F]CTT1057 PET/CT scan. 
9. 
Removed 
the 
sentence 
about 
aggregating results among readers for the 
intra-reader variability calculation. 
10. Added 3-day time window for post-
baseline lab and vital sign assessments.  
11.
 
Section 1.1, 1.2, 
2.1.1, 2.2, 2.3.1, 
2.4.2, 2.5.1, 
2.5.2, 2.6, 2.7.1, 
2.8.1, 2.8.3, 
2.8.4, 3 and 
Section 5.  


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
12. 
Minor 
typographical 
corrections, 
removal of duplicated wording and minor 
rewording 
implemented 
across 
the 
document. 
12-
Dec-
2023 
After dry 
run review, 
before 
DBL 
Incorporating 
changes 
made in the 
TFLs 
amendment 
v01. 
1.  Clarification added and modified 
analyses to be performed regarding 
patient disposition output to fully align with 
SC meeting. 
2. 
Added 
details 
regarding 
a 
supplementary analysis for the primary 
endpoints. 
3. Modified analysis set for calculating 
[18F]CTT1057 
scan 
inter/intra-reader 
variability. 
4. 
 
5.  Updated the patient disposition section 
to include analysis set (if different from 
FAS), 
6.  Added grouping information when 
tabulating primary tumor clinical stage, 
biopsy 
Gleason 
score, 
radical 
prostatectomy 
Gleason 
score 
(if 
applicable) per comments received from 
SC meetings. 
7.  Changed the name from AESI to STI 
to align with RLT program standard. 
8.  Added minor update to the imputation 
rule. 
9.  Minor updates to the estimand wording 
were made as compared to the protocol 
for clarification. 
10.  Replaced “subject” and “patient” with 
“participant” throughout the document, 
wherever applicable and appropriate. 
11.  Updated SAP template version.  
12. 
Minor 
typographical 
corrections, 
removal of duplicated wording and minor 
rewording 
implemented 
across 
the 
document.  
Section 1.2.1, 
2.1.1, 2.2, 2.3, 
2.4.2, 2.5.2, 
2.5.3, 2.5.4, 
2.5.6, 2.6, 2.7.1, 
2.8, 2.9 and 
Section 5. 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
1.2 
Study objectives, endpoints and estimands ........................................................... 11 
1.2.1 
Primary estimand(s) .............................................................................. 12 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 17 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 17 
2.3.1 
Patient disposition ................................................................................. 17 
2.3.2 
Demographics and other baseline characteristics ................................. 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 19 
2.5 
Analysis supporting primary objective(s) .............................................................. 20 
2.5.1 
Primary endpoint(s) ............................................................................... 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of intercurrent events ............................................................. 21 
2.5.4 
Handling of missing values not related to intercurrent event ............... 21 
2.5.5 
Sensitivity analyses ............................................................................... 21 
2.5.6 
Supplementary analyses ........................................................................ 22 
2.6 
Analysis supporting secondary objectives ............................................................. 22 
2.6.1 
Secondary endpoint(s) ........................................................................... 23 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.6.3 
Handling of intercurrent events ............................................................. 26 
2.6.4 
Handling of missing values not related to intercurrent event ............... 27 
2.6.5 
Sensitivity analyses ............................................................................... 27 
2.6.6 
Supplementary analyses ........................................................................ 27 
 27 
 27 


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 28 
 28 
 28 
 28 
2.8 
Safety analyses....................................................................................................... 28 
2.8.1 
Adverse events (AEs) ............................................................................ 28 
2.8.2 
Deaths .................................................................................................... 30 
2.8.3 
Laboratory data ..................................................................................... 30 
2.8.4 
Other safety data ................................................................................... 31 
2.9 
Pharmacokinetic endpoints .................................................................................... 32 
2.10 
PD and PK/PD analyses ........................................................................................ 35 
2.11 
Patient-reported outcomes ..................................................................................... 35 
2.12 
Biomarkers ............................................................................................................. 35 
 
 35 
2.14 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 35 
3.1 
Primary endpoint(s) ............................................................................................... 35 
4 
Change to protocol specified analyses .............................................................................. 37 
5 
Appendix ........................................................................................................................... 37 
5.1 
Imputation rules ..................................................................................................... 37 
5.1.1 
Study drug ............................................................................................. 37 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 37 
5.1.3 
Other imputations .................................................................................. 38 
5.2 
AEs coding/grading ............................................................................................... 38 
5.3 
Laboratory parameters derivations ........................................................................ 39 
5.4 
Statistical models ................................................................................................... 39 
5.4.1 
Analysis supporting primary objective(s) ............................................. 39 
5.4.2 
Analysis supporting secondary objective(s).......................................... 40 
 
 40 
6 
Reference ........................................................................................................................... 42 


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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 11 
Table 2-1 
Time windows ....................................................................................... 16 
Table 2-2 
Example 2 by 2 contingency table for each reader ............................... 26 
Table 2-3 
Clinically notable changes in vital signs ............................................... 32 
Table 2-4 
Non-compartmental pharmacokinetic parameters ................................ 33 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 37 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 38 
 
 41 
 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
 


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List of abbreviations 
ADT 
AE 
ATC 
BMI 
CI 
CRF 
CSR 
CT 
CTCAE 
CV 
DBP 
DMS 
Androgen Deprivation Therapy 
Adverse Event 
Anatomical Therapeutic Chemical 
Body Mass Index 
Confidence Interval 
Case Report Form 
Clinical Study Report 
Computed Tomography 
Common Terminology Criteria for Adverse Events 
Coefficient of Variation 
Diastolic Blood Pressure 
Document Management System 
DRL 
ECG 
EFF 
eCRS 
ePLND 
FAS 
FN 
FP 
HGLTs 
HLT 
HPLC 
HR 
IA 
Drug Reference Listing 
Electrocardiogram 
Efficacy Analysis Set 
Electronic Case Retrieval sheet 
Extended Pelvic Lymph Node Dissection 
Full Analysis Set 
False Negative 
False Positive 
High Level Group Terms 
High Level Terms 
High-Performance Liquid Chromatography 
Heart Rate 
Interim Analyses 
ICF 
IRT 
LN 
LPLV 
Informed Consent Form 
Interactive Response Technology 
Lymph Node 
Last Patient Last Visit 
MBq 
MedDRA 
mL 
NCI 
NMQ 
ng 
PAS 
PCa 
PD 
PET 
PK 
Mega-Becquerel 
Medical Dictionary for Drug Regulatory Affairs 
milliliter(s) 
National Cancer Institute 
Novartis MedDRA Queries 
nanogram(s) 
Pharmacokinetic Analysis Set 
Prostate Cancer 
Pharmacodynamic(s) 
Positron Emission Tomography 
Pharmacokinetics 
PLN 
PPS 
Pelvic Lymph Node 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
PS 
PSA 
Primary Staging 
Prostate Specific Antigen 


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PSMA  
PT 
RAP 
Prostate Specific Membrane Antigen 
Preferred Term 
Reporting & Analysis Process 
RR 
SAF 
SAP 
SAS 
Respiratory Rate 
Safety Set 
Statistical Analysis Plan 
Statistical Analysis System 
SBP 
SD 
SoC 
SoT 
STI 
Systolic Blood Pressure 
Standard Deviation 
Standard of Care 
Standard of Truth 
Safety Topic of Interest   
TFLs 
Tables, Figures, Listings 
TN 
TP 
WHO 
WHO-DD 
True Negative 
True Positive 
World Health Organization 
WHO Drug Dictionary 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CAAA405A12302, a Phase II/III study for evaluation of the diagnostic 
performance of [18F]CTT1057 PET imaging for the detection of Prostate Specific Membrane 
Antigen  (PSMA) positive tumors using histopathology as a standard of truth (SoT). 
The content of this SAP is based on protocol CAAA405A12302 version 01. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data. 
1.1 
Study design 
This is a multi-center, single-arm, open-label prospective study to evaluate the diagnostic 
performance of [18F]CTT1057 as a PET imaging agent for detection and localization of PSMA 
positive tumors, using histopathology as SoT. Tissue specimens from both the primary tumor 
and pelvic lymph nodes (PLN) dissected during surgery from participants with newly-
diagnosed high-risk prostate cancer (PCa) will be used for the histopathology assessments. 
Approximately 195 participants will be enrolled to ensure that at least 156 participants are 
evaluable for co-primary endpoints. Surgery (radical prostatectomy/ePLND) will be performed 
up to 6 weeks after [18F]CTT1057 PET/CT but not sooner than 48 hours after the completion 
of the [18F]CTT1057 PET/CT scan (in order to limit the potential confounding factors related 
to the effects of surgery for the assessment of [18F]CTT1057 PET/CT safety) for pathology 
assessment of the tissue specimens.  
The co-primary endpoints of patient-level sensitivity and region-level specificity will be 
assessed by comparing the central reading results of the [18F]CTT1057 PET/CT scan (see 
Section 4.1 and Section 8.3.1 for central read details and Section 6.4 for blinding details of the 
protocol) to the histopathology results in the dissected tissue specimens, i.e. both the primary 
tumor and the dissected PLNs (Maurer et al 2016, Woythal et al 2018, Kuten et al 2020). 
Pathology will be assessed by the local pathologists as per Standard of Care (SoC). Pathologists 
will be blinded to the PET data. For anatomical localization, a sextant anatomic template for 
the prostate and a left/right template for the PLNs will be used (see appendix Section 16.3 of 
the protocol). Pathology results should be available within 2 weeks after surgery. 
 
 
 
 
 
 
 
 
 
 
 


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. See Figure 1-1 for study design 
schema. There will be no interim analysis for this study. 
Figure 1-1 
Study design 
 
Screening Period 
Written informed consent form (ICF) must be obtained prior to any screening procedures. The 
participant must be registered in the Interactive Response Technology (IRT) for screening 
and [18F]CTT1057 requested. All procedures described in the Assessment Schedule as per 
Table 8-1 of the protocol must be carried out, prioritizing laboratory assessments to allow time 
to obtain the results at least 14 days prior the planned PET imaging day (Day 1). Eligibility 
must then be confirmed at the latest on Day -14. The screening period should last up to 28 days. 
[18F]CTT1057 PET imaging day 
[18F]CTT1057 PET imaging will be performed using a standard integrated PET/CT system. The 
following steps to take place during this day are described in Section 8.3.1 of the protocol. 
In the PK subset of approximately 10 participants at the same site, several blood and urine 
samples as well as additional ECG assessments for safety will be done at the pre-specified time 
points on PET imaging day. 
Safety Check 
All treated participants will be contacted by phone within 24 to 72 hours following the scan in 
order to capture potential occurring Adverse Events. 
Safety Follow-up  
Participants will come back to the hospital 14 days after the PET/CT scan day, for a safety visit 
including vital signs, lab and urine analysis, etc. For participants undergoing surgery prior to 
planned safety visit, these safety follow-up assessments will need to be performed before the 
surgery but not sooner than 48 hours after the PET/CT scan.  
Additional Follow-up 
Surgery (RP/ePLND) will be scheduled for all participants as planned per SoC on a date that 
must not be sooner than 48 hours after the completion of the [18F]CTT1057 PET/CT scan, and 


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no later than 6 weeks after completion of the [18F]CTT1057 PET/CT scan. Final histopathology 
results have to be obtained within 2 weeks after surgery. 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Evaluate the patient-level 
sensitivity of [18F]CTT1057  
• 
Sensitivity of [18F]CTT1057 PET imaging, considering PSMA 
positive patients as those who show at least one pathological 
[18F]CTT1057 uptake either in the primary tumor and/or 
metastatic 
PLN 
regions, 
with 
anatomically 
localized 
correspondence with the SoT. See Section 1.2.1 for Primary 
Estimand. 
• 
Evaluate the region-level 
specificity of [18F]CTT1057  
• 
Specificity of [18F]CTT1057 PET imaging, defined as 
proportion of PLN regions that test negative for lymph nodes 
on [18F]CTT1057 among those that are lymph node negative 
on the SoT. See Section 1.2.1 for Primary Estimand. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Evaluate the patient-level 
specificity of [18F]CTT1057  
• 
Specificity of [18F]CTT1057 PET imaging, considering PSMA 
negative patients as those who do not show any 
pathological [18F]CTT1057 uptake either in the primary tumor 
or PLNs and will be confirmed not having primary tumor or 
metastatic PLNs with the SoT 
• 
Evaluate the patient-level 
positive predictive value of 
[18F]CTT1057  
• 
Proportion of patients who are both [18F]CTT1057 and SoT 
positive (true positives (TP)) among those who test positive on 
[18F]CTT1057 (TP+ false positives(FP)) 
• 
Evaluate the patient-level 
negative predictive value of 
[18F]CTT1057  
• 
Proportion of patients who are both [18F]CTT1057 and SoT 
negative (true negatives (TN)) among those who test negative 
on [18F]CTT1057 (TN+ false negatives (FN)) 
• 
Evaluate the patient-level 
accuracy of [18F]CTT1057  
• 
Proportion of patients that are SoT and [18F]CTT1057 positive 
(TP) 
and 
negative 
(TN) 
among 
all 
patients 
in 
EFF(TP+TN+FP+FN) 
• 
Evaluate the region-level 
sensitivity of [18F]CTT1057 
for patients excluding 
micro-metastasis 
• 
Sensitivity of [18F]CTT1057 PET imaging in the PLN region, 
excluding from the analysis those lymph nodes showing 
metastasis <2mm (micro-metastasis)  
• 
Evaluate the region-level 
sensitivity of [18F]CTT1057  
• 
Proportion of PLN regions that test positive on both 
[18F]CTT1057 and SoT (TP) among those that are SoT positive 
(TP+FN) 
• 
Evaluate the region-level 
positive predictive value of 
[18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
positive (TP) among those regions that test positive on 
[18F]CTT1057 (TP+FP) 
• 
Evaluate the region-level 
negative predictive value of 
[18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
negative (TN) among those regions that test negative on 
[18F]CTT1057 (TN+FN) 


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Objective(s) 
Endpoint(s) 
• 
Evaluate the region-level 
accuracy of [18F]CTT1057  
• 
Proportion of PLN regions that are SoT and [18F]CTT1057 
positive (TP) and negative (TN) among all PLN regions 
assessed [18F]CTT1057 (TP+TN+FP+FN) 
• 
Detection of distant 
metastasis in PS patients  
• 
Number of distant metastasis (extra-PLN, visceral or skeletal) 
identified at PET/CT scan per patient, and percentage of 
patients with at least one distant metastatic lesion identified by 
PET/CT scan 
• 
Characterize the safety and 
tolerability of [18F]CTT1057 
• 
Incidence of AEs. Treatment emergent adverse event (TEAE) 
rate within 14 days of administration 
• 
[18F]CTT1057 scan inter-
reader variability 
• 
Inter-reader agreement of [18F]CTT1057 images 
• 
[18F]CTT1057 scan intra-
reader variability 
• 
Intra-reader agreement of [18F]CTT1057 images 
• 
To further assess 
[18F]CTT1057 
pharmacokinetics in 
humans in subset of 
approximately 10 patients 
• 
Summary 
statistics 
of 
[18F]CTT1057 
pharmacokinetic 
parameters (i.e. Cmax, Tmax, AUClast, AUCinf, T1/2, Vz and 
CL from blood radioactivity data; quantification of urinary 
excretion of [18F]CTT1057 from urine data) 
 
1.2.1 
Primary estimand(s) 
The primary clinical question of interest is: Does [18F]CTT1057 target PSMA expressing PCa 
cells, allowing to obtain adequate [18F]CTT1057 PET/CT images to detect and localize 
PSMA positivity using histopathology as SoT? 
The justification for the primary estimand is that we wish to assess the diagnostic performance 
of [18F]CTT1057 PET in detecting and localizing PSMA positivity. For this reason, newly-
diagnosed high risk PCa patients will undergo a [18F]CTT1057 PET/CT scan within 6 weeks 
before surgery (but not sooner than 48 hours after the completion of the [18F]CTT1057 PET/CT 
scan), and results of the [18F]CTT1057 PET/CT scans will be compared against the 


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histopathology results (SoT) in the dissected tissue specimens (primary tumor and PLNs), both 
at a patient and region level.  
The co-primary estimands are described by the following attributes: 
Primary estimand 1: 
1. Population: Untreated high risk PCa patients according to D’Amico classification (Stage ≥ 
T2c or PSA level >20ng/ml or Gleason score ≥8) (D'Amico et al 1998), who are scheduled 
or planned RP and lymph node resection. Further details about the population are provided 
in Section 5 of the protocol. 
2. Variable: Patient level sensitivity, defined as the proportion of participants that test positive 
on both [18F]CTT1057 and SoT (TP) among those that are SoT positive (TP + FN), 
considering PSMA positive participants are those who show at least one pathological 
[18F]CTT1057 uptake either in the primary tumor and/or metastatic PLN, with anatomically 
localized correspondence with the SoT.  
3. Treatment (investigational imaging agent) of interest: [18F]CTT1057 injected as a single 
intravenous dose of approximately 370 MBq and subsequent PET/CT scan. Further details 
about the investigational imaging agent are provided in Section 6 of the protocol. 
4. Intercurrent events:   
• Participants who received the investigational imaging agent [18F]CTT1057 but did not 
undergo/complete the PET/CT scan for any reasons (e.g. consent withdrawal, PET 
camera failures, etc.). Details on how to handle intercurrent events are provided 
in Section 2.5.3. 
5. Summary measure: Patient level sensitivity, along with two-sided exact binomial 95% CI. 
Further details on how the summary measure will be tested are provided in Section 2.5.2.  
Primary estimand 2: 
1. Population: the same as the primary estimand 1 
2. Variables: Regional level specificity, defined as the proportion of PLN regions that test 
negative on both [18F]CTT1057 and SoT (TN) among those PLN region that test negative 
on the SoT (TN + FP), considering PSMA negative PLN regions those that do not show any 
pathological [18F]CTT1057 uptake within the region. 
3. Treatment (investigational imaging agent) of interest: the same as the primary estimand 1 
4. Intercurrent events: the same as the primary estimand 1 
5. Summary measure: Region level specificity, along with two-sided exact binomial 95% CI. 
Further details on how the summary measure will be tested are provided in Section 2.5.2.  
 
2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed by Novartis. SAS version 9.4 or later will be used to 
perform all data analyses and to generate tables, figures and listings. 


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Data included in the analysis 
Only one final analysis is planned for the co-primary efficacy endpoints. All statistical analyses 
will be performed using all data collected in the database up to the cut-off date. The cut-off date 
for the final analysis of study data will be established after all enrolled participants have 
completed EOS visit (Last Patient Last Visit). 
All events with start date before or on the database lock date and end date after the database 
lock date will be reported as ‘ongoing’. The same rule will be applied to events starting before 
or on database lock date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these cases, the end date 
will not be imputed and therefore will not appear in the listings. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. No center effect will be assessed.  
Qualitative data (e.g., ECOG, race, etc.) will be summarized by tables; a missing category will 
be included as applicable. Percentages will be calculated using the number of participants in the 
relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight, height, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, 1st and 3rd quartiles, minimum, and 
maximum). 
2.1.1 
General definitions  
Investigational PET imaging agent: [18F]CTT1057  
Study treatment:  a single injection intravenously (i.v.) of approximately 370 MBq (range 
266 – 407 MBq) [18F]CTT1057 whether the PET/CT scan was acquired or not.  
Date of administration of investigational PET imaging agents 
The date of administration of investigational PET imaging agent is defined as the date when a 
non-zero dose of investigational PET imaging agent is administered and recorded on the study 
treatment (e)CRF. The date of administration of study treatment will also be referred as start of 
investigational PET imaging agent. 
Study day 
The study day describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 


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The reference date for all assessments (safety, efficacy, pk, etc) is the start of study 
treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety evaluations, the last available assessment prior to the administration of [18F]CTT1057 
(on or before the start of the study treatment date/time) is defined as “baseline” assessment. If 
participants have no value as defined above, the baseline result will be set to matching missing. 
Efficacy evaluations will not include any comparisons between baseline and post-baseline 
values, and therefore a baseline definition for efficacy evaluations does not apply.   
On-treatment assessment/event and observation periods  
For adverse event reporting, the overall observation period will be divided into three mutually 
exclusive segments:  
1. Pre-treatment period: from day of participant’s informed consent to the day and time 
before dosing of study medication. 
2. On-treatment period: from day of dosing of study medication to 14 days after dosing 
of study medication. 
3. Post-treatment period: starting 15 days after dosing of study medication. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on-treatment and 
post-treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).   
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 
Windows for multiple assessments  
In order to summarize weight, vital signs, ECGs, and laboratory tests collected over time 
(including unscheduled visits), the assessments will be time slotted. The following general rule 
will be applied in creating the assessment windows: If more than one assessment is done within 
the same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time window are equidistant from the target date, then the earlier of the 2 
assessments will be used. If there are multiple assessments on the same date, then the worst 


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case will be used. Data from all assessments (scheduled and unscheduled), including multiple 
assessments, will be listed. 
Table 2-1 
Time windows 
Time Window 
 Planned Visit Timing 
Time Window Definition 
On treatment 
 
 
Baseline  
(pre-treatment)  
On or before  
Study Day 1* 
Before Study Day 1, or on Study Day 1 but 
prior to [18F]CTT1057 injection 
 
Day 1 
 
Study Day 1 
 
Date of [18F]CTT1057 injection 
 
Day 15  
 
Study Day 15 
 
14 – 17 days after the date of  
[18F]CTT1057 injection 
 
 
 
 
*Study Day 1 = the date of [18F]CTT1057 injection 
 
Electrocardiograms (ECGs) (for the PK subset) and vital signs will be assessed pre-injection, 
post-injection/ pre-imaging and post-imaging on Study Day 1. Their results will be presented 
by timepoint. 
2.2 
Analysis sets  
The Full Analysis Set (FAS) includes all enrolled participants. 
The Efficacy Analysis Set (EFF) includes all enrolled participants who receive 
the dose of investigational treatment (i.e. [18F]CTT1057), have both an evaluable 
[18F]CTT1057 PET/CT scan and histopathology assessment, and have not received any 
prohibited systemic antineoplastic therapy before the completion of PET/CT and surgery. 
The Safety Set (SAF) includes all participants who received the investigational treatment (i.e. 
[18F]CTT1057). 
The Pharmacokinetic analysis set (PAS) includes all participants who provide at least one 
evaluable PK parameter. A profile is considered evaluable if all of the following conditions are 
satisfied: participant receives the investigational treatment (i.e. [18F]CTT1057) and provides at 
least one primary PK parameter. The PAS will be used for all PK analyses.  
Approximately 10 participants from the same site are expected to provide at least one evaluable 
PK parameter. 
Note: Participants may be removed from the estimation of certain PK parameters on an 
individual basis depending on the number of available blood samples. Specific time points 
might be removed from the analysis set if technical issues with sample are reported (e.g. 
sampling issues, missing information) or if Lower Limit of Quantification (LLOQ) sample is 
observed between measurable concentrations. These participants and concentration data points 
will be identified at the time of analysis. 


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The number (%) of participants in each analysis set will be summarized and information about 
analysis sets for each participant will be displayed in a listing. 
2.2.1 
Subgroup of interest 
The co-primary efficacy endpoints will be summarized by the following subgroups:  
(a) PSA level at baseline (from central laboratory) 
• PSA ≤ 20 ng/mL 
• PSA > 20 ng/mL 
 
(b) Gleason Score  
• Grade Group 1 Gleason score ≤ 6 
• Grade Group 2 Gleason score 7 (or 3 + 4 = 7) 
• Grade Group 3 Gleason score 7 (or 4 + 3 = 7)  
• Grade Group 4 Gleason score 8  
• Grade Group 5 Gleason score 9 or 10  
 
(c) Number of pelvic lymph nodes (PLNs) dissected during the surgery 
• PLNs < 12 
• PLNs ≥ 12 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Enrollment by country or subdivision and center will be summarized for all screened 
participants. The number (%) of screen failures and the reasons for screen failure will also be 
displayed. For participants screened more than once, the data from the last screening visit will 
be used in the summaries. 
The following summaries will be provided (with % based on the total number of FAS 
participants unless otherwise specified): 
• Number (%) of participants who were screened, and number (%) who were screened but 
not enrolled with the reasons for participants not enrolled (based on the ‘Disposition’ page 
and with % based on all screened participants) 
o Number (%) of participants who were not enrolled related to COVID-19 and primary 
relationships to COVID-19 (based on the ‘Disposition’ page and with % based on all 
screened participants) 
• Number of participants (%) who were enrolled (i.e. FAS, based on the ‘Subject ID’ page) 
• Number of participants (%) who completed study treatment phase (PET imaging completed) 
• Number of participants (%) who were discontinued from study treatment phase and reason 
for discontinuation 
o Number of participants (%) who were discontinued from study treatment phase related 
to COVID-19 and relationship to COVID-19 


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• Number of participants (%) who were dosed with [18F]CTT1057 but not scanned and reason 
for not scanned 
• Number of participants (%) who were not dosed with [18F]CTT1057 and reason for not 
dosed 
o Number of participants (%) who were not dosed with [18F]CTT1057 related to COVID-
19 and relationship to COVID-19 
• Number (%) of participants who completed the study (based on the ‘Disposition’ page) 
• Number (%) of participants who discontinued the study and the reason for discontinuation 
(based on the ‘Disposition’ page) 
o Number (%) of participants who discontinued the study related to COVID-19 and 
primary relationships to COVID-19 (based on the ‘Disposition’ page) 
Protocol deviations 
The number (%) of participants in the FAS with any confirmed protocol deviation will be 
tabulated by deviation category (as specified in the study Data Handling Plan). All protocol 
deviations will be listed. For all important protocol deviations, the relationship to COVID-19 
will also be captured. 
2.3.2 
Demographics and other baseline characteristics 
The FAS and EFF will be used for all baseline and demographic summaries and listings unless 
otherwise specified. Listings will be provided using the FAS. 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g.  Age groups: < 65 and ≥ 65 years, race, ethnicity, ECOG others as 
applicable) will be summarized by frequency counts and percentages; the number and 
percentage of participants with missing data will be provided. Continuous data (e.g. age, weight, 
height, body mass index (BMI), PSA level at screening from central laboratory) will be 
summarized by descriptive statistics (N, mean, median, 1st and 3rd quartile, standard deviation, 
minimum and maximum). BMI (kg/m2) will be calculated as weight[kg] / (height[m2]) using 
weight at Baseline. 
Diagnosis and extent of cancer  
Diagnosis and extent of cancer will be summarized and listed. This analysis will include the 
following: PSA level at time of initial diagnosis (ng/mL), primary tumor clinical stage (i.e. T2c 
or less, T3, T3a, T3b, T4 and Tx), biopsy predominant histology/cytology, percentage of each 
histological type/pattern, biopsy Gleason score (i.e. ≤ 6, 7 (3+4), 7 (4+3), 8, and 9 or 10), time 
since initial diagnosis (in months).  Note: biopsy Gleason score will be displayed along with 
the score details for each score combination in the table.  
Derivation:  
Time since initial diagnosis to PET scan (in months) = (date of PET scan – date of first 
prostate cancer diagnosis + 1) / 30.4375 


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ECOG Performance Status 
ECOG performance status at baseline will be presented in a summary table and will be listed. 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed. Separate summaries will be presented for 
ongoing and historical medical conditions.  The summaries will be presented by primary system 
organ class (SOC), preferred term (PT). Medical history and current medical conditions will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The following exposure information of [18F]CTT1057 as reported in the  ‘[18F]CTT1057 study 
treatment injection’ page of the eCRF will be summarized (with % based on the total number 
of SAF participants unless otherwise specified ): 
• Descriptive statistics of radioactivity dose administered (MBq)  
• Number (%) of participants who were dosed but with problems (i.e. extravasation) in 
administration  
• Number (%) of participants with dose administered outside the planned range (i.e. < 266 
MBq or > 407 MBq)  
• Time (in minutes) from injection to full-body PET imaging acquisition start time (based 
on the ‘[18F]CTT1057 PET/CT Imaging - Local reads’ page) 
• Number (%) of participants with additional pelvic PET imaging acquisition, with time (in 
minutes) from injection to additional pelvic PET imaging acquisition start time, if 
applicable (based on the ‘[18F]CTT1057 PET/CT Imaging - Local reads’ page) 
• Time (in days) from full-body PET imaging acquisition start time to the date of surgery 
(based on the ‘[18F]CTT1057 PET/CT Imaging - Local reads’ page and the ‘Radical 
prostatectomy and ePLN dissection - Local histopathology assessment’ page) 
Participant level listings of doses administered or not, along with reasons if not administered 
will be produced using the FAS.   
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of participants who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. Prior 
anti-neoplastic medications will be summarized by total number of regimens, setting (e.g. neo-
adjuvant, adjuvant, metastatic, etc.), and also by lowest ATC class and preferred term.  Prior 
anti-neoplastic radiotherapies will be summarized by method (i.e. external beam vs. internal 


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beam) and setting (e.g. neo-adjuvant, adjuvant, metastatic, etc.). Prior anti-neoplastic surgeries 
will be summarized by procedure (i.e. radical prostatectomy vs. other) and residual disease (e.g. 
yes, no, etc.).  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery using the FAS.  
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings.  
The above summary tables will be provided using the FAS and EFF. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a participant coinciding with the study treatment 
period. 
Concomitant 
therapy 
includes 
medications 
(other 
than 
study 
drugs) 
/therapies/procedures starting on or after the start date of study treatment or 
medications/therapies/procedures starting prior to the start date of study treatment and 
continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include: 
1. Medications/therapies/procedures starting on or after the start of study treatment but 
no later than 14 days after study treatment  
2. Medications/therapies/procedures starting prior to start of study treatment and 
continuing after the start of study treatment. 
The number of participants (%) who received diuretics (e.g. Furosemide) as concomitant 
medication on the day of PET/CT will also be summarized.  
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 14 days after the last date of study treatment 
will be flagged in the listing. The SAF will be used for all concomitant medication tables and 
listings.  
2.5 
Analysis supporting primary objective(s) 
The primary objectives of the study are to evaluate patient-level sensitivity of [18F]CTT1057and 
region-level specificity of [18F]CTT1057. 
2.5.1 
Primary endpoint(s) 
The co-primary endpoints evaluated for participants in the EFF are the following: 
Patient-level Sensitivity of [18F]CTT1057 PET imaging, defined as the proportion of 
participants that test positive on both [18F]CTT1057 and SoT (TP) among those that are SoT 


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positive (TP + FN), considering PSMA positive participants are those who show at least one 
pathological [18F]CTT1057 uptake either in the primary tumor (prostate region) and/or 
metastatic PLN region, with anatomically localized correspondence with the SoT. See 
Section 1.2.1 for Primary Estimand. 
Region-level Specificity of [18F]CTT1057 PET imaging, defined as the proportion of PLN 
regions that test negative on both [18F]CTT1057 and SoT (TN) among those PLN regions that 
test negative on the SoT (TN + FP), considering PSMA negative PLN regions are those which 
do not show any pathological [18F]CTT1057 uptake within the region. See Section 1.2.1 for 
Primary Estimand. 
 
  
2.5.2 
Statistical hypothesis, model, and method of analysis  
To address the co-primary efficacy objectives: 
Patient-level sensitivity along with two-sided exact binomial 95% CIs will be calculated.  
The lower bound of the 95% CI for patient-level sensitivity should be greater than 0.50 to attain 
the first co-primary endpoint. 
Region-level specificity along with two-sided exact binomial 95% CIs will be calculated. Only 
pelvic lymph node regions will be used to calculate the specificity.  The lower bound of the 95% 
CI for specificity should be greater than 0.70 for the study to attain the second co-primary 
endpoint. 
An individual PET reader will be considered successful if he/she meets the predefined 
thresholds for both co-primary endpoints, and at least two of three readers should be successful 
for overall study positivity. 
2.5.3 
Handling of intercurrent events  
The primary analysis will account for intercurrent events as explained in the following: 
• Participants who receive the investigational imaging agent [18F]CTT1057 but do not 
undergo/complete the  [18F]CTT1057 PET/CT scan for any reason (e.g. drop out, PET 
camera failures, etc)  will not be used for the co-primary endpoint analyses. Note that safety 
data for these participants will be collected after the administration of the investigational 
imaging agent and will be summarized.  
2.5.4 
Handling of missing values not related to intercurrent event 
This is a diagnostic study, where the co-primary endpoints are calculated on the basis of one-
time imaging assessment. Missing data will not be imputed. 
2.5.5 
Sensitivity analyses  
Not applicable  


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2.5.6 
Supplementary analyses 
As supplementary analyses performed for the EFF, patient-level sensitivity and region-level 
specificity and the corresponding 95% CIs will be obtained from a covariate-adjusted logistic 
regression model. Candidate covariates include categorized PSA level at baseline, diagnostic 
biopsy Gleason score, and categorized number of PLNs dissected as given below.  
• PSA level  
o PSA ≤ 20 ng/mL 
o PSA > 20 ng/mL 
• Gleason Score  
o Grade Group 1 Gleason score ≤ 6  
o Grade Group 2 Gleason score 7 (or 3 + 4 = 7) 
o Grade Group 3 Gleason score 7 (or 4 + 3 = 7)  
o Grade Group 4 Gleason score 8  
o Grade Group 5 Gleason score 9 or 10  
• Number of PLNs dissected 
o Number of PLNs < 12 
o Number of PLNs >= 12 
Estimates of patient-level sensitivity and region-level specificity and the corresponding 95% 
CIs will be obtained from the logistic regression model adjusting for covariates. The p-values 
from the Type III tests for each candidate covariate in the full model will be provided. The 
patient-level sensitivity and region-level specificity (and their 95% CIs) for each level of the 
covariates estimated from the full model including all candidate covariates as well as the final 
model including only statistically significant covariates (p-value < 0.05) will be displayed. In 
the case that there are no statistically significant covariates identified from the full model, 
patient-level sensitivity and region-level specificity (and their 95% CIs) from the unadjusted 
logistic regression model will be provided. 
 
2.6 
 Analysis supporting secondary objectives  
The secondary efficacy objectives are to: 
• Evaluate the patient-level specificity of [18F]CTT1057  
• Evaluate the patient-level positive predictive value of [18F]CTT1057  
• Evaluate the patient-level negative predictive value of [18F]CTT1057  
• Evaluate the patient-level accuracy of [18F]CTT1057  
• Evaluate the region-level sensitivity of [18F]CTT1057 for patients excluding micro-
metastasis 
• Evaluate the region-level sensitivity of [18F]CTT1057  
• Evaluate the region-level positive predictive value of [18F]CTT1057  
• Evaluate the region-level negative predictive value of [18F]CTT1057  
• Evaluate the region-level accuracy of [18F]CTT1057  
• Detection of distant metastasis in PS patients  
• Characterize the safety and tolerability of [18F]CTT1057 


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• [18F]CTT1057 scan inter-reader variability 
• [18F]CTT1057 scan intra-reader variability 
• To further assess [18F]CTT1057 pharmacokinetics in humans in a subset of 
approximately 10 patients 
2.6.1 
Secondary endpoint(s) 
Secondary endpoints are defined for the EFF unless otherwise specified with details given as 
follows: 
Patient-level specificity is defined as the proportion of TN  participants among those who are 
TN or FP. 
Patient-level positive predictive value is defined as the proportion of TP  participants among 
those who are TP or FP.  
Patient-level negative predictive value is defined as the proportion of TN  participants among 
those who are TN or FN.   
Patient-level accuracy is defined as the proportion of TP and TN participants among all 
participants in EFF (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN participants are defined as follows:  
• PSMA TP participants are those who show at least one pathological [18F]CTT1057 uptake 
either in the primary tumor and/or metastatic PLNs with anatomically localized 
correspondence with the SoT, regardless of co-existing FP lesions in those two regions. 
• PSMA TN participants are those who do not show any pathological [18F]CTT1057 uptake 
neither in the primary tumor nor metastatic PLNs and will be confirmed 
NOT having primary tumor nor metastatic PLNs with the SoT. 
• PSMA FP participants are those who are not TP and show at least one pathological 
[18F]CTT1057 uptake either in the primary tumor and/or metastatic PLNs but will be 
verified NOT having primary tumor nor metastatic PLNs with the SoT or none of the lesions 
is correctly localized in anatomical location by the SoT. 
• PSMA FN participants are those who do not show any pathological [18F]CTT1057 uptake 
neither in the primary tumor nor metastatic PLNs but will be confirmed having primary 
tumor or metastatic PLNs with the SoT. 
Number of TP, TN, FP, FN participants will be presented and used to calculate the diagnostic 
performance parameters.  
Two-sided exact binomial 95% CIs for diagnostic performance parameters will be calculated. 
Region-level sensitivity is defined as the proportion of TP PLN regions among those that are 
TP or FN. 
Region-level sensitivity will also be presented, excluding PLNs showing metastasis < 2 mm 
(micro-metastasis). 
Region-level positive predictive value is defined as the proportion of TP PLN regions among 
those that are TP or FP. 


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Region-level negative predictive value is defined as the proportion of TN PLN regions among 
those that are TN or FN. 
Region-level accuracy is defined as the proportion of TP and TN PLN regions among those 
that are identified on [18F]CTT1057 (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN regions are defined as follows: 
• PSMA TP regions are regions that test positive for PLN on [18F]CTT1057 and confirmed 
positive on the SoT  
• PSMA TN regions are regions that test negative for PLN on [18F]CTT1057 and confirmed 
negative on the SoT  
• PSMA FP regions are regions that test positive for PLN on [18F]CTT1057 but verified 
negative on the SoT 
• PSMA FN regions are regions that test negative for PLN on [18F]CTT1057 but verified 
positive on the SoT 
The number of TP, TN, FP, FN PLN regions will be presented and used to calculate the 
diagnostic performance parameters.  
Two-sided exact binomial 95% CIs for diagnostic performance parameters will be calculated. 
[18F]CTT1057 scan inter-reader variability is defined as the agreement rate among reader 
determinations and will be assessed by Fleiss' Kappa statistic. See details given in Section 2.6.2. 
 
[18F]CTT1057 scan intra-reader variability is defined as the within-reader agreement rate 
and will be assessed by Cohen's Kappa statistic. See details given in Section 2.6.2. 
 
Detection number of distant metastasis is defined as number of distant metastasis (extra-PLN, 
visceral or skeletal) identified at PET scan for each participant in all participants with an 
evaluable [18F]CTT1057 PET/CT scan. Summary statistics will be provided by region, i.e. 
extra-PLN, visceral and skeletal. 
 
Detection rate of distant metastasis is defined as the percentage of participants with at least 
one distant metastatic lesion (extra-PLN, visceral or skeletal) identified by PET scan in all 
participants with an evaluable [18F]CTT1057 PET/CT scan. Detection number of distant 
metastasis will be presented and used to calculate Detection rate of distant metastasis, along 
with two-sided exact binomial 95% CIs for detection rate will be calculated. 
 
Characterize the safety and tolerability of [18F]CTT1057 
Further discussion of the safety and tolerability endpoints to support the secondary objective 
analysis is included in Section 2.8. 
 
Pharmacokinetics in humans in subset of approximately 10 patients 
Further discussion of the pharmacokinetics analysis is included in Section 2.9. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Patient-level diagnostic performance parameters include: 


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• Patient-level specificity  
• Patient-level positive predictive value  
• Patient-level negative predictive value  
• Patient-level accuracy  
• Detection rate of distant metastasis evaluated for all other regions (i.e. extra PLN, 
skeletal and visceral) 
See details given in Section 2.6.1. 
 
Region-level diagnostic performance parameters include: 
• Region-level sensitivity including and excluding micro-metastasis 
• Region-level positive predictive value  
• Region-level negative predictive value  
• Region-level accuracy 
See details given in Section 2.6.1. 
 
[18F]CTT1057 scan inter-reader variability will be assessed by Fleiss' Kappa (𝜅𝜅1) statistic 
(Fleiss 1971) defined below: 
𝜅𝜅1 = 
𝑃𝑃 ഥ−𝑃𝑃ത𝑒𝑒
1− 𝑃𝑃ത𝑒𝑒. 
Let N represent the total number of participants who have evaluable PET/CT, n the number of 
central readings per participant 𝑛𝑛= 3 (￼), and 𝑘𝑘= 2 the number of outcome categories (￼) 
into which assignments are made. Participants𝑖𝑖= 1, … , 𝑁𝑁by𝑗𝑗= 1, … , 𝑘𝑘￼𝑛𝑛𝑖𝑖𝑖𝑖￼𝑖𝑖￼ represent 
the number of readers who assigned the ￼𝑗𝑗participant to the 𝑗𝑗th category. Then 
 𝑃𝑃𝑖𝑖= 
1
𝑛𝑛(𝑛𝑛−1) ∑
𝑛𝑛𝑖𝑖𝑖𝑖൫𝑛𝑛𝑖𝑖𝑖𝑖−1൯      and      𝑃𝑃ത= 
1
𝑁𝑁 ∑
𝑃𝑃𝑖𝑖 
𝑁𝑁
𝑖𝑖=1
𝑘𝑘
𝑗𝑗=1
; 
𝑝𝑝𝑗𝑗= 
1
𝑁𝑁𝑁𝑁∑
𝑛𝑛𝑖𝑖𝑖𝑖
𝑁𝑁
𝑖𝑖=1
       and       𝑃𝑃ത𝑒𝑒= ∑
𝑝𝑝𝑗𝑗
2
𝑘𝑘
𝑗𝑗=1
. 
A contingency table of N row (N is the number of participants who have evaluable PET/CT) by 
2 (the number of outcome categories) will summarize the frequency of agreements among the 
3 readers for each case and each patient-level outcome (i.e. positive, negative). The counts 
across each of the N rows will sum up to 3 (number of readers).  
Based on the contingency table as described above, a Fleiss’s Kappa statistic and corresponding 
95% confidence interval will be estimated based on asymptotic estimation of the standard error 
(i.e.   
𝑠𝑠𝑠𝑠
ෞ(𝜅𝜅1) =
√2
∑
𝑝𝑝𝑗𝑗൫1−𝑝𝑝𝑗𝑗൯ඥ𝑁𝑁𝑁𝑁(𝑛𝑛−1)
𝑘𝑘
𝑗𝑗=1
ටቀ∑
𝑝𝑝𝑗𝑗
𝑘𝑘
𝑗𝑗=1
 ൫1 −𝑝𝑝𝑗𝑗൯ቁ
2
− ∑
𝑝𝑝𝑗𝑗(1 −𝑝𝑝𝑗𝑗)(1 −2𝑝𝑝𝑗𝑗)
𝑘𝑘
𝑗𝑗=1
(Fleiss, 
Nee, Landis 1979; Fleiss J, Levin B, Paik MC 2003) and the normality assumption (i.e. 95% CI 


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can be calculated as: 𝜅𝜅1 ± 1.96𝑠𝑠𝑠𝑠
ෞ(𝜅𝜅1)). An additional table will be presented to show the 
distribution of agreements with the number (%) of scans agreed by two readers and the number 
(%) of scans agreed by all three readers. Inter-reader variability will be calculated for the SAF. 
 
[18F]CTT1057 scan intra-reader variability will be assessed by Cohen's Kappa (𝜅𝜅2)  statistic. 
To assess the intra-reader variability, each of the three readers will re-read the same 20 
randomly selected cases (with evaluable PET/CT) but each case will be presented to each reader 
in a random order. The readers will not reference any previous read results nor discuss any of 
these cases at any time during the read process. Each reader will use the same method to read 
the randomly presented cases as they did in the previous reads. Intra-reader agreement will first 
be evaluated separately for each of the 3 readers using Cohen’s kappa statistic ( 𝜅𝜅2)  as described 
below:  
Step 1: A 2 by 2 contingency table (e.g. Table 2-2) will be calculated to summarize the 
frequency of concordance and discordance for patient-level positivity or negativity. The counts 
in the table will add up to 20 in total (i.e. a + b+ c + d = 20). 
Table 2-2 
Example 2 by 2 contingency table for each reader 
 
New Reads 
Positive 
Negative 
Original 
Reads 
Positive 
a 
b 
Negative 
c 
d 
 
Step 2: Based on the contingency tables described above, a simple agreement rate, i.e.  
𝑎𝑎+𝑑𝑑
𝑎𝑎+𝑏𝑏+𝑐𝑐+𝑑𝑑 
and its corresponding 95% confidence interval (Agresti A, Coull BA 1998) will be estimated 
based on normal approximation.  
Step 3: Finally, a Cohen’s kappa statistic  (𝜅𝜅2)  and its corresponding 95% confidence interval 
will be estimated (Cohen J 1960; Cohen J 1968; Fleiss J, Levin B, Paik MC 2003) using the 
formula 𝜅𝜅2 ± 1.96𝑆𝑆𝑆𝑆, where 𝑆𝑆𝑆𝑆= ට
𝑝𝑝𝑜𝑜(1−𝑝𝑝𝑜𝑜)
𝑁𝑁(1−𝑝𝑝𝑒𝑒)2  (McHugh M 2012).  Let 𝑁𝑁 denote the number 
of re-reads (𝑁𝑁= 20), 𝑘𝑘 the number of categories (𝑘𝑘= 2), 𝑛𝑛𝑖𝑖1the number of times the original 
reads were assigned to 𝑖𝑖 (𝑖𝑖= 1, … , 𝑘𝑘) and 𝑛𝑛𝑖𝑖2the number of times the re-read were assigned to 
𝑖𝑖 (𝑖𝑖= 1, … , 𝑘𝑘). Then Cohen’s kappa can be calculated as 𝜅𝜅2 = 
𝑝𝑝𝑜𝑜−𝑝𝑝𝑒𝑒
1−𝑝𝑝𝑒𝑒, where 𝑝𝑝𝑜𝑜 is the relative 
agreements among the original and re-reads (𝑝𝑝𝑜𝑜= 
𝑎𝑎+𝑑𝑑
𝑎𝑎+𝑏𝑏+𝑐𝑐+𝑑𝑑 in Table 2-2) and  𝑝𝑝𝑒𝑒= ∑
𝑛𝑛𝑖𝑖1
𝑁𝑁
𝑛𝑛𝑖𝑖2
𝑁𝑁
𝑘𝑘
𝑖𝑖=1
 
(𝑝𝑝𝑒𝑒=
𝑎𝑎+𝑏𝑏
𝑁𝑁
𝑎𝑎+𝑐𝑐
𝑁𝑁+ 
𝑐𝑐+𝑑𝑑
𝑁𝑁
𝑏𝑏+𝑑𝑑
𝑁𝑁 in Table 2-2). Intra-reader variability will be calculated for the SAF. 
2.6.3 
Handling of intercurrent events  
Though no secondary estimands are defined for the study, intercurrent events defined in the 
primary estimands will impact secondary endpoints analysis. Thus they will be handled in the 
same way as in primary estimands analyses. Participants who receive the investigational 


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imaging agent [18F]CTT1057 but do not undergo/complete the  [18F]CTT1057 PET/CT scan 
for any reasons (e.g. drop out, PET camera failures, etc) will not be used for the secondary 
efficacy endpoint analysis, but safety data for these participants will be collected after the 
administration of the investigational imaging agent and will be summarized.  
2.6.4 
Handling of missing values not related to intercurrent event 
This is a diagnostic study, where the secondary endpoints are calculated on the basis of a one-
time imaging assessment. Missing data will not be imputed. 
2.6.5 
Sensitivity analyses 
No sensitivity analyses are planned for the secondary endpoints.  
2.6.6 
Supplementary analyses 
No supplementary analyses are planned for the secondary endpoints.  


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2.8 
Safety analyses 
All safety analyses will be based on the safety set. 
2.8.1 
Adverse events (AEs) 
Adverse events are coded using MedDRA terminology. The latest MedDRA version used for 
reporting will be specified in the CSR and as a footnote in the applicable tables/listings. AEs 
will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. AE summaries will include all AEs that started or worsened during the on-treatment 
period. (See Section 2.1.1) All AEs that started or worsened within 14 days after the 
[18F]CTT1057 dose, and adverse events that were reported as related to [18F]CTT1057 
irrespective of time of onset will be regarded as treatment emergent AEs. 


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AEs will be summarized by the number and percentage of participants having at least one AE, 
having at least one AE in each primary system organ class (SOC) and for each preferred term 
(PT) using MedDRA coding. A participant with multiple occurrences of an AE will be counted 
only once in the respective AE category. A participant with multiple CTCAE grades for the 
same preferred term will be summarized under the maximum CTCAE grade recorded for the 
event. AE with missing CTCAE grade will be included in the ‘All grades’ column of the 
summary tables. 
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency.  
The following adverse event summaries will be produced: overview of all adverse events and 
deaths (number and % of participants who died, with any AE, any SAE, any dose change, drug 
withdrawn, etc.), AEs by SOC and PT, by relationship (all AEs and AEs related to study 
treatment), seriousness (SAEs and non-SAEs), leading to treatment discontinuation, leading to 
dose change, and leading to fatal outcome. In addition, a summary of serious adverse events 
with number of occurrences will be produced (an occurrence is defined as >1 day between start 
and prior end date of record of same preferred term). To help evaluate the impact of the COVID-
19 on the safety, the incidence of COVID-19 related adverse event preferred terms will be 
presented. All COVID-related AEs will be included in the listings. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables for on-
treatment emergent adverse events which are not serious adverse events with an incidence of 
greater than 5% and on-treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by SOC and PT for the SAF. 
• If for the same participant, several consecutive AEs (irrespective of study treatment 
causality, seriousness and severity) occurred with the same SOC and PT: a single occurrence 
will be counted if there is ≤ 1 day gap between the end date of the preceding AE and the 
start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
All AEs collected in the AE (e)CRF page will be listed along with the information collected on 
those AEs, e.g. AE relationship to study drug, AE outcome, etc. All AEs, deaths, and serious 
adverse events (including those from the pre- and post-treatment periods) will be listed and 
those collected outside of the on-treatment period will be flagged. 
2.8.1.1 
Safety topics of interest / grouping of AEs 
A safety topic of interest (STI) is a grouping of adverse events that are of scientific and medical 
concern specific to the tracer [18F]CTT1057. These groupings are defined using MedDRA terms, 


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SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may 
also be used. A NMQ is a customized group of search terms which defines a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 
need. It may include a combination of single terms and/or an existing SMQ, narrow or broad. 
STI will be defined at the project level and may be regularly updated. The grouping of AEs in 
STI according to project standards will be specified in the electronic Case Retrieval Sheet 
(eCRS). For each specified STI, the number and percentage of participants with at least one 
event of the STI occurring during on-treatment period will be summarized. 
STIs will be summarized by grade, SAE, relationship, leading to treatment discontinuation, 
leading to dose adjustment/interruption, hospitalization, death etc. A listing of all grouping 
levels down to the MedDRA preferred terms used to define each STI will be generated. All the 
analyses will be carried out for the SAF. 
2.8.2 
Deaths 
Two separate summaries, one for on-treatment and the other for all deaths (including post-
treatment deaths) will be produced, by system organ class and preferred term. The number of 
deaths resulting from SAEs suspected to be related to study treatment will also be summarized. 
See details given in Section 2.8.1. 
All deaths will be listed, post-treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened participants. 
2.8.3 
Laboratory data 
Laboratory data from all sources (central and local laboratories) will be combined for the 
analysis. The summaries will include all assessments available for the lab parameter collected 
prior to (baseline) and during the on-treatment period (14 + 3 day-window) after the study 
treatment administration.  
All laboratory data will be listed by participant and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) CTCAE version 5.0. The calculation of CTCAE grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology and biochemistry 
tests: 


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• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges. 
For laboratory tests where grades are defined by CTCAE version 5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-
treatment value 
For laboratory tests where grades are not defined by CTCAE version 5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
The number and percentage of participants with an abnormal ECG (clinically significant) at 
screening will be presented. ECG data will be read and interpreted locally. A listing of all ECG 
assessments will be produced. These analyses will be performed for the FAS. 
In addition, for the approximately 10 PK subset participants: 
Specified parameters PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead 
ECGs for each participant in the PK subset on treatment day (Day 1) at pre-injection, post-
injection/pre-imaging, and post-imaging and at Safety follow-up Day 15. 
The number and percentage of PK subset participants with notable ECG values will be 
presented.  
• QT, QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤ 60ms 
- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 60 bpm 
• PR 
- 
Increase from baseline >25% and to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and to a value > 120 ms 
- 
New values of QRS > 120 ms 


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2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: body temperature, blood pressure, pulse rate, respiratory 
rate.  
Data handling 
Vital signs collected prior to (baseline) and on-treatment (14 + 3 day-window after the study 
treatment administration) will be summarized. Values measured outside of the on-treatment 
period will be flagged in the listings. 
Data analysis 
For analysis of vital signs, the clinically notable vital sign criteria are provided in Table 2-3 
below. 
Table 2-3 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
Increase  
Decrease 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Body 
temperature 
(°C) 
>= 39.1  
- 
Pulse rate 
(bpm) 
> 100 with increase from baseline  
of > 25% 
< 60 with decrease from baseline  
> 25% 
Respiratory 
rate 
> 22  breaths per minute 
<14  breaths per minute 
The number and percentage of participants with notable vital sign values (high/low) will be 
presented.  Descriptive statistics will be tabulated for baseline, at each post-baseline time point 
and changes from baseline at each post-baseline time point for each vital sign measure.         
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected outside of on-treatment period will be flagged. 
2.9 
Pharmacokinetic endpoints   
All PK analyses will be carried out on the PAS. 
The [18F]CTT1057 pharmacokinetic analysis will be performed based on decay-corrected blood 
radioactivity concentration data obtained by measuring the blood samples drawn at pre-defined 
time points (Table 8-6 of the protocol) using a calibrated gamma-counting device. Blood mass 
concentration data were also planned to be summarized per protocol, however the conversion 


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of radioactivity concentration to mass concentration will not be possible due to missing 
information of mass concentration of the drug product during the manufacturing process. 
Radioactivity concentration in blood will be calculated using the following formula: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅= ൫𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
ൗ
൯ / 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷1 
where, RDCNNDB is radioactivity concentration in blood (not decay corrected), ACTMENDC 
is radioactivity measured (not decay corrected), SAMPVOL is volume of the sample measured, 
and DURSFLT1 is gamma counter calibration factor. 
Decay correction of the radioactivity concentration in blood will be performed using the 
following formula: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅= 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 × 𝑒𝑒−𝜆𝜆∙(𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅&𝑇𝑇𝑇𝑇𝑇𝑇−𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸) 
where, RDCNDCB is radioactivity concentration in blood (decay corrected), λ is decay constant, 
RDACTDAT&TIM is radioactivity measurement date and time, and ECSTDTC is dose 
administered date and time. 
Decay constant (λ) is calculated using the following formula: 
𝜆𝜆= 𝑙𝑙𝑙𝑙2 𝑡𝑡1/2
ൗ
 
where, t1/2 is half-life of 18-F which is 109.7 min. 
Blood radioactivity concentration data will be listed by participant and visit/sampling time point. 
Pharmacokinetic parameters will be listed by participant. Descriptive summary statistics will 
be provided by visit/sampling time point. Summary statistics will include mean (arithmetic and 
geometric), standard deviation (SD), coefficient of variation (CV) (arithmetic and geometric), 
median, minimum, and maximum. An exception to this is Tmax, where only median, minimum, 
and maximum will be presented. 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin® (Version 8 or 
higher): Cmax, Tmax, AUClast, AUCinf, T1/2, Vz and CL (Table 2-4). 
Table 2-4 
Non-compartmental pharmacokinetic parameters 
AUC%Extrap1 
Area under the plasma concentration-time curve 
extrapolated from the time t to infinity as a 
percentage of total AUC (%) 
AUClast 
The AUC from time zero to the last measurable 
concentration sampling time (tlast) (mass x time 
x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time 
x volume-1) 
Clast2 
Last measurable concentration (mass x volume-
1) 
Cmax 
The maximum (peak) observed plasma, blood 
serum, or other body fluid drug concentration 


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after single dose administration (mass x volume-
1) 
Tmax 
The time to reach maximum (peak) plasma, 
blood, serum, or other body fluid drug 
concentration after single dose administration 
(time) 
T1/2 
The elimination half-life associated with the 
terminal slope (λz) of a semi logarithmic 
concentration-time curve (time) 
Tlast2 
Last measurable concentration sampling (time) 
Rsqadj1 
Square of the correlation coefficient associated 
with lambda_z 
CL 
The total body clearance (CL) of drug from 
plasma, blood serum, or other body fluid drug 
concentration (volume x time-1) 
Vz 
The apparent volume of distribution during 
terminal phase (associated with λz) (volume) 
1 AUC%Extrap and Rsqadj will be used in the interpretation of the primary PK parameters and 
therefore will be included in the listings only.  
2 Clast and Tlast will only be listed but not summarized 
The elimination of the compound in urine will be evaluated based on decay-corrected urine 
radioactivity concentration data obtained by measuring the urine samples drawn at pre-defined 
time points (Table 8-7 of the protocol) using a calibrated gamma-counting device. Urine 
elimination data will be expressed as the percentage of injected activity (%ID) in each specified 
time interval and also as cumulative %ID excreted up to the end of each time interval. Urine 
elimination data will be listed by participants. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, and 
maximum. 
Radioactivity concentration in urine will be calculated using the following formula: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅= ൫𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
ൗ
൯ / 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷1 
where, RDCNNDU is radioactivity concentration in urine (not decay corrected), ACTMENDC 
is radioactivity measured (not decay corrected), SAMPVOL is volume of the sample measured, 
and DURSFLT1 is gamma counter calibration factor. 
Decay correction of the radioactivity concentration in urine will be performed using the 
following formula: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅= 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 × 𝑒𝑒−𝜆𝜆∙(𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅&𝑇𝑇𝑇𝑇𝑇𝑇−𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸) 
where, RDCNDCU is radioactivity concentration in urine (decay corrected), λ is decay constant, 
RDACTDAT&TIM is radioactivity measurement date and time, and ECSTDTC is dose 
administered date and time. 
Decay constant (λ) is calculated using the following formula: 
𝜆𝜆= 𝑙𝑙𝑙𝑙2 𝑡𝑡1/2
ൗ
 


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where, t1/2 is half-life of 18-F which is 109.7 min. 
The percentage of injected activity (%ID) will be calculated using the following formula: 
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃= ൫𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅× 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸× 1000
ൗ
൯× 100(%) 
where, PCTINDS is percentage of injected activity (%ID) in urine, and ECDOSE is decay-
corrected administered dose (MBq). 
2.10 
PD and PK/PD analyses 
No PD and PK/PD analyses are planned in the study.  
2.11 
Patient-reported outcomes 
No patient-reported outcomes analyses are planned in the study.  
2.12 
Biomarkers 
No biomarker analyses are planned in the study.  
2.14 
Interim analysis 
No interim analysis is planned for this study.  
3 
Sample size calculation 
The sample size calculation is based on the co-primary endpoints of patient-level sensitivity 
and region-level specificity. 
Overall, a total study sample size of approximately 195 participants will be enrolled in order to 
get at least 156 evaluable participants for the co-primary endpoints (i.e. those who have both an 
evaluable PET/CT scan and histopathology assessment and have not received any prohibited 
systemic antineoplastic therapy before the completion of PET/CT and surgery). These 
calculations were made using the software PASS 11 and R 3.6.1. 
3.1 
Primary endpoint(s) 
This study is planned to recruit approximately 195 participants. The primary objective is to 
evaluate the patient-level sensitivity of [18F]CTT1057 (evaluated for all participants including 
primary tumors and PLN) and the region-level specificity of [18F]CTT1057 (evaluated only for 
PLN regions). The sample size calculation is based on the co-primary endpoints of patient-level 
sensitivity and region-level specificity of [18F]CTT1057. 
The rationale for the choice of the co-primary endpoints is provided below. 
In PS patients before surgery, both the primary tumor and the metastatic PLN are expressing 
PSMA, which is the target for [18F]CTT1057 binding. After surgery, pathology of both the 
primary tumor and the dissected pelvic LN will be used as a SoT. A patient-level analysis would 


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allow to identify positive lesions in both regions. A region-level analysis for sensitivity is not 
considered appropriate for the primary endpoint as 156 PLN would be needed in order to 
determine, approximately 520 participants would have to receive the radioactive investigational 
PET tracer to yield 156 participants with positive PLN. In order to limit the number of 
participants exposed to radiation for this purpose and given that both the primary tumor and 
affected PLN are [18F]CTT1057 targets, sensitivity is proposed to be analyzed on the patient 
level. Region-level sensitivity is included as a secondary endpoint. On the other hand, 
specificity can be assessed on the regional level (at the PLN region) since a sufficient number 
of participants with negative PLN are expected to be obtained at pathology. 
The assumptions for sample size calculations are based on estimates available from prior studies 
as described below. 
A large variability in sensitivity of PSMA-PET in the primary staging setting has been reported. 
Two recent systematic reviews of [68Ga]PSMA PET /CT diagnostic accuracy focused on the 
PS population using pathology as SoT, sensitivity of 33–99% across studies has been reported 
(Corfield et al 2018), as well as pooled sensitivity and specificity ranges of 23-100% and 67-
100% respectively (Petersen and Zacho 2020). Recent preliminary data on the diagnostic 
efficacy of F-18-rhPSMA-7.3 PET imaging in PS patients compared to histopathology (n=56) 
reported a 95% CI low bound patient. A meta-analysis on the diagnostic accuracy of CT and 
MRI in the staging of pelvic lymph nodes in patients with PCa). A study evaluating the 
diagnostic value of [68Ga]PSMA PET versus CT and MRI for lymph node staging in 130 
consecutive patients who got RP and PLN).   
Taking all the above into consideration, an overall patient-level sensitivity of 50% and a region 
level specificity of 70% will be considered as unacceptably low. Hence, the sample size 
calculation will be performed based on the null and alternative hypotheses as follows.  
 
Patient-level sensitivity  
For patient-level sensitivity, the null hypothesis (H0: patient-level sensitivity p0 = 0.50) will be 
tested against the alternative hypothesis (H1: p1 > 0.50)Assuming a sensitivity of 0.63 under 
the alternative hypothesis, approximately 156 participants with primary tumor and/or metastatic 
PLN would achieve 90% statistical power to detect a change in sensitivity of 0.13 using a one-
sided binomial test at a targeted one-sided significance level of 2.5%.  Taking into account a 
20% dropout rate, 195 participants can ensure the 90% statistical power.  
The lower bound of the 95% CI for sensitivity should be greater than 0.50 to be considered a 
success. 
 
Region-level specificity 
For region-level specificity, the null hypothesis (H0: region-level specificity p0 = 0.70) will be 
tested against the alternative hypothesis (H1: p1 > 0.70). Assuming a specificity of 0.85 under 
the alternative hypothesis, approximately 123 participants (which includes 37 participants with 
PLN based on a 30% prevalence) would achieve 90% statistical power to detect a change in 
specificity of 0.15 using a one-sided binomial test at a targeted significance level of 2.5 %. 
Taking into account a 20% dropout rate, 154 participants can ensure the 90% statistical power.  


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The lower bound of the 95% CI for specificity should be greater than 0.70 for the study to be 
considered a success. 
A total sample size of 195 participants can ensure 90% statistical power for patient-level 
sensitivity and 99% statistical power for region-level specificity resulting in an overall study 
statistical power of at least 89.1% (0.9 x 0.99). 
4 
Change to protocol specified analyses 
Minor updates to the estimand wording were made as compared to the protocol for clarification. 
Blood mass concentration data were planned to be summarized per protocol as part of the PK 
analysis, however the conversion of radioactivity concentration to mass concentration will not 
be possible due to missing information of mass concentration of the drug product during the 
manufacturing process. Section 2.9 of the SAP clarifies the analyses that will be summarized. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The complete date of dose administration is required for this study. Completely or partially 
missing date will not be imputed and should be considered as a data issue and the statistician 
should contact the data manager of the study. 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than date 
of dose administration then set start date = 01JanYYYY  
o Else set start date = date of dose administration.  
• If available year > year of date of dose administration then 
01JanYYYY 
• If available year < year of date of dose administration then 
01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of date of dose 
administration then  
o If stop date contains a full date and stop date is earlier than date 
of dose administration then set start date= 01MONYYYY.  
o Else set start date = date of dose administration. 
• If available month and year > month and year date of dose 
administration then 01MONYYYY   
• If available month and year < month year of date of dose 
administration then 15MONYYYY   
 
Table 5-2 
Imputation of end dates (AE, CM) 
Missing 
Element 
Rule  
(*=date of dose administration plus 15 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
 
If imputed end date is < start date, set end date = start date. 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
5.1.3 
Other imputations 
For the date of initial diagnosis, missing day is defaulted to the 15th of the month and missing 
month and day is defaulted to 01-Jan.  
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 


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CTCAE grading is by definition a 5-point scale generally corresponding to mild, moderate, 
severe, life threatening, and death. This grading system inherently places a value on the 
importance of an event, although there is not necessarily proportionality among grades (a grade 
2 is not necessarily twice as bad as a grade 1).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 (specify version used in the 
RAP). The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. The criteria to assign CTCAE grades are 
given in Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 5.0 at the time of 
analysis will be used. For laboratory tests where grades are not defined by CTCAE v5.0, results 
will be graded by the low/normal/high (or other project-specific ranges, if more suitable) 
classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.02 [40 (g/L) - Albumin (g/L)] 
For calculation of laboratory CTC grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
Patient-level sensitivity and two-sided exact binomial 95% CIs will be calculated.  


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Only pelvic lymph node regions will be used to calculate the specificity. Region-level 
specificity and two-sided exact binomial 95% CIs will be calculated. 
Exact binomial confidence intervals (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated (Clopper and Pearson 1934). 
The supplementary analyses for the co-primary endpoints of patient-level sensitivity and 
region-level specificity and the corresponding 95% CIs will be calculated based on a covariate-
adjusted logistic regression model. The LOGISTIC procedure in SAS will be used to implement 
the logistic regression model adjusting for covariates. This analysis will be applied to each of 
the three central reader via the (BY READER) statement. 
The predicted probability and 100 (1-α)% confidence limits for patient-level sensitivity 𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 
for each central reader can be obtained from SAS using the logistic regression model with 
covariates. 
𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 (𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆) = log ൜
𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
1 −𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
ൠ=  𝛼𝛼+ 𝛽𝛽1 𝑋𝑋𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 2 + 𝛽𝛽3𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 3
+ 𝛽𝛽4𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 4 + 𝛽𝛽5𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 5 + 𝛽𝛽6𝑋𝑋𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 
The predicted probability and 100 (1-α)% confidence limits for region-level specificity 𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 
for each central reader can be obtained from SAS using the logistic regression model with 
covariates. 
 𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 ൫𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆൯= log ൜
𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
1−𝑃𝑃𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆ൠ=  𝛼𝛼+ 𝛽𝛽1 𝑋𝑋𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 2 + 𝛽𝛽3𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 3 +
𝛽𝛽4𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 4 + 𝛽𝛽5𝑋𝑋𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐺𝐺𝐺𝐺𝐺𝐺 5 + 𝛽𝛽6𝑋𝑋𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 
 
5.4.2 
Analysis supporting secondary objective(s) 
For patient-level efficacy endpoints, their estimation and two-sided exact binomial 95% CIs 
will be calculated (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) (Clopper and Pearson 1934). 
Only pelvic lymph node regions will be used to calculate region-level efficacy endpoints, and 
their estimation and two-sided exact binomial 95% CIs will also be calculated.  
For inter- and intra-reader variability, 95% CIs will be calculated based on normal 
approximation with details given in Section 2.6.2.  


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6 
Reference 
Agresti A, Coull, BA (1998) Approximate is better than "Exact" for interval estimation 
of binomial proportions. The American Statistician: 52(2):119-26.Cohen, J. (1960). A 
coefficient of agreement for nominal scales. Educational and psychological 
measurement; 20(1): 37-46. 
Cohen, J. (1968). Weighted kappa: nominal scale agreement provision for scaled 
disagreement or partial credit. Psychological bulletin; 70(4): 213.Corfield J, Perera M, Bolton 
D, et al (2018) 68Ga-prostate specific membrane antigen (PSMA) positron emission 
tomography (PET) for primary staging of high-risk prostate cancer: a systematic review. 
World J Urol; 36:519-27. 
Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrical, 26, 404-413. 
D'Amico AV, Whittington R, Malkowicz SB, et al (1998) Biochemical outcome after radical 
prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically 
localized prostate cancer. JAMA; 280(11):969-74. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45:228-47. 


Novartis 
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Study No. CAAA405A12302 
 
Fleiss J. L. (1971). Measuring nominal scale agreement among many raters. Psychological 
bulletin; 76(5): 378-382. 
Fleiss J, Levin B, Paik MC (2003) Statistical Methods for Rates and Proportions, 3rd Ed, 
Wiley Series in Probability and Statistics. 
Fleiss J, Nee J, Landis J (1979) . The large sample variance of kappa in the case of different 
sets of raters. Psychological bulletin; 86(5): 974-977. 
Hövels AM, Heesakkers RAM, Adang EM, et al (2008) The diagnostic accuracy of CT and 
MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. 
Clin Radiol; 63:387-95. 
Kuten J, Fahoum I, Savin Z, et al (2020) Head-to-Head Comparison of 68Ga-PSMA-11 with 
18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and 
Immunohistochemical Analysis as a Reference Standard. J Nucl Med; 61(4):527-32. 
Maurer T, Gschwend JE, Rauscher I, et al (2016) Diagnostic Efficacy of (68)Gallium-PSMA 
Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging 
of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol; 
195:1436-43. 
Maurer T, Langbein T, Kroenke M, et al (2020) Diagnostic efficacy of 18F-RHPSMA-7.3 
imaging for n-staging patients with high-risk prostate cancer [abstract]. J Urol; 203 Suppl 
4:e952A 
McHugh, M (2012) Interrater reliability: the kappa statistic. Biochemia Medica; 22(3): 276-
282. 
Petersen LJ, Zacho HD (2020) PSMA PET for primary lymph node staging of intermediate 
and high-risk prostate cancer: an expedited systematic review. Cancer Imaging; 20:10 
Woythal N, Arsenic R, Kempkensteffen C, et al (2018) Immunohistochemical Validation of 
PSMA Expression Measured by 68Ga-PSMA PET/CT in Primary Prostate Cancer. J Nucl 
Med; 59(2):238-43.