Clinical trial NCT04838613
Conditions: Prostatic Neoplasms Prostate Cancer Recurrence
Keywords: [18F]CTT1057 [68Ga]Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography PET/CT Radioligand Imaging Biochemical recurrence BCR Composite Truth Standard CTS Prostate Cancer PCa
Sponsor: Novartis Pharmaceuticals
Start date: 2021-09-30; Completion date: 2023-11-23
Enrollment: 190 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The current study aimed at evaluating the diagnostic performance of \[18F\]CTT1057 as a PET imaging agent for detection and localization of Prostate specific membrane antigen (PSMA) positivity in patients diagnosed of biochemical recurrence of prostate cancer (PCa), using a composite truth standard.

Approximately 190 participants were to be enrolled to ensure at least 152 participants were evaluable (i.e. have both an evaluable \[18F\]CTT1057 Positron emission tomography/Computed Tomography (PET/CT) scan imaging and at least one evaluable Composite Truth Standard (CTS) assessment and had not received any prohibited systemic antineoplastic therapy before the completion of PET/CTs and CTS procedures, which were required for the calculation of the co-primary endpoints.

Detailed description:
This was a prospective, open-label, multi center, single-arm Phase III study to evaluate the diagnostic performance of \[18F\]CTT1057 as a PET imaging agent for detection and localization of PSMA positive tumors in PCa patients diagnosed with biochemical recurrence (BCR) after initial definitive therapy with either radical prostatectomy (RP) or curative intent radiation therapy (RT), using a CTS as reference.

The CTS to be used as reference were hierarchical in nature, with 3 levels of Standard of Truth (SoT) procedures, that were applied as follows:

CTS Level 1: Histopathology if available for the lesion (from prospective biopsy or salvage surgery performed within 8 weeks after the \[18F\]CTT1057 PET/CT scan); OR in case that histopathology was not available for a lesion, inconclusive or negative (for biopsy only).

CTS Level 2: Imaging diagnostic procedures performed on each patient as clinically indicated per SoC, which included at least a high resolution CT scan with contrast and a \[68Ga\]Ga-PSMA-11 PET/CT) performed within 8 weeks (either before or after) the \[18F\]CTT1057 PET/CT scan. Three-month follow-up imaging (from baseline) were also be used as part of the CTS level 2 in cases where it is clinically required for the diagnosis of particular lesion(s); OR if neither of the two above were feasible or deemed appropriate or they were inconclusive.

CTS Level 3: 50% or greater decline in PSA following radiation therapy (as long as no concomitant androgen deprivation therapy (ADT) was given) as per Prostate Cancer Working Group 3 (PCWG3) criteria.

All participants underwent 2 PET/CT scans: one with the investigational agent \[18F\]CTT1057 and another with \[68Ga\]Ga-PSMA-11 (as a component of the CTS Level 2 and for a secondary endpoint of assessment of concordance between the 2 PET/CT scans for detection of lesions). The 2 PET imaging procedures were performed at least 14 days apart, and the PET/CT scan sequence for each participant was assigned at random in a 1:1 ratio.

Arms: arm 1: All eligible participants were assigned to one of the following two PET/CT scan sequences at random in a 1:1 ratio:

* Sequence 1: \[18F\]CTT1057 on Day 1 (investigational imaging agent of interest) followed by \[68Ga\]Ga-PSMA-11 at least 14 days apart (as part of CTS if required, and for secondary endpoint)
* Sequence 2: \[68Ga\]Ga-PSMA-11 (as part of CTS if required, and for secondary endpoint) on Day 1 followed by \[18F\]CTT1057 (investigational imaging agent of interest) at least 14 days apart
Interventions: intervention 1: [18F]CTT1057 intervention 2: [68Ga]Ga-PSMA-11
Intervention descriptions: intervention 1: Single intravenous dose of approximately 370 Mega-Becquerel (MBq) and subsequent PET/CT scan intervention 2: Single intravenous dose of approximately 150 MBq and subsequent PET/CT scan

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Document type: 
Amended  Protocol Version 
EUDRACT number: 
2020-003959-16 
Version number: 
01  (Amended Protocol Clean) 
Clinical Trial Phase: 
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 CAAA405A12301/ NCT04838613
 
 
Phase III study for evaluation of the diagnostic 
performance of [18F]CTT1057 PET imaging in
 
patients with
 
 
prostate cancer with rising PSA levels
 
[biochemical
 
 
recurrence (BCR)] (GuidePath)


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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 ............................................................................................................. 21 
1 
Introduction ....................................................................................................................... 25 
1.1 
Background ............................................................................................................ 25 
1.2 
Purpose .................................................................................................................. 28 
2 
Objectives and endpoints ................................................................................................... 28 
2.1 
Primary estimands ................................................................................................. 31 
2.2 
Secondary estimands ............................................................................................. 33 
3 
Study design ...................................................................................................................... 33 
4 
Rationale ............................................................................................................................ 36 
4.1 
Rationale for study design ..................................................................................... 36 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 39 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 39 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 39 
4.5 
Risks and benefits .................................................................................................. 39 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 40 
5 
Study Population ............................................................................................................... 40 
5.1 
Inclusion criteria .................................................................................................... 41 
5.2 
Exclusion criteria ................................................................................................... 41 
6 
Treatment ........................................................................................................................... 42 
6.1 
Study treatment ...................................................................................................... 42 
6.1.1 
Investigational and control drugs .......................................................... 42 
6.1.2 
Additional study treatments .................................................................. 43 
6.1.3 
Supply of study treatment ..................................................................... 43 
6.1.4 
Treatment arms/group ........................................................................... 44 


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6.1.5 
Treatment duration ................................................................................ 44 
6.2 
Other treatment(s) .................................................................................................. 44 
6.2.1 
Concomitant therapy ............................................................................. 44 
6.2.2 
Prohibited medication ........................................................................... 45 
6.3 
Participant numbering, treatment assignment, randomization .............................. 45 
6.3.1 
Participant numbering ........................................................................... 45 
6.3.2 
Treatment assignment, randomization .................................................. 45 
6.4 
Treatment blinding ................................................................................................ 46 
6.5 
Dose escalation and dose modification.................................................................. 46 
6.5.1 
Follow-up for toxicities ......................................................................... 46 
6.6 
Additional treatment guidance ............................................................................... 46 
6.6.1 
Treatment compliance ........................................................................... 46 
6.7 
Preparation and dispensation ................................................................................. 47 
6.7.1 
Handling of study treatment and additional treatment .......................... 47 
6.7.2 
Instruction for preparing and administering study treatment ................ 49 
7 
Informed consent procedures ................................................................................. 50 
8 
Visit schedule and assessments ............................................................................. 51 
8.1 
Screening ............................................................................................................... 59 
8.1.1 
Eligibility screening .............................................................................. 59 
8.1.2 
Information to be collected on screening failures ................................. 59 
8.2 
Participant demographics/other baseline characteristics ....................................... 59 
8.3 
Efficacy .................................................................................................................. 60 
8.3.1 
Imaging for tumor assessment .............................................................. 60 
8.3.2 
Histopathology assessments .................................................................. 64 
8.3.3 
PSA level assessments .......................................................................... 64 
8.3.4 
Appropriateness of efficacy assessments .............................................. 64 
8.4 
Safety ..................................................................................................................... 64 
8.4.1 
Laboratory evaluations .......................................................................... 66 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 68 
8.4.3 
Pregnancy and contraception ................................................................ 68 
8.4.4 
Appropriateness of safety measurements .............................................. 68 
8.5 
Additional assessments .......................................................................................... 68 


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8.5.1 
Other Assessments ................................................................................ 68 
9 
Study discontinuation and completion .................................................................. 69 
9.1 
Discontinuation from study treatment and study ................................................... 69 
9.1.1 
Discontinuation from study treatment ................................................... 69 
9.1.2 
Discontinuation from study ................................................................... 70 
9.1.3 
Lost to follow-up ................................................................................... 70 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 70 
9.3 
Early study termination by the sponsor ................................................................. 71 
9.4 
Study completion and post-study treatment .......................................................... 71 
10 
Safety monitoring and reporting ............................................................................ 72 
10.1 
Definition of adverse events and reporting requirements ...................................... 72 
10.1.1 
Adverse events ...................................................................................... 72 
10.1.2 
Serious adverse events .......................................................................... 73 
10.1.3 
SAE reporting........................................................................................ 74 
10.1.4 
Pregnancy reporting .............................................................................. 75 
10.1.5 
Reporting of study treatment errors including misuse .......................... 75 
10.2 
Additional Safety Monitoring ................................................................................ 76 
10.2.1 
Steering Committee ............................................................................... 76 
11 
Data Collection and Database management .......................................................... 76 
11.1 
Data collection ....................................................................................................... 76 
11.2 
Database management and quality control ............................................................ 76 
11.3 
Site monitoring ...................................................................................................... 77 
12 
Data analysis and statistical methods .................................................................... 77 
12.1 
Analysis sets .......................................................................................................... 77 
12.2 
Participant demographics and other baseline characteristics ................................. 78 
12.3 
Treatments ............................................................................................................. 78 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 78 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 78 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 79 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 79 
12.4.4 
Handling of missing values not related to intercurrent event ............... 79 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 79 


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12.4.6 
Supplementary analysis ......................................................................... 79 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 80 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 80 
12.5.2 
Safety endpoints .................................................................................... 82 
 
 84 
12.7 
Interim analyses ..................................................................................................... 84 
12.8 
Sample size calculation.......................................................................................... 84 
12.8.1 
Primary endpoint(s) ............................................................................... 85 
13 
Ethical considerations and administrative procedures ........................................... 86 
13.1 
Regulatory and ethical compliance ........................................................................ 86 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 86 
13.3 
Publication of study protocol and results............................................................... 87 
13.4 
Quality Control and Quality Assurance ................................................................. 87 
14 
Protocol adherence................................................................................................. 87 
14.1 
Protocol amendments............................................................................................. 88 
15 
References.............................................................................................................. 89 
16 
Appendices ............................................................................................................ 95 
16.1 
Appendix 1: Common Terminology Criteria for Adverse Events......................... 95 
16.2 
Appendix 2: Response Evaluation Criteria in Solid Tumors................................. 96 
16.3 
Appendix 3: PCWG3 ............................................................................................. 97 
16.4 
Appendix 4: Patient Management questionnaire ................................................... 98 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 28 
Table 6-1 
Investigational PET imaging agents ...................................................... 42 
Table 8-1 
Assessment Schedule ............................................................................ 52 
Table 8-2 
Imaging Assessment Collection Plan .................................................... 61 
Table 8-3 
Assessments and Specifications ............................................................ 66 
Table 8-4 
Performance Status................................................................................ 66 
Table 8-5 
Laboratory assessments ......................................................................... 67 
Table 10-1 
Guidance for capturing the study treatment errors including misuse ... 75 


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List of figures 
Figure 3-1 
Study Design ......................................................................................... 34 
 


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List of abbreviations 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ASCT2 
Alanine, Serine, Cysteine Transporter 2 
AST 
Aspartate Aminotransferase 
ASTRO 
American Society for Radiation Oncology 
ATC 
Anatomical Therapeutic Chemical 
AUA 
American Urological Association 
BCR 
Biochemical recurrence 
BUN 
Blood Urea Nitrogen 
CDR 
Correct Detection Rate 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CLR 
Correct localization rate  
CMO&PS 
Chief Medical Office and Patient Safety 
CO 
Country Organization 
COVID-19 
Coronavirus disease 2019 
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 
cTNM 
Clinical Stage 
CTS 
Composite Truth Standard 
DBP 
Diastolic Blood Pressure 
EANM 
European Association of Nuclear Medicine 
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 
EOT 
End of Treatment 
ePLND 
extended Pelvic Lymph Node Dissection 
eSAE 
electronic Serious Adverse Event 
EU 
European Union 
F-SAF 
[18F]CTT1057 Safety Set 


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FAS 
Full Analysis Set 
FDG 
Fluorodeoxyglucose 
FN 
False Negative 
FP 
False Positive 
Ga-SAF 
[68Ga]Ga-PSMA-11 Safety Set 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
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 
LAT-1 
L-Type Amino Acid Transporter 1 
LDH 
lactate dehydrogenase 
LHRH 
Luteinizing Hormone-Releasing Hormone 
MBq 
Mega-Becquerel 
MCH 
Mean Corpuscular Hemoglobin 
mCi 
Millicurie 
mCRPC 
metastatic-Castration Resistant Prostate Cancer 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
mSV 
millisievert 
NCI 
National Cancer Institute 
p.i. 
post-injection 
PCa 
Prostate Cancer 
PCWG3 
Prostate Cancer Working Group 3 
PET 
Positron Emission Tomography 
PLN 
Pelvic Lymph Node 
PPV 
Positive Predictive Value 
PSA 
Prostate Specific Antigen 
PSMA 
Prostate Specific Membrane Antigen 


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pTNM 
pathological stage 
QC 
Quality Control 
QMS  
Quality Management System 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP 
Radical Prostatectomy  
RR 
Respiratory Rate  
RT 
Radiation therapy 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee  
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 participants 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 


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Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
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 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
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. 


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Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
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, 20 subjects have been randomized in the study 
(12 dosed). 
The main purpose of the amendment is to clarify the inclusion criterion on PSA level requirements for 
confirmation of biochemical recurrence (BCR) following radiation therapy and following Radical 
Prostatectomy (RP) to avoid misinterpretation and ensure full alignment with the published definitions 
for BCR per AUA and ASTRO-Phoenix guidelines and with the targeted study population (patients who 
have BCR following initial definitive therapy). The amendment also clarifies that subjects with prior 
salvage radiation therapy or salvage surgery are not eligible for the study to ensure alignment with the 
targeted patient population. 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 2.1 
Section 3 
Section 5 
Targeted population in 
the study 
Additional information 
provided. 
Clarification that targeted population for 
the study is prostate cancer patients 
diagnosed with biochemical recurrence 
(BCR) after initial definitive therapy (with 
either RP or curative intent RT) 
Section 3 
Clarification of safety 
assessments follow-up 
timing 
Updated to ensure that safety assessments 
to be performed at the safety follow-up at 
14 days (+ 3 day window) after each 
PET/CT scan day are also performed 
before any surgery/radiation 
therapy/initiation of antineoplastic 
medication, in the event where the patient 
would undergo surgery, radiation therapy 
or initiating any antineoplastic medication 
(provided all CTS procedures have been 
completed before this initiation) prior to 
planned safety visit. 
Protocol summary 
Section 5.1 
Update of Inclusion 
criterion #3 
For patients who had 
prior RP, BCR must be 
confirmed by an initial 
serum PSA of ≥0.2 
ng/mL measured at least 
Modified inclusion criterion (numbered 3a) 
to clarify the requirements for biochemical 
recurrence (BCR) following initial 
definitive therapy with either RP or 
curative-intent radiation therapy (RT) and 
fully align with the definitions of BCR 
from the publications referred to for AUA 


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6 weeks after RP with a 
second confirmatory 
persistent PSA level 
of >0.2 ng/mL. For 
patients who had prior 
curative-intent radiation 
therapy (RT), BCR is 
defined as a rise of 
serum PSA 
measurement of 2 or 
more ng/mL above the 
nadir PSA observed post 
RT. 
and ASTRO-Phoenix criteria and the 
targeted population. 
Protocol summary 
Section 5.2 
Section 6.2.2 
Removal of exclusion 
criterion #6 and 
update of exclusion 
criterion #7 and 
clarification that 
LHRH analogues 
include LRHR agonists 
or antagonists 
Exclusion criterion #6 is removed as this is 
not relevant for the purpose of this study to 
completely exclude prior treatment with 
LHRH analogues (agonists or antagonists) 
which are part of ADT. Many subjects 
receive ADT (including LHRH analogues) 
in combination with primary curative intent 
radiation therapy. The same washout 
period as for other ADTs (9 months) 
should apply for LHRH analogues. 
Exclusion criterion #7 was updated 
accordingly (numbered 7a) to exclude any 
prior ADT including LHRH analogues 
(agonists or antagonists) within 9 months 
before screening. 
Section 6.2.2 was also updated to clarify 
that LHRH analogues include LHRH 
agonists or antagonists. 
Protocol summary 
Section 5.2 
Addition of a new 
exclusion criteria (#12) 
 
 
Clarification that patients who received 
prior salvage surgery or salvage RT are not 
eligible for the study as the targeted 
population is patients with BCR following 
initial definitive therapy.  
Protocol summary 
Table 2-1Section 
12.6 
Update of Secondary 
endpoint and 
Clarification that the secondary endpoint 
(based on central imaging reads) and 
for concordance between 
[18F]CTT1057 and [68Ga]Ga-PSMA-11 for 
detection of PSMA-positive lesions (in 
terms of number of lesions detected and 


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their location) will be assessed at lesion 
level, not patient level.  
Protocol summary 
Section 3 
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. patient who have both an 
evaluable [18F]CTT1057 PET/CT 
scan imaging,  and at least one evaluable 
CTS assessment and have not received any 
prohibited systemic antineoplastic therapy 
before the completion of PET/CTs and 
CTS procedures.  
Section 3 
Section 4.1 
Section 8.3.1 
 
Clarification on 
[68Ga]Ga-PSMA-11 
PET/CT scan 
acquisition 
requirements 
Clarification that [68Ga]Ga-PSMA-11 
PET/CT scan is mandatory for all patients 
randomized. 
Section 3 
Section 4.1 
Section 8.3.1 
 
Clarification on 
Standard of Care 
imaging part of CTS 
level 2 timing 
Clarification that the high resolution CT 
scan and any other imaging diagnostic 
procedure clinically indicated as per SoC 
part of CTS level 2 must be acquired 
within the 8 weeks either prior to or 
following the [18F]CTT1057 PET/CT scan. 
Section 8.3.1 
Addition of Table 8-2 
Addition to provide clarity to sites on the 
imaging procedures expected for this study 
and their timing. Subsequent tables in the 
document were re-numbered accordingly.  
Section 8.3.1 
 
 
 
  
Section 8.3.1 
Clarification on 
Characteristics of 
lesions 
Clarification that the characteristics of 
lesions should be documented for lesions 
that are visually positive on the [68Ga]Ga-
PSMA-11 PET but not considered as 
prostate cancer (i.e. non prostate cancer 
tumoral lesions, or benign non tumoral 
lesions). 
Section 3 
Section 12.5.1 
Section 16.4 
(Appendix 4) 
Addition of a new 
option in questionnaire 
#2 
Addition of a new option named 
“Radiation alone with change in radiation 
treatment plan”, which will be applicable 
only for questionnaire 2, in order to capture 
any intended change in the radiation plan 


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(e.g. change in the extent of the field of 
radiations).  
Section 6.2.1 
Clarification of use of 
diuretics  
Clarification that the 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. 
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 CTS 
procedures, to ensure that the same lesions 
are assessed on PET/CT scans and CTS 
procedures without potential reduction in 
lesion size and therefore detectability due 
to administration of antineoplastic 
medications. 
Section 8.5.1 
Clarification of patient 
management 
questionnaire #2  
Timing for completion 
Clarification that patient management 
questionnaire 2 should be completed before 
[68Ga]Ga-PSMA-11 PET/CT is performed 
for subjects assigned to sequence 1.  
Section 10.1.3 
Section 10.1.5 
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 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 
Incidence of AEs 
wording clarification 
Updated 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 


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for AEs occurring during each treatment 
period (i.e. within 14 days after each PET 
tracer administration) as described in 
Section 12.5.2. 
Protocol summary 
Table 2-1 
Section 12.4.6 
Subgroup of patients 
definition update 
The names for the 2 subgroups of patients 
defined for subgroup analyses are corrected 
to patients with prior RP and patients with 
prior curative intent radiation therapy 
Section 3 
Screening assessments 
update 
Updated to remove imaging assessments 
from screening period paragraph as 
imaging procedures to be performed in the 
study do not belong to screening 
assessments. 
Protocol summary 
Section 3 
Section 4.1 
Section 8.3.1 
Section 12.4.1 
Section 12.5.1 
Clarification of the 
different CTS levels 
Clarification that the different CTS levels 
will be applied hierarchically at lesion 
level for efficacy analyses. CTS level 2 
will be used as SoT if histopathology is not 
available for a lesion, inconclusive (if 
biopsy/surgery tissue sample is not 
evaluable for histopathology assessment 
due to sample quality or inadequate 
quantity or any other technical causes) or 
negative (for biopsy only). CTS level 3 
will be used as SoT if CTS level 2 imaging 
diagnostic procedures are not available or 
inconclusive (i.e. if images are not 
interpretable due to poor or inadequate 
image quality that precludes reliable 
assessment). Section 4.1 also clarified that 
for CTS level 3, the lesion on the 
[18F]CTT1057 PET/CT scan that was 
irradiated will be classified as a true 
positive (TP) in case of ≥50% PSA 
decrease 3 months after RT, or as FP 
otherwise. 
Section 4.1 
Section 12.5.1 
Section 12.8.1 
 
Regions definition for 
region-level efficacy 
endpoints analysis 
Updated to clearly mention the different 
regions considered for this study as used 
for the region-level efficacy endpoints 
analyses: prostate region (comprising 
prostate bed/prostate gland and any local 
invasion of the urinary bladder, rectum or 
seminal vesicles), pelvic lymph nodes 
(PLN) region, extra-PLN region, skeletal 
region and visceral region). 


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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 
assessments 
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 
Clarification on PSA 
levels requirement in 
CTS level 3  
Clarification that PSA levels should be 
tested prior RT and 90 days post RT as part 
of additional follow-up if CTS level 3 is 
applicable for the patient, as described in 
Section 8.3.3. 
Table 8-1 (footnote*) 
Addition of footnote* 
Addition of footnote* to clarify that all 
screening assessments to confirm 
eligibility must be done prior 
randomization. 
Table 8-1 
Clarification of timing 
of enrolment and Day 
1  
The table is updated to clarify that 
enrolment 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 (first dosing 
visit) should occur maximum 14 days after 
enrolment. 
Table 8-1 (footnote 
7) 
Update on ordering 
requirements 
Updated to mention that ordering should be 
done after randomization and based on the 
radiopharmaceutical that requires the 
longest period from order to delivery 
Table 8-1 
Update of Day 1 visit 
window 
The table is updated to allow a visit 
window of 7 days since the 
enrolment/randomization could occur 
earlier than 14 days prior Day 1 
Table 8-1 
Clarification of 
urinalysis 
requirements  
Updated 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 8.2 was also updated to reflect that 
urinalysis test results (that are part of 
baseline characterictics data) will be 
assessed but not captured in eCRF. 


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Section 8.3.2 
Table 8-1 
(Footnote #2) 
 
Additional information 
and update on 
histopathology 
assessment  
Information updated (footnote #10 
removed) to separate histopathology 
(biopsy/salvage surgery) assessment (CTS 
level 1) in the table from the SoC 
diagnostic procedures performed as part of 
CTS level 2 and also clarify the specific 
timing for each assessment. If indicated for 
the subject, biopsy/salvage surgery should 
be performed within 8 weeks after the 
[18F]CTT1057 PET/CT scan AND after 
[68Ga]Ga-PSMA-11 PET/CT scan. SoC 
diagnostic procedures, which include at 
least a high resolution CT scan with 
intravenous and oral contrast (or MRI if 
CT scan with contrast is medically 
contraindicated), and any other SoC 
imaging diagnostic procedure as clinically 
indicated per SoC (CT/MRI, Bone Scan, 
etc.), should be performed within 8 weeks 
before or after [18F]CTT1057 scan. 
Section 8.3.1 
Table 8-1 
(Footnote #9) 
Terminology update 
for CT scan 
Updated to remove the “low dose” 
terminology which is no longer used in 
clinical practice for the CT portion of 
PET/CT (transmission scan). 
Section 8.2 
 
Diagnostic criteria 
redundancy removed 
Updated to remove that diagnostic criteria 
is to be reported in the eCRF as this is 
redundant with the already mentioned 
collection of Gleason grade, PSA and 
clinical stage at diagnosis in the eCRF. 
Section 8.4 
Table 8-3 
Correction of 
misplaced information 
on collection of vital 
signs 
Updated 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 any clinically significant finding 
from local laboratory results available for 
the patient should also be considered for 
eligibility assessment, notably for 
exclusion criterion #2. 
Section 8.4.1 
Table 8-5 
Clarification of lab 
tests  
Updated for clarification that phosphorus 
laboratory parameter is phosphate 


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(inorganic phosphorus) and that glucose is 
non-fasting glucose. 
Section 8.4.2 
Clarification on ECG 
review requirements 
Update to add that ECG will be locally 
collected and evaluated. 
Section 9.1 
Clarification in the 
discontinuation 
definition and wording 
Update to separate discontinuation from 
study treatment and discontinuation from 
study. 
Section 9.1.2 
Addition of section 
Update to separate discontinuation from 
study treatment 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 discontinuation of 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 
Clarification on SAE 
reporting  
Update to emphasize reporting timelines 
requirements and all related 
documentation.  
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 
 
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. 


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Section 12.5.2 
Clarification on lab 
values listing 
Updated to indicate that clinically notable 
values or changes in vital signs will be 
flagged in listings. 
All sections 
Minor updates 
Minor typographical corrections, removal 
of duplicated wording and minor 
rewording were implemented across the 
document. 
 
Protocol Summary 
Protocol 
number 
CAAA405A12301 
Full Title 
Phase III study for evaluation of the diagnostic performance of [18F]CTT1057 
PET imaging in patients with prostate cancer with rising PSA levels [biochemical 
recurrence (BCR)] (GuidePath) 
Brief title 
Study of diagnostic performance of [18F]CTT1057 in BCR 
Sponsor and 
Clinical Phase 
Novartis Phase 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 tumour 
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 current study aims at evaluating the diagnostic performance of 
[18F]CTT1057 as a PET imaging agent for detection and localization of PSMA 
positivity in patients diagnosed of biochemical recurrence of prostate cancer 
(PCa), using a composite truth standard. 
Primary 
Objective(s)  
The co-primary objectives of this study are 
• 
to evaluate the region-level correct localization rate (CLR) of 
[18F]CTT1057 
• 
to evaluate the patient-level positive predictive value (with anatomical 
localization) of [18F]CTT1057 
The primary clinical question of interest is: What is the probability that a positive 
[18F]CTT1057 PET/CT scan  truly detects and localizes (PSMA-expressing) 
tumor recurrence in BCR PCa patients? 
Secondary 
Objectives 
• 
To evaluate the patient-level sensitivity of [18F]CTT1057 
• 
To evaluate the patient-level specificity of [18F]CTT1057 


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• 
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 
• 
To evaluate the region level specificity of [18F]CTT1057 
• 
To evaluate the region level negative predictive value of [18F]CTT1057 
• 
To evaluate the region level accuracy of [18F]CTT1057 
• 
To evaluate correct detection rate (CDR) 
• 
To evaluate detection rate 
• 
To evaluate the patient-level positive predictive value related to PSA levels 
• 
To characterize the safety and tolerability of [18F]CTT1057 
• 
[18F]CTT1057 scan inter-reader variability 
• 
[18F]CTT1057 scan intra-reader variability 
• 
Concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection 
of lesions at lesion level using central reads 
• 
To evaluate the change in patient management plans attributed to the 
PET/CT scan 
• 
Assess all the above primary and secondary objectives independently in the 
subgroup of patients with prior radical prostatectomy (RP) and the subgroup 
of patients  with prior curative intent radiation therapy (RT). 
Study design 
This is a prospective, open-label, multi center, single-arm Phase III study to 
evaluate the diagnostic performance of [18F]CTT1057 as a PET imaging 
agent for detection and localization of PSMA positive tumors in PCa patients 
diagnosed with biochemical recurrence (BCR) after initial definitive therapy with 
either radical prostatectomy (RP) or curative intent radiation therapy (RT), using 
a CTS as reference.  
The CTS to be used as reference will be hierarchical in nature, with 3 levels of 
Standard of Truth (SoT) procedures, that will be applied as follows: 
CTS Level 1: Histopathology if available for the lesion (from prospective biopsy 
or salvage surgery performed within 8 weeks after the [18F]CTT1057 PET/CT 
scan); OR in case that histopathology is not available for a lesion, inconclusive 
or negative (for biopsy only): 
CTS Level 2: Imaging diagnostic procedures performed on each patient as 
clinically indicated per SoC, which must include at least a high resolution CT 
scan with contrast and a [68Ga]Ga-PSMA-11 PET/CT) performed within 8 weeks 
(either before or after) the [18F]CTT1057 PET/CT scan. Three-month follow-up 
imaging (from baseline) will also be used as part of the CTS level 2 in cases 
where it is clinically required for the diagnosis of particular lesion(s); OR if 
neither of the two above are feasible or deemed appropriate or they are 
inconclusive:  
CTS Level 3: 50% or greater decline in PSA following radiation therapy (as 
long as no concomitant androgen deprivation therapy (ADT) is given) as per 
Prostate Cancer Working Group 3 (PCWG3) criteria. 
All participants will undergo 2 PET/CT scans: one with the investigational agent 
[18F]CTT1057 and another with [68Ga]Ga-PSMA-11 (as a component of the 
CTS Level 2 and for a secondary endpoint of  assessment of concordance 
between the 2 PET/CT scans for detection of lesions). The 2 PET imaging 
procedures will be performed at least 14 days apart, and the PET/CT scan 
sequence for each participant will be assigned at random in a 1:1 ratio. 


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Study 
population 
Male participants ≥ 18 years of age, with biopsy proven prostate 
adenocarcinoma and rising PSA after definitive therapy with RP or curative 
intent radiation therapy (external beam or brachytherapy), diagnosed of 
biochemically recurrent PCa. Approximately 190 participants will be enrolled to 
ensure at least 152 participants are evaluable (i.e. have both an evaluable 
[18F]CTT1057 PET/CT scan imaging,  and at least one evaluable CTS 
assessment and have not received any prohibited systemic antineoplastic 
therapy before the completion of PET/CTs and CTS procedures) 
, 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 
• 
Biopsy proven prostate adenocarcinoma. 
• 
Biochemical recurrence following initial definitive therapy (with either radical 
prostatectomy or curative-intent radiation therapy) as defined: 
o 
by American Urological Association (AUA) criteria for patients who have 
undergone  RP: Initial serum PSA of ≥0.2 ng/mL measured at least 6 
weeks after RP with a second confirmatory persistent PSA level of >0.2 
ng/mL, or  
o 
 by American Society for Radiation Oncology (ASTRO)-Phoenix criteria 
for patients who have undergone curative-intent RT: Rise of serum PSA 
measurement of 2 or more ng/mL above the nadir PSA observed post 
RT. 
• 
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, 
uncontrolled infection, active hepatitis B or C, and Coronavirus Disease 
2019 (COVID-19) 
• 
Prior major surgery undergone less than 12 weeks prior to screening (with 
the exception of any surgery related to prostatic cancer) 
• 
Known allergy, hypersensitivity, or intolerance to [18F]CTT1057, [68Ga]Ga-
PSMA-11, or to CT contrast  
• 
Prior and current use of PSMA targeted therapies 
• 
Prior ADT (first or second generation), including Luteinizing Hormone-
Releasing Hormone (LHRH) analogues (agonists or antagonists) within 9 
months before screening  
• 
Any 5-alpha reductase inhibitors within 30 days before screening 
• 
Use of other investigational drugs within 30 days before screening 
• 
Castration-resistant patients 
• 
Patients with small cell or neuroendocrine PCa in more than 50% of biopsy 
tissue 
• 
Prior salvage surgery or salvage radiation therapy 


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Study 
treatment 
The term “Study Treatment” indicates the administration of at least one of the 
two PET imaging agents: [18F]CTT1057 and [68Ga]Ga-PSMA-11 independently 
of whether the PET/CT scans were acquired or not 
Treatment of 
interest 
In this study, the investigational imaging agent of interest is [18F]CTT1057, 
injected as a single intravenous dose of approximately 370 Mega-
Becquerel (MBq) and subsequent PET/CT scan.  
Efficacy 
assessments 
Hierarchical CTS with 3 levels: 
• 
Level 1: Histopathology assessments 
• 
Level 2: Imaging diagnostic assessments: at least a high-resolution CT with 
contrast and a [68Ga]Ga-PSMA-11 PET/CT. Other SoC imaging modalities if 
clinically indicated. Imaging data will be read centrally 
• 
Level 3: PSA assessments 
[18F]CTT1057 PET/CT assessments, read centrally 
Key safety 
assessments 
• 
Adverse Events (AEs) 
• 
Serious Adverse Events (SAEs) 
• 
Vital signs, physical examinations 
• 
Electrocardiograms (ECGs) 
• 
Laboratory parameters including hematology, clinical chemistry 
• 
Concomitant medications and/or therapies 
Other 
assessments 
• 
Patient management questionnaire for secondary endpoint to evaluate the 
change in patient management plans attributed to the PET/CT scan 
Data analysis 
The following data analyses are planned for the study: 
The co-primary endpoints of the study are region-level CLR and patient-level 
Positive Predictive Value (PPV) 
• 
Region-level CLR is defined as the proportion of regions containing at least 
one true positive (TP) lesion (exactly localized correspondence between 
PET imaging and the reference standard), regardless of any co-existent 
false positive (FP) findings within the same region, out of all regions 
containing at least one PET-positive finding. 
Region-level CLR and its 95% confidence interval (CI) will be calculated using 
logistic random-effects models taking into account the correlation among regions 
within one patient. The lower bound of the 95% CI for CLR should be greater 
than 0.5 to attain the first co-primary endpoint.  
• 
Patient-level PPV is defined as the proportion of patients who have at least 
one TP lesion (exactly localized correspondence between PET imaging and 
the reference standard), regardless of any co-existent FP findings, out of all 
patients who are PET/CT scan positive. Patient-level PPV and its 95% 
CI will be calculated based on the binomial distribution. The lower bound of 
the 95% CI for patient-level PPV should be greater than 0.2 to attain the 
second co-primary endpoint.  
Analyses for co-primary endpoints will be based on the efficacy analysis set 
(EFF).  
Centralized imaging assessments (CTS Level 2) will be used as reference 
standard if pathology (CTS Level 1) is not available for a lesion, inconclusive or 
negative (for biopsy only). 


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Other secondary endpoints including patient-level sensitivity, patient-level 
specificity, patient-level negative predictive value, patient-level accuracy, patient-
level correct detection rate, patient-level detection rate, [18F]CTT1057 scan inter-
reader agreement, [18F]CTT1057 scan intra-reader agreement, change in patient 
management plans, region-level sensitivity, region-level specificity, region-level 
negative predictive value, region-level accuracy, concordance between 
[18F]CTT1057 and [68Ga]Ga-PSMA-11 will also be analyzed. Detailed statistical 
methodology for these analyses will be provided in the statistical analysis plan 
(SAP). 
Key words 
[18F]CTT1057, [68Ga]Ga-PSMA-11, PET/CT, Radioligand, Imaging, BCR, CTS, 
PCa  
 
1 
Introduction 
1.1 
Background 
Prostate-specific membrane antigen (PSMA) and prostate cancer 
Prostate-specific membrane antigen is a transmembrane protein, also known as folate hydrolase 
or glutamate carboxypeptidase II. PSMA is highly overexpressed on the tumor cells of prostate 
adenocarcinomas (Hupe et al 2018, Bravaccini et al 2018), and has also been reported to be 
overexpressed on tumor cells and tumor-vasculature of endometrial and ovarian cancer 
(Wernicke et al 2017), and mainly on 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 most 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 174,650 in 2019 
(Siegel et al 2018, 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 future, radioligand therapy (Oh and Kantoff 1999, Roscigno et al 
2005, Jani 2006). Prostate-specific membrane antigen 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 


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decisions for patients with PCa. Identification of distant metastatic disease at the early stages 
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-PSMA PET/CT (Yaxley et al 2019a). This 
is very important, as the morbidity of a surgery could be avoided, given the change in 
management from one of curative intent, to management that will require a multimodality 
approach after treatment of the prostate primary tumor (Yaxley et al 2018, Yaxley et al 2019b). 
Up to 40% of the patients with PCa develop biochemical recurrence (BCR) within 10 years 
after initial treatment (Isbarn et al 2010). Usually an increase of the PSA-level precedes a 
clinically detectable recurrence by months to years (Van Poppel et al 2006). However, it cannot 
differentiate between local, regional or systemic disease with the necessary precision that is 
essential for further disease management (Bott 2004). 
It is relevant, therefore, to detect smaller and distant lesions as early as possible.  With the 
emergence of PSMA-targeted radioligand therapy, in addition to early diagnosis, it is useful to 
diagnose PSMA-positivity to determine the future use of radioligand therapy. This is now 
becoming a reality since the recent approval of  [68Ga]Ga-PSMA-11 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 ([68Ga]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 radioligand therapy options are available for treatment. While solid target 
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. 
Positron Emission Tomography (PET) imaging in prostate cancer  
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 more 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) 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 
examinations are needed (Hricak et al 1987, Shinohara et al 1989, Scheidler et al 1999, 


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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). 
Several head to head comparison studies have been performed on the uptake of 
[18F]Fluciclovine vs [68Ga]Ga-PSMA-11 for localization of PCa BCR. Detection rates were 
superior for [68Ga]Ga-PSMA-11 vs [18F]Fluciclovine after RP in patients with PSA < 2.0 ng/ml 
on per-patient and per-region basis (Calais et al 2018). However, a larger prospective head-to-
head comparison study on [18F]Fluciclovine vs [68Ga]Ga-PSMA-11 in patients with BCR of 
PCa found no statistical differences in the overall detection rate for PCa recurrence between the 
two different radioligands (Pernthaler et al 2019). The differences between these studies may 
be attributed to various factors, including but not limited to sample size differences, differences 
in PSA levels of median values of < 2.0 ng/ml vs 14.9 ng/mL, time between scanning sessions, 
and standardization of the imaging study protocols. 
Fluciclovine is a synthetic amino acid, which is transported across cell membranes by amino 
acid transporters known to be upregulated in cancer tumors, such as L-Type Amino Acid 
Transporter 1 (LAT-1) and Alanine Serine Cysteine Transporter 2 (ASCT2). [18F]Fluciclovine 
uptake is not specific for PCa and may occur in other cancer types. In addition, the lack of 
selectivity for PCa may contribute to false-positive cases, which may be associated with 
inflammatory responses to therapeutic interventions. Contrarily, radioligands selective for the 
PSMA, such as [68Ga]Ga-PSMA-11, provide greater sensitivity and specificity for imaging 
patients with PCa. 
[18F]CTT1057: A promising investigational PSMA-PET radiotracer 
Most experts in the field agree, the future of PSMA-based PET imaging will be with 18F-labeled 
tracers because of the practical advantages: 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 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. 


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A [18F]CTT1057 Phase-I study in 20 PCa patients (n = 5 primary staging and 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 standard of truth (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). 
1.2 
Purpose 
The current study aims at evaluating the diagnostic performance of [18F]CTT1057 as a 
PET imaging agent for detection and localization of PSMA positivity in patients diagnosed of 
biochemical recurrence of PCa , using a composite truth standard. 
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 region-level correct 
localization rate (CLR) of [18F]CTT1057 
• 
Proportion of regions containing at least one 
TP lesion (anatomically localized 
correspondence between PET imaging and 
the reference standard), regardless of any co-
existent FP findings within the same region, 
out of all regions containing at least one PET-
positive finding by central assessments. See 
Section 2.1 for Primary Estimand 
• 
Evaluate the patient-level positive 
predictive value (with anatomical 
localization) of [18F]CTT1057 
• 
Proportion of patients who have at least one 
TP lesion (anatomically localized 
correspondence between PET imaging and 
the reference standard), regardless of any co-
existent FP findings, out of all patients who 
are PET/CT scan positive by central 
assessments. See Section 2.1 for Primary 
Estimand 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 


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Objective(s) 
Endpoint(s) 
• 
Evaluate the patient-level sensitivity of 
[18F]CTT1057 
• 
Proportion of patients that test positive on 
[18F]CTT1057 and CTS (TP) among those 
that are CTS positive (TP or FN) 
• 
Evaluate the patient-level specificity of 
[18F]CTT1057 
• 
Proportion of patients that test negative on 
[18F]CTT1057and CTS (TN) among those that 
are CTS negative (TN or FP) 
• 
Evaluate the patient-level negative 
predictive value of [18F]CTT1057  
• 
Proportion of patients who are both 
[18F]CTT1057 and CTS negative (TN) among 
those who test negative on [18F]CTT1057 (TN 
or FN) 
• 
Evaluate the patient-level accuracy of 
[18F]CTT1057  
• 
Proportion of patients that are CTS and 
[18F]CTT1057 positive (TP) and negative (TN) 
among those patients that identified on 
[18F]CTT1057 (TP, TN, FP or FN) 
• 
Evaluate correct detection rate (CDR)  
• 
Proportion of patients who have at least one 
TP lesion (exactly localized correspondence 
between PET imaging and the reference 
standard), regardless of any co-existent FP 
findings, out of all patients who are scanned 
• 
Evaluate detection rate 
• 
Proportion of patients who have at least one 
PET positive lesion, regardless of TP or FP 
findings, out of all patients who are scanned 
• 
Evaluate the region level sensitivity of 
[18F]CTT1057  
• 
Proportion of regions that test positive on both 
[18F]CTT1057 and CTS (TP) among those 
regions that are CTS positive (TP or FN) 
• 
Evaluate the region level specificity of 
[18F]CTT1057  
• 
Proportion of regions that test negative on 
both [18F]CTT1057 and CTS (TN) among 
those regions that are CTS negative (FP, or 
TN) 
• 
Evaluate the region level negative 
predictive value of [18F]CTT1057  
• 
Proportion of regions that are CTS and 
[18F]CTT1057 negative (TN) among those 
regions that test negative on [18F]CTT1057 
(TN or FN) 
• 
Evaluate the region level accuracy of 
[18F]CTT1057  
• 
Proportion of regions that are CTS and 
[18F]CTT1057 positive (TP) and negative (TN) 
among those regions that identified on 
[18F]CTT1057 (TP, TN, FP and FN) 
• 
 Evaluate the patient-level positive 
predictive value related to PSA levels  
• 
Percentage of patients who have at least one 
TP lesion (exactly anatomically localized 
correspondence between [18F]CTT1057 PET 
imaging and the reference standard), 
regardless of any co-existent FP findings, out 
of all patients who are [18F]CTT1057 positive, 
stratified by PSA levels 
• 
Characterize the safety and tolerability of 
[18F]CTT1057 
• 
Incidence of AEs Treatment emergent 
adverse event (TEAE) rate within 14 days 
after each PET tracer administration 


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Objective(s) 
Endpoint(s) 
• 
[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 
• 
Concordance between [18F]CTT1057 and 
[68Ga]Ga-PSMA-11 for detection of lesions 
at lesion level using central reads 
• 
Concordance between [18F]CTT1057 and 
[68Ga]Ga-PSMA-11  for detection of PSMA-
positive lesions (location and number) using 
central reads 
• 
Evaluate the change in patient 
management plans attributed to the 
PET/CT scan 
• 
Percentage of patients who underwent a 
change in intended treatment plan attributed 
to the PET/CT scan as assessed by pre and 
post imaging questionnaires 
• 
Assess all the above primary and 
secondary objectives independently in the 
subgroup of patients  with prior radical 
prostatectomy and the subgroup of 
patients  with prior curative intent radiation 
therapy 
• 
All the above primary and secondary 
endpoints independently in the subgroup of 
patients with prior RP  and the subgroup of 
patients with prior curative intent radiation 
therapy 


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2.1 
Primary estimands 
The primary clinical question of interest is: What is the probability that a positive [18F]CTT1057 
PET/CT scan truly detects and localizes (PSMA-expressing) tumor recurrence in BCR PCa 
patients? 
The justification for the primary estimand is that we wish to assess the diagnostic performance 
of [18F]CTT1057 PET/CT in detecting and localizing PSMA positivity in PCa patients 
diagnosed of biochemical recurrence (BCR), which represents a stage of PCa where there is an 
increase in PSA levels after initial treatment. Correct identification of disease location and 
extent guides treatment decisions. It is relevant, therefore, to detect smaller lesions as early as 
possible. Sensitivity and specificity of [18F]CTT1057 PET/CT in detecting and localizing 
PSMA positivity using histopathology as SoT will be assessed in an independent study in newly 
diagnosed high-risk PCa patients candidate to surgery. However, in this primary staging 
population a low prevalence and high variability of metastatic lymph nodes has been reported 
(from 4-58%) (Petersen and Zacho 2020). Therefore, an additional study in the BCR setting is 
needed, since this is a relevant patient population which is expected to have an adequate 
representation of metastasis-positive and metastasis-negative patients by any available 
reference standard. In this population, a CTS is needed for reference (for CTS details see 
Section 3 and Section 4.1). Pathology is available in only a limited number of cases, and 
morphological imaging is negative in a substantial number of cases. This makes the 
identification of true and false negative results a challenge, thus complicating the evaluation of 
sensitivity and specificity. Therefore, the region-level correct localization rate (CLR) defined 
as the region-level PPV with anatomical localization and the patient-level PPV with anatomical 
localization are more appropriate co-primary endpoints than sensitivity and specificity in the 
BCR setting. The patient-level PPV with anatomical localization, as the conditional probability 
of positivity given the result of the PET/CT scan is more meaningful than the correct detection 
rate (CDR) defined as the percentage of true-positive patients in the whole population 


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(unconditional probability of positivity). Moreover, the CDR has reported to be dependent of 
the PSA levels in the BCR population using another [18F]-PSMA labeled PET agent 
(Chantadisai et al 2020). 
The primary estimands are described by the following attributes: 
Primary estimand 1: 
1. Population: Patients with biopsy proven prostate adenocarcinoma and rising PSA after 
definitive therapy with RP or curative-intent radiation therapy (external beam or 
brachytherapy), diagnosed of biochemically recurrent PCa. Further details about the 
population are provided in Section 5. 
2. Variable: Proportion of regions containing at least one TP lesion (anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the reference standard), 
regardless of any co-existent FP findings within the same region, out of all regions 
containing at least one [18F]CTT1057 PET-positive finding, using central readings 
3. Treatment of interest: [18F]CTT1057 injected as a single intravenous dose of 
approximately 370 MBq and subsequent PET/CT scan. Further details about the 
investigational treatment is 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 scan for any reasons 
(e.g. consent withdrawal, PET camera failures, etc.) Details on how to handle intercurrent 
events are provided in Section 12.4.3. 
5. Summary measure: Estimate of proportion of regions containing at least one TP lesion 
(anatomically localized correspondence between [18F]CTT1057 PET imaging and the 
reference standard), regardless of any co-existent FP findings within the same region, out 
of all regions containing at least one [18F]CTT1057 PET-positive finding (CLR) and CLR 
along with 95% CI estimated using logistic random-effects models taking into account the 
correlation among regions within one patient.  
Primary estimand 2: 
1. Population: the same as primary estimand 1 
2. Variable: Proportion of patients who have at least one TP lesion (anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the reference standard), 
regardless of any co-existent FP findings, out of all PET positive patients, using central 
readings. 
3. Treatment of interest: the same as primary estimand 1 
4. Handling of remaining of intercurrent events: the same as primary estimand 1 
5. Summary measure: Estimate of proportion of patients who have at least one TP lesion 
(anatomically localized correspondence between [18F]CTT1057 PET imaging and the 
reference standard), regardless of any co-existent FP findings, out of all patients who are 
PET/CT scan positive (PPV) and PPV along with 95% CI estimated using binomial 
distribution. 


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2.2 
Secondary estimands 
Not applicable  
3 
Study design 
This is a prospective, open-label, multi center, single-arm Phase III study to evaluate the 
diagnostic performance of [18F]CTT1057 as a PET imaging agent for detection and localization 
of PSMA positive tumors in PCa patients diagnosed with biochemical recurrence (BCR) after 
initial definitive therapy with either RP or curative-intent RT, using a CTS as reference.  
Approximately 190 participants will be enrolled to ensure at least 152 participants are evaluable 
for the co-primary endpoints. [18F]CTT1057 PET/CT scan imaging will be read in a central 
Contract Research Organization (CRO) by 3 independent nuclear medicine physicians who will 
be blinded to any other patient data. See Section 4.1 and Section 8.3.1 for central read details. 
The CTS to be used as reference will be hierarchical in nature, with 3 levels of SoT procedures 
that will be applied as follows: 
 Level 1) 
• Histopathology if available for a lesion (from prospective biopsy or salvage surgery 
performed within 8 weeks after the [18F]CTT1057 PET/CT scan); OR in case that 
histopathology is not available for a lesion, inconclusive (i.e. if biopsy/surgery tissue 
sample is not evaluable for histopathology assessment due to  sample quality or 
inadequate quantity or any other technical causes) or negative (for biopsy only): 
Level 2)  
• Imaging diagnostic procedures performed on each patient as clinically indicated per SoC, 
which must include the [68Ga]Ga-PSMA-11 PET/CT scan that is mandatory for all 
subjects randomized in the study and at least a high resolution CT scan (covering at least 
chest, abdomen, and pelvis and any other region as clinically indicated) with intravenous 
and oral contrast (or MRI if CT scan with contrast is medically contraindicated).  The high 
resolution CT scan and any other imaging diagnostic procedure clinically indicated as per 
SoC must be acquired within the 8 weeks either prior to or following the [18F]CTT1057 
PET/CT scan. Three-month follow-up imaging (from baseline) will also be used as part of 
the CTS level 2 in cases where it is clinically required for the diagnosis of particular 
lesion(s); OR if neither of the two above are feasible or deemed appropriate or they are 
inconclusive (i.e. images are not interpretable due to poor or inadequate image quality that 
precludes reliable assessment):  
Level 3)  
• 50% or greater decline in PSA following radiation therapy (as long as no concomitant 
androgen deprivation therapy (ADT) is given) as per PCWG3 criteria (Scher et al 2016).  
In the cases where pathology will be available, assessments by the local pathologists will be 
performed as per SoC, and results should be available within 2 weeks after surgery. Pathologists 
will be blinded to any PSMA-PET data (i.e. both PET/CT scans). In this case, only pathology 
will be used as SoT for the concerned lesion(s).  


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In the cases where pathology will not be available for a lesion, the central read results of the 
[68Ga]Ga-PSMA-11 PET/CT scan (performed for all subjects randomized) and other imaging 
diagnostic procedures to be performed on each participant for the CTS level 2 will be used as 
SoT for the co-primary endpoint calculations. See Section 4.1 for central read details. 
All patients will undergo a [68Ga]Ga-PSMA-11 PET/CT as part of the study, for both the CTS 
Level 2 (in case it is required as SoT) and the secondary endpoint of assessment of concordance 
between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of lesions (as detailed 
in Section 2). 
In addition to central review, local review of SoC images (including [68Ga]Ga-PSMA-11) will 
be performed to be used by the treating physician/Clinical Study Investigator for patient 
management decisions and overall assessment. 
See Section 8.3.1 for assessment details and Section 6.4 for blinding requirements. 
A questionnaire on the planned patient management will be filled-in by the treating 
physician/Clinical Study Investigator before (questionnaire 1) and within 14 days after 
(questionnaire 2) knowing the results of the [18F]CTT1057 PET/CT scan. A local review of 
[18F]CTT1057 PET/CT images will also be performed by a local nuclear medicine physician or 
radiologist with expertise in reading oncology PET/CT scans and the results will be provided 
to the treating physician/Clinical Study Investigator for completion of questionnaire 2. Options 
will be given in the questionnaire to capture possible management plan, such as Surgery, 
Radiation alone, Radiation alone with change in radiation treatment plan (only applicable for 
questionnaire 2), Radiation plus ADT, ADT alone, Observation/surveillance, Other (free text 
box). Any change in patient management plan between the questionnaire 1 and questionnaire 2 
should not be based only on [18F]CTT1057 PET/CT scan results since this is an investigational 
diagnostic imaging product. Other diagnostic procedures should be performed as per SoC in 
order to confirm and implement the changed management plan. See Figure 3-1 for study design 
schema. 
Figure 3-1 
Study Design 
 


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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. 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 first 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. 
Once eligibility is confirmed, the participants will be randomized in IRT to be assigned to one 
of the following two PET/CT scan sequences at random in a 1:1 ratio: 
• Sequence 1: [18F]CTT1057 on Day 1 (investigational imaging agent of interest) followed 
by [68Ga]Ga-PSMA-11 at least 14 days apart (as part of CTS if required, and for 
secondary endpoint) 
• Sequence 2: [68Ga]Ga-PSMA-11 (as part of CTS if required, and for secondary endpoint) 
on Day 1 followed by [18F]CTT1057 (investigational imaging agent of interest) at least 14 
days apart 
PET Imaging days 
The 2 PET imaging procedures will be done at least 14 days apart. The day of the first 
PET imaging agent injection will be considered study Day 1. Please refer to Section 8.3.1 for 
the steps that will take place on each PET imaging day. 
Both visits will also be considered as the End of Treatment (EOT) visits. 
Safety Checks 
All treated participants will be contacted by phone within 24 to 72 hours following each 
PET/CT scan in order to capture potential occurring Adverse Events. 
Safety Follow-up 
Participants will come back to the hospital 14 days (+ 3 day window) after each PET/CT scan 
day, for a safety visit including vital signs, lab and urine analysis. For participants undergoing 
surgery, radiation therapy or initiating any antineoplastic medication (provided all CTS 
procedures have been completed before this initiation) prior to planned safety visit, these safety 
follow-up assessments will need to be performed before the surgery/radiation therapy/initiation 
of antineoplastic medication.  
Additional Follow-up 
Additional follow up period will be applicable where additional diagnostic procedures are to be 
performed. These may include SoC pathology, imaging or other modality disease assessments 
(CTS Levels 1 or 2) up to 8 weeks after [18F]CTT1057 PET/CT scan or three-month follow-up 
imaging (from baseline) where it is clinically required for the diagnosis of particular lesion(s). 
In addition, in cases where the CTS Level 2 is not feasible/appropriate or inconclusive, and the 
CTS Level 3 will apply and will include the assessment of PSA levels prior to starting 
RT (which should commence within 8 weeks of completing [18F]CTT1057 PET/CT scan) 
and at approximately 90 days from last day of radiation. 


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4 
Rationale 
4.1 
Rationale for study design 
In this study, a single-dose of the radiopharmaceutical [18F]CTT1057 (investigational imaging 
agent) will be administered intravenously, in an open-label, single-arm design.  
[18F]CTT1057 PET/CT results will be compared to the applicable SoT from the corresponding 
level of the CTS (as described in Section 3) for calculation of the co-primary endpoints and the 
diagnostic performance yielding secondary endpoints. 
Novel imaging agents are routinely evaluated comparing imaging results with histopathological 
findings. In the BCR setting, pathology is expected to be available only in approximately 35-
40% of the patients, and in a subset of the lesions (Fendler et al 2019). Therefore, a combination 
of conventional diagnosis procedures, relying on a combination of biopsy (when possible), 
imaging procedures, and clinical follow up or changes in biomarkers such as PSA levels, 
collectively known as the composite truth standard (CTS), has been used to evaluate the 
diagnostic accuracy of new diagnostic agents in BCR patients. This methodology has 
limitations as the ascertainment of CTS may be subject to non-homogeneous evaluation 
between subjects as biopsy may not be feasible in all patients with metastatic lesions. Therefore, 
diagnosis based on CTS in the majority of the patients relies on conventional imaging, mainly 
morphological imaging procedures which are based on the detection of changes in lesion's size 
and has limitations, including the inability to detect smaller lesions accurately. Accordingly, for 
lesions that cannot be subjectively characterized on a single CT/MRI scan, serial follow up 
scans are obtained in order to observe changes in the morphology over time. Serial CT/MRI 
scans may, therefore, increase the accuracy of diagnosis of smaller, doubtful lesions observed 
on a single scan at the expense of time. However, in the proposed BCR population, conventional 
imaging will be negative in a substantial proportion of cases (Hövels et al 2008). 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 (AfsharOromieh et al 2015, AfsharOromieh et 
al 2017, Fendler et al 2019). It has also demonstrated high sensitivity in detecting PSMA 
positivity when comparing its diagnostic accuracy with histopathologic findings in these 
patients (Fendler et al 2019). Based on this body of evidence, and given the recent approval of 
[68Ga]Ga-PSMA-11 in the USA ([68Ga]GaPSMA11 USPI), it can be used to significantly 
enhance and address the limitations of routinely used CTS for the evaluation of new diagnostics. 
Given the acknowledged lack of optimal reference standard in patients with biochemical 
recurrence (BCR) in cases where pathology is not available, [68Ga]Ga-PSMA-11 PET/CT will 
provide a validated approximation to the truth, for new, upcoming PSMA-PET imaging agents 
that overcome the 68Ga production and delivery hurdles. In this study, the CTS imaging 
component (CTS Level 2) must include at least a high resolution CT scan with i.v. and oral 
contrast (or MRI if CT scan with contrast is medically contraindicated) and a [68Ga] Ga-PSMA-
11 PET/CT scan. Given that in the proposed BCR population, morphological imaging has been 
reported to be negative in a substantial proportion of cases (Hövels et al 2008), the recently 
approved [68Ga]Ga-PSMA-11 PET imaging agent is considered a surrogate standard of truth. 
In addition, any other imaging diagnostic procedures clinically indicated for each patient as per 


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SoC will be included in the CTS Level 2). An 8-week time window before and after the 
investigational PET/CT scan is proposed for the performance of the imaging diagnostic 
component of the CTS Level 2, since no major changes in the disease are expected within this 
timeframe.  
Anatomically localized positive lesions in [18F]CTT1057 PET/CT and the applicable SoT from 
the hierarchical CTS will be considered true positives for the region-level correct localization 
rate (CLR, i.e. region-level PPV)  and patient-level PPV calculations as the co-primary 
endpoints of the study.  
In the cases where pathology will be available, it will be used as SoT (CTS Level 1). Pathology 
may be available in case of identified lesions that can be either biopsied or suitable for salvage 
surgery (in case of solitary or few localized lymph nodes). Local pathologists who will be 
blinded to any PSMA-PET data (i.e. both PET/CT scan results) will assess the tissue specimens 
as per SoC (see Section 6.4 for blinding details) 
If pathology is not available for a lesion, inconclusive or negative (for biopsy only), CTS Level 
2 (imaging diagnostic procedures) will be used as SoT. These must include at least a high-
resolution CT scan with i.v. and oral contrast (or MRI if CT scan with contrast is medically 
contraindicated) and a[68Ga]Ga-PSMA-11 PET/CT scan, but will include also any other 
imaging diagnostic procedures clinically indicated for each patient as per SoC. In order to 
reduce variability of image readings across multiple study sites, a centralized reading of these 
imaging diagnostic procedures will be performed in a CRO by 3 readers who will be blinded to 
[18F]CTT1057 PET/CT scan results, but not to other patient data. The majority rule (2/3 readers) 
will be used as a final outcome of the reads. Further details will be provided in the imaging 
charter. See also Section 6.4 and Section 8.3 for blinding and reading details. 
If neither of the two first CTS components (i.e. pathology or imaging) are feasible, conclusive 
or deemed appropriate, then CTS Level 3 (50% or greater decline in PSA following radiation 
therapy (as long as no concomitant androgen deprivation therapy (ADT) is given) as per 
PCWG3 criteria) will be used as SoT. The lesion on the [18F]CTT1057 PET/CT scan that was 
irradiated will be classified as a TP in case of ≥50% PSA decrease 3 months after RT, or as FP 
otherwise. 
A central read of the [18F]CTT1057 PET/CT scans will be performed at a CRO by three 
independent nuclear medicine physicians or radiologists experienced in reading PET, who will 
be blinded to patient data, including the clinical condition of the patient, results of 
histopathology/biopsy, results of conventional imaging and PSA levels. Patients and regions 
will be graded on a two-point scale by each reader (0 = negative; 1 = positive). The 3 PET 
readers’ results will be individually compared to the SoT to generate per-reader performance. 
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. 
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: 


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• A patient will be judged 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 (Eiber et al 2015, Ceci et al 2015, Fendler et al 2019). 
Consistency of the PET 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.  
All patients will undergo 2 PET/CT scans: a [18F]CTT1057 PET/CT scan (investigational 
imaging agent) and a [68Ga]Ga-PSMA-11 PET/CT scan (as part of the CTS level 2 if required, 
and for the secondary endpoint of assessment of concordance between [18F]CTT1057 and 
[68Ga]Ga-PSMA-11 for detection of lesions) (see Section 3). The two scans will be performed 
at least 2 weeks apart for each participant in order to ensure a clean safety profile assessment 
for each PET imaging radiopharmaceutical. Moreover, in order to counter-balance any potential 
change in lesions between the 2 PET/CT scans, the PET/CT scan sequence for each patient will 
be assigned at random, in a 1:1 ratio after enrolment (see Section 6.1.4 for the definition of 
PET/CT scan sequence). 
There is preliminary evidence that PSMA PET imaging allows detection and localization of 
metastases in some BCR patients leading to significant changes in therapeutic approaches 
(Afshar-Oromieh et al 2017). Therefore, assessment of the clinical impact of [18F]CTT1057 
PET/CT in patient management by means of 2 questionnaires has been included as a secondary 
endpoint. Further details on the questionnaire are provided in Section 3. In order to reproduce 
as much as possible the real clinical context, the treating physician / Clinical Study Investigator 
will receive the [18F]CTT1057 PET/CT scan report from a local nuclear medicine physician 
who will be blinded to the results of the [68Ga]Ga-PSMA-11 PET/CT scan, but will not be 
blinded to other patient data. 
In addition, the imaging diagnostic procedures included in CTS Level 2 will be read by local 
nuclear medicine physician or radiologist with expertise in reading oncology PET/CT scans as 
per SoC, who will be blinded to the [18F]CTT1057 PET/CT scan results, but not to other patient 
data. 
 
 
 
. 
 See also Section 6.4 and Section 8.3 for blinding and reading details. 


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4.2 
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 (range 
266– 407 MBq). This dose was shown to be safe and well tolerated in the Phase I study 
(NCT02916537), and it is in line with the recommended dose of the commercial product [18F]-
FDG 
according 
to 
the 
European 
Association 
of 
Nuclear 
Medicine 
(EANM) 
(Boellaard et al 2015). Human dosimetry was studied in the Phase I study. The effective dose 
(ED) was estimated at 0.023±0.007 millisievert (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. injection of 370 MBq of [18F]CTT1057 is 8.51 mSV. Moreover, this dose allowed 
to obtain an optimal image quality, which was rated 76 ± 5.4 on a Visual Analog Scale (VAS) 
of 1 to 100 (1 = non diagnostic, 100 = perfect study), by 2 experienced nuclear medicine 
physicians (Behr et al 2019). Further details on [18F]CTT1057 can be found in the IB. 
The [68Ga]Ga-PSMA-11 radiopharmaceutical will be administered as a single intravenous (i.v.) 
dose of approximately 150 MBq. Administered doses must not be lower than 111 MBq or 
higher than 185 MBq in case. [68Ga]Ga-PSMA-11 PET/CT scans will be used as part of the 
imaging component of the CTS. Refer to the [68Ga]Ga-PSMA-11 USPI for an overview of 
[68Ga]Ga-PSMA-11 recommendations. Refer to Section 6.7 for study drug preparation and 
dispensation. Further details on [68Ga]Ga-PSMA-11 can be found in the IB. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
The use of [68Ga]Ga-PSMA-11 for PET scanning of PCa patients has been ongoing since 2011 
to assess disease burden in the setting of primary staging (localized disease), biochemical 
recurrence (BCR; rising PSA) and advanced/metastatic disease. There are now numerous 
centers around the world that have clinical experience with [68Ga]Ga-PSMA-11, which has been 
approved by the FDA for clinical use in the US ([68Ga]Ga-PSMA-11 USPI). 
The published data consistently demonstrates that imaging with [68Ga]Ga-PSMA-11 is well 
tolerated. Four publications report on a total of 7047 PCa patients that have received [68Ga]Ga-
PSMA-11 (N=1007 (Afshar-Oromieh et al 2017), N=1256 (Von Eyben et al 2018), N=635 
(Fendler et al 2019), N=4149 (Hope et al 2019)). These four studies have further reinforced the 
ability of [68Ga]Ga-PSMA-11 to identify PSMA-expressing PCa and demonstrate it is well 
tolerated. 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 ([68Ga]Ga-PSMA-11 USPI). The risk-benefit ratio is expected to be favorable to the 
[68Ga]Ga-PSMA-11 imaging agent. Further details of [68Ga]Ga-PSMA-11 can be found in the 
IB. 
Subsequently, other PSMA-PET agents have been investigated and are under clinical 
development, 
all 
of 
them 
showing 
a 
good 
safety 
and 
tolerability 
profile. 
(Kuten et al 2020, Szabo et al 2015). The [18F]CTT1057 PET Phase-I study in 20 PCa patients 
(n=5 primary staging, n=15 mCRPC (NCT02916537) has shown an acceptable safety profile, 
without any radiotracer-related adverse reactions (Behr et al 2019). The bio distribution 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 and 
human dosimetry studies, and clinical experience with [18F]CTT1057 suggest good imaging 
quality properties and a favorable safety profile. 
As this is a diagnostic study patients enrolled are not expected to derive direct benefit even 
though 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 appropriate management plan, which will 
not be based on the investigational procedure alone, but confirmed by SoC diagnostic 
procedures. 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. Appropriate eligibility criteria are 
included in this protocol. 
The risk-benefit ratio is expected to be favorable to the [18F]CTT1057 imaging 
agent. Additional details of the nonclinical and clinical experience with [18F]CTT1057 are 
provided in the IB. 
4.6 
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 male participant ≥ 18 years of age, with 
biopsy proven prostate adenocarcinoma and rising PSA after definitive therapy with RP or 
curative-intent radiation therapy (external beam or brachytherapy), diagnosed of biochemically 
recurrent PCa. 
Approximately 190 participants will be enrolled to ensure at least 152 participants are evaluable 
(i.e. have both an evaluable [18F]CTT1057 PET/CT scan imaging,  and at least one evaluable 


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CTS assessment and have not received any prohibited systemic antineoplastic therapy before 
the completion of PET/CTs and CTS procedures), which will be required for the calculation of 
the co-primary endpoints. Refer to Section 12.8.1 for sample size calculation. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Biopsy proven prostate adenocarcinoma. 
3a. Biochemical recurrence following initial definitive therapy (with either RP or curative 
intent radiation therapy) as defined: 
• by AUA criteria (Cookson et al 2007) for patients who have undergone RP: Initial 
serum PSA of ≥0.2 ng/ml measured at least 6 weeks after RP with a second 
confirmatory persistent PSA level of >0.2 ng/ml, or  
• by ASTRO-Phoenix criteria (Roach et al 2006) for patients who have undergone 
curative-intent radiation therapy (RT): Rise of serum PSA measurement of 2 or more 
ng/mL above the nadir PSA observed post RT.  
4. ECOG performance status 0-2 
5. Participants must be adults ≥ 18 years of age 
5.2 
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. Prior major surgery undergone less than 12 weeks prior to screening (with the exception 
of any surgery related to prostatic cancer) 
4. Known allergy, hypersensitivity, or intolerance to [18F]CTT1057, [68Ga]Ga-PSMA-11, or 
to CT contrast  
5. Prior and current use of PSMA targeted therapies 
7a. Prior ADT (first or second generation), including LHRH analogues (agonists or   
antagonists), within 9 months before screening  
8. Any 5-alpha reductase inhibitors within 30 days before screening 
9. Use of other investigational drugs within 30 days before screening 
10. Castration-resistant patients 


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11. Patient with small cell or neuroendocrine PCa in more than 50% of biopsy tissue 
12. Prior salvage surgery or salvage radiation therapy 
 
 
6 
Treatment 
6.1 
Study treatment 
The term “Study Treatment” indicates the administration of at least one of the two PET imaging 
agents: [18F]CTT1057 and [68Ga]Ga-PSMA-11 independently of whether the PET/CT scans 
were acquired or not. In this study, the investigational imaging agent of interest is the 
radioligand imaging compound [18F]CTT1057. [68Ga]Ga-PSMA-11 will be used as a 
component of the CTS Level 2 if required, and in all participants for the secondary endpoint of 
assessment of concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of 
lesions (as detailed in Section 2). 
Participants will be administered both agents at least 2 weeks (14 days) apart as an intravenous 
injection (Refer to Section 6.7 for study drug preparation and dispensation) according to the 
randomly assigned PET/CT scan sequence after enrolment. 
Participants will be administered [18F]CTT1057 and [68Ga]Ga-PSMA-11 as an intravenous 
injection, single dose (Refer to Section 6.7 for study drug preparation and dispensation). Both 
agents will be provided by Novartis. 
The general doses of the study treatment are listed in Section 6.1.  
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational PET imaging agents 
Investigational 
PET imaging 
agents  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
[18F]CTT1057 
370 MBq/mL at 
Calibration time 
(Tc) 
Radiopharmaceut
ical solution for 
injection  
Intravenous use 
Open label, vial 
or syringe 
Sponsor (global) 


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Investigational 
PET imaging 
agents  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
[68Ga]Ga-PSMA-
11 
(150 MBq) 
Either provided 
as Kit for the 
radiopharmaceuti
cal preparation of 
[68Ga]Ga-PSMA-
11 or as ready to 
use 
radiopharmaceuti
cal solution for 
injection  
Intravenous use 
Open label, vial 
or syringe 
Sponsor (global) 
For background and additional details on [18F]CTT1057, refer to Section 6.7 for study drug 
preparation 
and 
dispensation 
and 
to 
the [18F]CTT1057 IB. 
The [18F]CTT1057 
radiopharmaceutical will be administered intravenously at a dose of approximately 370 MBq 
(range 266 – 407 MBq). The exact dose that will have been administered to each patient will 
be recorded in the case report form (CRF) after measurement of the syringe both before and 
after administration in a dose calibrator. 
For background and additional details on [68Ga]Ga-PSMA-11, refer to Section 6.7 for study 
drug preparation and dispensation and to the [68Ga]Ga-PSMA-11 IB. The [68Ga]Ga-PSMA-11 
radiopharmaceutical will be administered as a single intravenous (i.v.) dose of approximately 
150 MBq. Administered doses must not be lower than 111 MBq or higher than 185 MBq in any 
case. The exact dose that will have been administered to each patient will be recorded in the 
CRF after measurement of the syringe both before and after administration in a dose calibrator. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational imaging agent and the component of CTS imaging 
agent are included in this trial. 
6.1.3 
Supply of study treatment 
The investigational imaging agent [18F]CTT1057 will be provided: 
• as a single mono-dose 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. . 
The component of CTS imaging agent [68Ga]Ga-PSMA-11 will be provided: 


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• as a kit for radiopharmaceutical preparation: single vial with a white lyophilized powder to 
be locally reconstituted with a solution of gallium-68 chloride (68GaCl3) in HCl eluted 
from an approved 68Ge/68Ga generator (for the clinical sites equipped with an 
approved 68Ge/68Ga generator).  
• as a single dose ready to use radiopharmaceutical solution: vial or syringe with the 
radiopharmaceutical solution supplied by the partner radiopharmacy (for the clinical sites 
not equipped with an approved 68Ge/68Ga generator).  
The volume of [68Ga]Ga-PSMA-11 solution for injection, corresponding to the radioactive dose 
to be administered, is calculated according to the estimated time of injection, on the basis of the 
current activity provided by the generator and of physical decay of the radionuclide (half-life = 
68 min). After reconstitution, the [68Ga]Ga-PSMA-11 solution must be used according to 
instructions provided in the Pharmacy Manual.  
The process of ordering and delivery, as well as the procedure for any solution preparations is 
described in the Pharmacy Manual. 
Both products must be handled and administered by qualified/authorized personnel only and 
must be prepared in accordance with pharmaceutical quality requirements and radiation safety 
regulations. 
6.1.4 
Treatment arms/group 
This is a single-arm study. However, the PET/CT scan sequences for each participant will be 
assigned at random in a 1:1 ratio after enrolment: 
• Sequence 1: [18F]CTT1057 (investigational imaging agent of interest) followed by 
[68Ga]Ga-PSMA-11 (as part of CTS [if required] and for secondary endpoint). 
• Sequence 2: [68Ga]Ga-PSMA-11 (as part of CTS [if required] and for secondary endpoint) 
followed by [18F]CTT1057 (investigational imaging agent of interest). 
Please refer to Section 6.3.2 for assignment details. 
6.1.5 
Treatment duration 
The planned duration of treatment period (i.e. single-dose administration of the 2 PET imaging 
agents) is at least 2 weeks, with single i.v. injection performed at Day 1 and approximately at 
Day 15. Participants may be discontinued from treatment due to unacceptable toxicity following 
the first administered imaging agent or at the discretion of the investigator or the participant. 
Upon end of treatment and the study, participants may be treated with any other medications 
per discretion of the treating physician. 
6.2 
Other treatment(s) 
6.2.1 
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. 


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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 
randomizing 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. 
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. 
 
6.2.2 
Prohibited medication 
Any medication, therapy or procedure (other than the study treatment) that may interfere with 
PSMA PET imaging is not allowed. Prior to completing both PET imaging scans and CTS 
procedures, 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. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment 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. 
6.3.2 
Treatment assignment, randomization 
The IRT will be used to assign the PET/CT scan sequence to each eligible participants at random 
(1:1 ratio), and the randomization numbers will be stored in 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 [18F]CTT1057 or [68Ga]Ga-PSMA-11  dose  
prior to the scheduled dosing date (refer to Pharmacy Manual). Each 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. 


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6.4 
Treatment blinding 
Treatment and PET/CT scan sequence assignment 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 
read by 3 independent readers blinded to patient data collected in clinical database (such 
as medical history details or diagnostic test results). 
• In addition, [18F]CTT1057 PET/CT images will be read by local nuclear medicine 
physician or radiologist with expertise in reading oncology PET/CT scans at each site, 
who will be blinded to [68Ga]Ga-PSMA-11 PET/CT imaging results, but not to other 
patient data. The results will be shared with the treating physician / Clinical Study 
Investigator to support the completion of the patient management questionnaire 2.  
• Images from diagnostic procedures included in the CTS Level 2 will be submitted to a 
CRO for independent centralized read by independent readers, blinded to [18F]CTT1057 
PET/CT images, but not to other patient data collected in clinical database. 
• In addition, these CTS images will be read by a local nuclear medicine physician or 
radiologist with expertise in reading oncology PET/CT scans at each site as per SoC, who 
will be blinded to [18F]CTT1057 PET/CT imaging results, but not to other patient data. 
• In the cases where pathology will be available, assessments by the local pathologists will 
be performed as per SoC. Pathologists will be blinded to any PSMA-PET data (i.e. both 
PET/CT scans). 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not applicable 
in this study in which each imaging agent is administered only once. 
6.5.1 
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. 
6.6 
Additional treatment guidance 
6.6.1 
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. 


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6.7 
Preparation and dispensation 
Each study site will be supplied with study investigational imaging agent in packaging as 
described under investigational and control drugs Section 6.1.1. 
For [18F]CTT1057 and [68Ga]Ga-PSMA-11 preparation and administration, please refer to 
procedure and instructions contained in the Pharmacy Manual. 
Investigator staff will know the study treatments to dispense to the participant by accessing the 
IRT 
during 
the 
screening 
period 
(between 
Day 
-28 
and 
Day 
-14). 
For [18F]CTT1057 and [68Ga]Ga-PSMA-11 ordering, please refer to procedure and instructions 
contained in the Pharmacy Manual. 
Following administration of the study treatments to the participant, the site personnel will 
capture this information in the source document and will complete the accountability logs for 
traceability purposes. For more detailed instructions please refer to the Pharmacy Manual. 
6.7.1 
Handling of study treatment and additional treatment 
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. 
[18F]CTT1057 
The packaging [18F]CTT1057 consists in a white glass multidose vial (For EU) or a monodose 
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 imaging 
agent is intended at the clinical site, except the: 
• dispensation into monodose 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. 


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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 Phamacy 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 no, expiry date. 
[68Ga]Ga-PSMA-11 
The packaging of PSMA-11 kit consists of a box (secondary packaging) and one 10 mL glass 
vials (primary packaging). 
[68Ga]Ga-PSMA-11 will be supplied by Sponsor as a sterile, one-vial kit for reconstitution with 
68Ga solution eluted from approved commercial Good Manufacturing Practice (GMP) 
68Ge/68Ga generator to: 
1. the clinical site, in case of the kit’s reconstitution and radiolabelling will be performed at 
hospital’s radiopharmacy, 
2. the radiopharmacy appointed by the sponsor, in case of an external radiopharmacy will be 
in charge of the kit’s reconstitution and radiolabeling. 
In the second case, the clinical site will order the [68Ga]Ga-PSMA-11 single dose ready to use 
solution for injection following the instructions described in the Pharmacy manual. 
[68Ga]Ga-PSMA-11 must be prepared and administered at the investigational site by 
appropriately trained personnel. The instruction for radiolabeling procedure and dispensing 
[68Ga]Ga-PSMA-11, cautionary notes, analytical controls and stability of the radiolabeled 
product will be provided to each site (please refer to the Pharmacy Manual). 
After reconstitution with 68Ga solution eluted from GMP 68Ge/68Ga generator, the imaging 
agent is a radioactive substance which must be stored, handled and administered by 
qualified/authorized personnel only as described in the Pharmacy Manual and must be prepared 
in accordance with pharmaceutical quality requirements and radiation safety regulations. 
The kit for the preparation of [68Ga]Ga-PSMA-11 should be stored upon receipt according to 
storage conditions as described in the medication label. 
The imaging agent [68Ga]Ga-PSMA-11 will be locally discarded according to all disposal 
requirements and local regulations for radioactive materials. The disposal of all study treatment 
will 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. 
Kits 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. 


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[68Ga]Ga-PSMA-11 ready to use radioactive solution labels will be in the local language and 
comply with the legal requirements of each country. They will include storage conditions, batch 
no and expiry date. 
6.7.2 
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. 
[18F]CTT1057 will be injected intravenously at approximately 370 MBq (range 266 – 407 
MBq), then flushed by 10 mL of saline during the imaging day.  
The investigational product is a radioactive substance which must be used, handled and 
administered by qualified/authorized personnel only and must be prepared in accordance 
with the Pharmacy Manual, pharmaceutical quality requirements and radiation safety 
regulations. 
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. 
[68Ga]Ga-PSMA-11 
Preparation 
In case of the kit’s reconstitution and radiolabelling will be performed at hospital’s 
radiopharmacy. 
The instruction for radiolabeling procedure, cautionary notes, analytical controls and stability 
of the radiolabeled product will be provided to each site (please refer to the Pharmacy Manual). 
In case of an external radiopharmacy will be in charge of the kit’s reconstitution and 
radiolabeling, the clinical site will receive the [68Ga]Ga-PSMA-11 single dose ready to use 
solution for injection. 
Administration 
[68Ga]Ga-PSMA-11 must be administered at the dose as presented in Section 6.1.1 
investigational site by appropriately trained personnel. The instruction for radiolabeling 
procedure and dispensing [68Ga]Ga-PSMA-11, cautionary notes, analytical controls and 


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stability of the radiolabeled product will be provided to each site (please refer to the Pharmacy 
Manual). 
After reconstitution with 68Ga solution eluted from GMP 68Ge/68Ga generator, the 
investigational product is a radioactive substance which must be used, handled and administered 
by qualified/authorized personnel only and must be prepared in accordance with the Pharmacy 
Manual, pharmaceutical quality requirements and radiation safety regulations. The total activity 
administered must be recorded (GBq, Millicurie (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). 
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/she 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 Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice (GCP) 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. 


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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 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 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 who discontinue 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 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 administered imaging agents should be 
reconciled, and the adverse event and concomitant medications not previously reported must be 
recorded on the 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 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
Informe
d 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT 
Participa
nt 
Registra
tion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusio
n / 
Exclusio
n 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
History 
& 
Demogr
aphics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
Electroc
ardiogra
m 
(ECG) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG 
Perform
ance 
Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical 
Examina
tion 
S (short) 
  
S 
(short) 
  
  
  
  
  
S 
(short) 
  
  
  
  
  
S 
(short
) 
  
  
Body 
Weight 
X 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
Body 
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital 
Signs4 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
Hematol
ogy5 
X 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
Clinical 
Chemist
ry 
X 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
PSA 
level 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X (Prior RT 
and 90 
days post 
RT) 
  
Urinalysi
s6 
S 
  
S 
  
  
  
  
  
S 
  
  
  
  
  
S 
  
  
IRT 
Random
ization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
[18F]CTT
1057 
and 
[68Ga]G
a-
PSMA-
11 
Ordering
7 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse 
Events 
 
AEs to be collected throughout this period 
  
  


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
[18F]CTT
1057 / 
[68Ga]G
a-
PSMA-
11 or 
[68Ga]G
a-
PSMA-
11 / 
[18F]CTT
1057 
Administ
ration8 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
Concom
itant 
Medicati
ons 
Concomitant Medications to be collected throughout this period 
  
  


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
[18F]CTT
1057 
/[68Ga]G
a-
PSMA-
11 
PET/CT 
Imaging
9 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Patient 
Manage
ment 
Questio
nnaire 
Before and within 14 days after [18F]CTT1057 PET/CT scan results 
  
  
Histopat
hology, 
if 
applicab
le 
 
  
  
If indicated, biopsy/salvage 
surgery should be performed 
within 8 weeks after completion 
of the  [18F]CTT1057 PET/CT 
scan AND after completion of 
the   [68Ga]Ga-PSMA-11 
PET/CT scan  


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
SoC 
diagnost
ic 
imaging 
procedu
res 
assess
ment  
At least a high resolution CT scan with intravenous and oral contrast (or MRI if CT scan with contrast is medically contraindicated), and any other SoC imaging 
diagnostic procedure as clinically indicated per SoC (CT/MRI, Bone Scan, etc.), performed within 8 weeks before or after [18F]CTT1057 scan  
Safety 
Follow 
up Call 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
End of 
Phase 
Dispositi
on 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
X 
* All Screening assessments to confirm eligibility into the study must be performed prior randomization. 
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 Participants will undergo either [68Ga]Ga-PSMA-11 PET/CT followed by [18F]CTT1057 PET/CT at least 14 days apart, or [18F]CTT1057 PET/CT followed by [68Ga]Ga-
PSMA-11 PET/CT at least 14 days apart 
2   Additional follow-up includes any SoC pathology assessment (of a biopsy/salvage surgery performed up to 8 weeks from [18F]CTT1057 PET/CT scan, CTS level 1) 
and/or any SoC imaging diagnostic procedures assessments (at least a high-resolution CT with contrast)  performed up to 8 weeks from [18F]CTT1057 PET/CT scan for 
CTS level 2; If CTS level 3 is applicable for the participant (in case Levels 1 or 2 are not feasible, inconclusive or negative), the PSA levels will be assessed prior to RT, 


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Period 
Screening* 
Treatment 
Additional 
Follow-up 
Study 
Completion 
Visit 
Name 
Screeni
ng 
Random
ization 
PET Imaging 11 
Safe
ty 
Che
ck 1 
PET Imaging 21 
Safet
y 
Chec
k 2 
Safet
y 
Follo
w-up 
Additional 
Follow-
up2 
EOS 
Days 
Day -28 
to Day -
14 
Day –28 
to Day -
14  
Day 1  
(+7) 
Day 
2 to 
3 
Day 15 (+7) 
Day 
16 to 
17 
Day 
29 (+ 
3) 
up to 90 
days after 
RT 
Day 29 to 
Follow-up 
end 
Time 
(post-
dose) 
- 
- 
Pre-
Injecti
on 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 1 
- 
Pre-
Injecti
on3 
Inje
ctio
n 
Post-
Injection/ 
Pre-Imaging 
Ima
gin
g 
Post-
Imaging / 
EOT 2 
- 
- 
- 
- 
which should commence within 8 weeks after [18F]CTT1057 PET/CT scan and after both PET/CTs are completed, and at approx. 90 days from the last day of radiation 
3 Assessments done prior to starting 2nd injection will be also considered as safety follow-up 14 days after the first PET Imaging Day 
4 Vital signs will be performed at screening, at Imaging days (pre and post-injection and then before patient discharge) and at Safety follow-up visit (Day29) 
5 Peripheral venous blood samples will be collected at screening, PET Imaging Days pre-injection and at Safety follow-up (Day 29) 
6 Urine sample will be collected at screening and imaging days and analyzed at the clinical site if dipstick results are abnormal 
7 Order to be placed after randomization and based on  the radiopharmaceutical that requires the longest period from order to delivery  
8 Participant will be injected intravenously either approximately 370 MBq (range 266–407 MBq) of [18F]CTT1057 or approximately 150 MBq (range 111-185MBq) of 
[68Ga]Ga-PSMA-11, 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. 50-100 min after [68Ga]Ga-PSMA-11 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.   
 


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8.1 
Screening 
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, eligibility reviewed and, once eligible, study treatment 
ordered. 
Laboratory assessments should be carried out as priority to allow the necessary time to obtain 
the results and to confirm participant eligibility prior to randomization and study treatment 
ordering in IRT. All Screening assessments to confirm eligibility into the study should be 
performed between Day -28 and Day -14 as per Visit Assessment Schedule in 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 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.  
8.1.1 
Eligibility screening 
Following registering 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. 
Please refer and comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization 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). If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 


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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. 
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. 
Participant demographic and baseline characteristic data to be assessed on all subjects include: 
• Demographic information: age, gender, self-identified race and ethnicity 
• Vital signs: body temperature, blood pressure, heart rate (HR), respiratory rate (RR), 
• Weight and height 
• ECOG Performance status scale 
• 12 Lead ECG 
• Laboratory evaluations: hematology, chemistry, urinalysis test and PSA (see 
Section 8.4.1). 
Participant medical history to be documented in eCRF include:  
• Date of diagnosis of PCa  
• Gleason grade at diagnosis, PSA at diagnosis, Clinical stage (cTNM) at diagnosis 
• In patients with RP or patients with RT: PSA at diagnosis, gleason score of the RP 
specimen, pathological stage (pTNM) at diagnosis, information on additional salvage RT 
(prostate bed, lymphatic drainage), PSA nadir, first PSA >2ng/ml.  
• PSA nadir after RT (if applicable) 
• 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). 
8.3 
Efficacy 
Efficacy assessments in this study include disease assessment per SoC at baseline (and if 
clinically indicated, post-baseline) as well as assessments of PET/CT images using the two 
PET agents. Please refer to the schedule of assessments provided in Table 8-1 and Section 8.3.1. 
8.3.1 
Imaging for tumor assessment 
The imaging assessment collection plan for this study is presented in Table 8-2. 


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Table 8-2 
Imaging Assessment Collection Plan  
 
 Imaging procedures 
Mandatory or Optional 
Image Acquisition Timing 
[18F]CTT1057 PET/CT 
Mandatory - all 
participants 
Day 1 or Day 15* 
[68Ga]Ga-PSMA-11 PET/CT 
Mandatory - all 
participants 
Day 1 or Day 15* 
High Resolution CT with i.v. 
and Oral Contrast (or MRI if 
CT scan with contrast is 
medically contraindicated) of 
at least Chest Abdomen and 
Pelvis (and any additional 
region as clinically indicated) 
Mandatory - all 
participants 
+/- 8 weeks from 
[18F]CTT1057 PET/CT 
Acquisition 
Other 
Standard 
of 
Care 
Imaging diagnostic procedures 
(MRI, Bone Scan, PET with 
other imaging agents, etc.) 
As clinically indicated per 
SoC  
+/- 8 weeks from 
[18F]CTT1057 PET/CT 
Acquisition 
Follow-up Standard of Care 
Imaging diagnostic procedures 
(CT, MRI, Bone Scan, PET 
with other imaging agents, etc.) 
If clinically required per 
SoC for the diagnosis of 
particular lesion(s) 
3 months after the initial 
imaging procedure performed 
*Day 1 or 15 determined by participant’s randomization into sequence 1 or 2.  
Imaging diagnostic procedures (CT/MRI, bone scan, or other modalities) should be performed 
as clinically indicated for each patient per SoC within 8 weeks (either before or after) the 
[18F]CTT1057 PET/CT scan. Any imaging assessments already completed during the regular 
work-up of the participant within 8 weeks prior to [18F]CTT1057 PET/CT scan, including 
before signing the main study ICF, can be considered as part of imaging component of the CTS 
Level 2. 
CTS Level 2 will be used as reference for co-primary endpoints if pathology is not available for 
a lesion, inconclusive or biopsy is negative.  
The CTS level 2 imaging diagnostic procedures must include at least a high-resolution CT scan 
with i.v. and oral contrast (or MRI if CT scan with contrast is medically contraindicated) and 
the [68Ga]Ga-PSMA-11 PET/CT scan. It may include also any other imaging diagnostic 
procedures clinically indicated for each participant as per SoC (including three-month follow-
up imaging where it is clinically required for the diagnosis of particular lesion(s)). A centralized 
reading of these imaging diagnostic procedures will be performed in a CRO by 3 readers who 
will be blinded to [18F]CTT1057 PET/CT scan results, but not to other patient data collected in 


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clinical database. The majority rule (2/3 readers) will be used as a final outcome of the reads. 
Further details will be provided in the Imaging Charter. 
In addition, the imaging diagnostic procedures included in CTS level 2 will be read by local 
nuclear medicine physicians or radiologists with expertise in reading oncology PET/CT scans 
as per SoC, who will be blinded to the [18F]CTT1057 PET/CT scan results, but not to other 
patient data.
 
 
 
 The criteria to be 
applied for PET positivity are detailed in Section 4.1. 
SoC imaging data to be documented in eCRF will include the outcome of assessments, i.e. if 
negative or positive for PCa tumor or metastases, regions where lesions are identified, number 
and location of the lesions. For lesions that are visually positive on the [68Ga]Ga-PSMA-11 PET 
but not considered as PCa, their characteristics will be documented (i.e. non-prostate cancer 
tumoral or benign, such as inflammatory, degenerative, necrotic, other). For CT/MRI lesion 
size measurements RECIST 1.1 guidelines will be applicable (Section 16.2). 
Post-baseline PET imaging assessments 
PET imaging assessments as described in Table 8-1 should be performed at the timepoints, at 
Day 1 and approximately at Day 15. The following steps will take place on each PET imaging 
day: 
[68Ga]Ga-PSMA-11 PET imaging day (as part of the imaging component of CTS): 
1. Participant will be asked to drink 1-2 glasses of water before arrival at the clinic 
2. Participants 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 a single dose of approximately 150 MBq of 
[68Ga]Ga‑PSMA‑11, administered doses must not be lower than 111MBq or higher than 
185MBq in any case then flushed by 10 ml of saline. For [18F]CTT1057 administration, 
please see below 
4. Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be recorded 
after the injection 
5. Participant will void immediately prior to the scan. If it is not possible for the patient to 
void, an urethral catheterization will be considered 
6. Approximately 50 to 100 minutes (min) later, 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 participant will be 
allowed to void again, and uretheral 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 approximately 120+60 min post-injection (p.i.) 


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8. Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be recorded 
again at the completion of the study (prior to participant discharge) 
9. Participant will be discharged with the reminder of the safety follow up as described in the 
Informed Consent Form (ICF). 
[18F]CTT1057 (investigational imaging agent) PET imaging day: 
1. Participant will be asked to drink 1-2 glasses of water before arrival at the clinic 
2. Participants 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 
5. Participant will void immediately prior to the scan. If it is not possible for the patient 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 participant will be 
asked to void again, and uretheral 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 approximately 
8. Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be recorded 
again at the completion of the study (prior to participant discharge) 
9. Participant will be discharged with the reminder of the safety follow up as described in the 
Informed Consent Form (ICF). 
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, regions where lesions are identified, 
number and location of the lesions as well as their characteristics. 
[18F]CTT1057 PET/CT images will be submitted to the designated imaging CRO for 
independent central review. All reviewers have to be blinded to patient data (including clinical 
condition, histopathology and imaging results). Central read results will not be provided to the 
treating physician/Clinical 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, blinded to [68Ga]Ga-
PSMA-11 PET/CT scan results, but not to other patient data. The report from this local reader 


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will be provided to the treating physician / Clinical Study Investigator to complete the patient 
management questionnaire 2. 
[68Ga]Ga-PSMA-11 PET/CT images will be both centrally and locally read as all the other 
imaging procedures included in CTS Level 2.  
8.3.2 
Histopathology assessments 
In the cases where pathology will be available (from prospective biopsy or salvage 
surgery  performed within 8 weeks after the completion of [18F]CTT1057 PET/CT scan and 
after the completion of  [68Ga]Ga-PSMA-11 PET/CT scan), assessments by the local 
pathologists will be performed as per SoC, and results are to be provided within 2 weeks of the 
biopsy. Pathologists will be blinded to any PSMA-PET data (i.e. both PET/CT scans), but not 
to other patient data. 
Pathology data to be documented in eCRF 
will include among others the 
procedure/methodology used, the outcome of the assessment, i.e. if negative or positive for 
adenocarcinoma, if other tumor histological types are present or not and their nature, number, 
location as well as size of the tumor and/or metastatic lesions within the tissue specimens.   
8.3.3 
PSA level assessments 
For CTS Level 3, increases and decreases of PSA levels will be tracked to assess PSA responses 
before and after RT (third component of the CTS) as per PCWG3 for participants where 
pathology or radiological assessments are not available or conclusive. 
RT should commence within approximately 8 weeks of completing the study treatment (i.e. 
both PET/CT scans) and PSA should be assessed prior to starting the RT and then at 
approximately 90 days from last day of radiation.  
8.3.4 
Appropriateness of efficacy assessments 
[18F]CTT1057 PET/CT efficacy assessments will be based on a Composite Truth Standard 
(CTS), as described in Section 3 (in brief: CTS Level 1=pathology, CTS Level 2= imaging 
diagnostic procedures, CTS Level 3= PSA changes). See Section 1.1 for the rationale of using 
a CTS in the BCR setting. 
For CT/MRI lesion size measurements, applicable RECIST v1.1 guidelines Section 16.2 will 
be used. For PSA measurements after RT (third component of the CTS) PCWG3 guidelines 
Section 16.3 will apply. PCWG3 is an international working group of clinical and translational 
experts in PCa who developed international recognized recommendations.  
8.4 
Safety 
Safety assessments are specified below (Table 8-3) 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. 
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, 


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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 AE section. 


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Table 8-3 
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 site 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 below (Table 8-4). 
Table 8-4 
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 
8.4.1 
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. 


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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 
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 8-5 
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) 


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Test Category 
Test Name 
PSA 
PSA 
8.4.2 
Electrocardiogram (ECG) 
A standard 12 Lead ECG 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 
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. ECG tracing should be labeled with the study number, participant 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. 
8.4.3 
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 investigational imaging agents. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
8.5.1 
Other Assessments 
Patient Management questionnaire will be completed by the treating physician/ Clinical Study 
Investigator before and within 14 days after having the results of the [18F]CTT1057 
PET imaging assessment by an independent local nuclear medicine physician or radiologist 
with expertise in reading oncology PET/CT scans. For subjects assigned to sequence 1, 
questionnaire 2 should be completed before [68Ga]Ga-PSMA-11 PET/CT is performed. Refer 
to Section 16.4 for details. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation from study treatment and study 
9.1.1 
Discontinuation from study treatment    
Discontinuation of study treatment for a participant occurs when either one of the two injections 
of study treatment is not given as planned per protocol and can be initiated by either the 
participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from Study treatment is required under the following circumstances: 
• Participant non-compliance or voluntary withdrawal from study or from study 
treatment/guardian decision 
• Unacceptable toxicity, as assessed by the Investigator, after the first administration of 
imaging agent that precludes the safe administration of the second imaging agent 
• 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 
• Any other situation in which continued study participation might result in a safety risk to 
the participant 
• At the Sponsor's or Investigator's discretion. 
For study participants for whom it is required to discontinue from study treatment due to 
unacceptable toxicity resulting in a SAE, refer to Section 10.1.3 for the reporting requirements. 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation of study treatment and 
record this information in the source documents and relevant eCRF pages. 
Participants who discontinue from study treatment can agree to return for the end of 
treatment and follow-up visits and any efficacy assessment 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 discontinuation from study treatment, at a minimum, in abbreviated visits, 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. 


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9.1.2 
 Discontinuation from study  
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. If the 
participant agrees, a final evaluation at the time of the participant’s study discontinuation should 
be made as detailed in the assessment table (refer to Section 8 ). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose their use of data or biological samples, 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. 
9.2 
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) 
• andNo longer wishes to receive study treatment 
and 
• Does not want to participate in the study anymore, 
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/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 be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 


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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. 
 
9.3 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Discontinuation of study compound (i.e. the investigational imaging agent) 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 (e.g. safety follow up period must be 
completed if applicable with required 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.  
9.4 
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 randomized and/or treated participants will have a Safety Follow up visit at Day 29. The 
information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Please refer to Table 8-1 for the required 
assessments at this visit.  
Additional follow up period will be applicable where SoC additional diagnostic procedures are 
to be performed. These may include SoC pathology, imaging or other modality disease 
assessments (CTS Levels 1 or 2) up to 8 weeks after [18F]CTT1057 PET imaging, or three-
month follow-up imaging (from baseline) if clinically required for the diagnosis of particular 
lesion(s). 


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In addition, for participants at CTS Level 3 (i.e. in case CTS Levels 1 or 2 are not feasible or 
conclusive), PSA levels to be assessed prior to starting RT and at approx. 90 days from the last 
day of radiation. 
End of Study visit should be done once all post-treatment follow-up assessments are completed 
and can be done via a phone call. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
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): 
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. 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, or the imaging 
agent [68Ga]Ga-PSMA-11. 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 


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5. Action taken regarding the study treatment (i.e. discontinuation from 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 
study treatment. 
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. 
10.1.2 
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 E15D (2004) Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 


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• 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 E15D (2004) Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
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. 
10.1.3 
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 electronic 
Serious Adverse Event (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 


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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. 
10.1.4 
Pregnancy reporting 
Not applicable 
10.1.5 
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 medicinal product/study treatment is intentionally and 
inappropriately used not in accordance with the protocol. 
Study treatment 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. 
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. 


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10.2 
Additional Safety Monitoring 
10.2.1 
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial and Novartis representatives from the Clinical Trial Team. 
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 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (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. 
11.2 
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 
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, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant will be 


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tracked using an IRT. The system will be supplied by a vendor, who will also manage the 
database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines. 
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 that time can only 
be made after written agreement by Novartis development management. 
11.3 
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, on the efficacy analysis set and safety set respectively. Cut-off for the 
final analysis will be the last visit for last subject in the study. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) includes all randomized participants. 


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The Efficacy Analysis Set (EFF) includes all randomized participants who receive 
the dose of investigational treatment (i.e. [18F]CTT1057) and have both an evaluable 
[18F]CTT1057 PET/CT scan imaging,  and at least one evaluable CTS assessment and have not 
received any prohibited systemic antineoplastic therapy before the completion of PET/CTs and 
CTS procedures. 
The [18F]CTT1057  Safety Set (F-SAF) includes all participants who received the 
investigational treatment (i.e. [18F]CTT1057). 
The [68Ga]Ga-PSMA-11 Safety 
Set 
(Ga-SAF) includes 
all 
participants 
who 
received  [68Ga]Ga-PSMA-11. Participants will be analyzed according to the study treatment 
received. 
12.2 
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. 
12.3 
Treatments 
Actual received dose of [18F]CTT1057 and [68Ga]Ga-PSMA-11 will be summarized by means 
of descriptive statistics using the F-SAF and Ga-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. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The primary objective of the study is described in Table 2-1. 
Efficacy analysis will use EFF 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The co-primary endpoints of the study are region-level CLR and patient-level PPV 
• Region-level CLR is defined as the proportion of regions containing at least one TP lesion 
(exactly localized correspondence between PET imaging and the reference standard), 
regardless of any co-existent FP findings within the same region, out of all regions 
containing at least one PET-positive finding.  


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• Patient-level PPV is defined as the proportion of patients who have at least one TP lesion 
(exactly localized correspondence between PET imaging and the reference standard), 
regardless of any co-existent FP findings, out of all patients who are PET/CT scan 
positive. 
Centralized imaging assessments (CTS Level 2) will be used as reference standard if pathology 
(CTS Level 1) is not available for a lesion, inconclusive or negative (for biopsy only). 
12.4.2 
Statistical model, hypothesis, and method of analysis 
To address the co-primary efficacy objectives: 
Region-level CLR and its 95% CI  will be calculated using logistic random-effects models 
taking into account the correlation among regions within one patient. .The lower bound of the 
95% CI for CLR should be greater than 0.5 to attain the first co-primary endpoint. 
Patient-level PPV and its 95% CI will be calculated based on the binomial distribution. The 
lower bound of the 95% CI for patient-level PPV should be greater than 0.2 to attain the second 
co-primary endpoint. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
The primary analyses will account for intercurrent events as explained in the following: 
Patients receive the investigational imaging agent [18F]CTT1057 but do not undergo/complete 
the PET/CT scan for any reasons: they will not be used for the co-primary endpoint analyses, 
but safety data will be collected as planned after the administration of the investigational 
imaging agent. 
12.4.4 
Handling of missing values not related to intercurrent event 
This is a diagnostic study, co-primary endpoints are calculated on the basis of one-time imaging 
assessment, missing data not related to intercurrent events will not be imputed. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
The lower level of CTS will be used to verify positivity or negativity for the sensitivity analysis. 
For instance, if pathology (CTS Level 1) is used as true standard for primary estimand, imaging 
component of CTS (Level 2) will be used as true standard for sensitivity analysis for primary 
estimand. However, for those using changes in PSA level (CTS Level 3) as the true standard 
for primary estimand, their positivity status cannot be replaced by another component of CTS 
for sensitivity analysis. 
12.4.6 
Supplementary analysis 
As supplementary analyses performed in the EFF, the region-level CLR and patient-level PPV 
and 95% CIs will be obtained from covariate adjusted logistic regression model. Important 
covariate will be specified in the SAP.  
Subgroup analyses for region-level CLR and patient-level PPV will be performed: 
• patients with prior radical prostatectomy 


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• patients  with prior curative intent radiation therapy 
If the co-primary endpoints 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.  
12.5 
Analysis of secondary endpoints/estimands 
The secondary objectives and related endpoints are described in Table 2-1. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Following secondary endpoints, centralized imaging assessment will be used as reference 
standard if pathology assessment is not available for a lesion. 
Patient-level sensitivity is defined as the proportion of TP patients among those who are TP or 
FN 
Patient-level specificity is defined as the proportion of TN patients among those who are TN 
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 scanned 
patients (regardless of TP, TN, FP, FN) 
Patient-level correct detection rate is defined as the proportion of TP patients among all 
scanned patients (regardless of TP, TN, FP, FN) 
Patient-level detection rate is defined as the proportion of TP and FP patients among all 
scanned patients (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN patients are defined as follows:  
• PSMA TP patients are those who have at least one TP lesion with anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the CTS. 
• PSMA TN patients are those who do not show any pathological [18F]CTT1057 uptake and 
will be confirmed NOT having any lesions with the CTS. 
• PSMA FP patients are those who show at least one pathological [18F]CTT1057 uptake but 
will be verified NOT having any lesions with the CTS or none is correctly localized in 
anatomical location by the CTS. 
• PSMA FN patients are those who do not show any pathological [18F]CTT1057 uptake but 
will be confirmed having at least one with the CTS. 
Number of TP, TN, FP, FN patients 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. 


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[18F]CTT1057 scan inter-reader variability is defined as agreement among three readers 
determinations and will be assessed by Fleiss' Kappa statistic. Details of calculation of Fleiss' 
Kappa statistic in SAP. 
[18F]CTT1057 scan intra-reader variability is defined as within-reader agreement for two 
different time points and will be assessed by Cohen's Kappa statistic. A subset of imaging 
reading will be performed at two different time points by each reader. See details in imaging 
charter. Details of calculation of Cohen's Kappa statistic in SAP. 
Change in patient management plans attributed to the [18F]CTT1057  PET/CT scan is defined 
as the percentage of patients who undergo a change in intended treatment plan attributed to the 
PET/CT scan as assessed by pre imaging questionnaire 1 and post imaging questionnaire 2  
Numbers and percentage of patients on each category of treatment plan:  surgery, radiation 
alone, radiation alone with change in radiation treatment plan (only applicable for questionnaire 
2), radiation plus ADT, ADT alone, observation/surveillance, other (free text box) in two 
questionnaires will be calculated. 
Treatment plan change is defined as a pair of categories (one category of questionnaire 1, one 
category of questionnaire 2) 
Numbers and percentage of patients on the treatment change defined above will be calculated. 
The following secondary endpoints, centralized imaging assessment will be used as reference 
standard if pathology assessment is not available for a lesion. 
Region-level sensitivity is defined as the proportion of TP regions among those that are TP or 
FN 
Region-level specificity is defined as the proportion of TN regions among those that are TN or 
FP 
Region-level negative predictive value is defined as the proportion of TN regions among those 
that are TN or FN 
Region-level accuracy is defined as the proportion of TP and TN 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 containing at least one TP lesion (anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the CTS).  
• PSMA TN regions are regions containing no lesions with pathological [18F]CTT1057 
uptake and confirmed by CTS. 
• PSMA FP regions are regions containing lesions with pathological [18F]CTT1057 uptake 
but will be verified negative by CTS or none is correctly localized in anatomical location 
by the CTS. 
• PSMA FN regions are regions containing no lesions with pathological [18F]CTT1057 
uptake but will be confirmed having at least one lesions with the CTS. 
Number of TP, TN, FP, FN regions will be presented and used to calculate the diagnostic 
performance parameters.  


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95% CI for region-level diagnostic performance parameters will be calculated using logistic 
random-effects models taking into account the correlation among regions within one patient.  
For different regions ( i.e.  prostate region, PLN, extra-PLN, skeletal, visceral), 95% CI for 
region-level diagnostic performance parameters will be calculated based on the binomial 
distribution respectively. 
Patient-level positive predictive value will be also calculated for different categorical PSA 
levels. 
Concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of lesions, 
positive percent agreement will be calculated to assess the concordance. 
12.5.2 
Safety endpoints 
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). [18F]CTT1057 treatment-emergent AEs, [68Ga]Ga-PSMA-11 
treatment-emergent AEs will be presented using F-SAF and Ga-SAF separately.  
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 treatment 
2. On-treatment period: from day of dosing of study medication to approximately 14 days 
after dosing of study treatment. 
3. Post-treatment period: starting at day 15 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 treatment emergent adverse events (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, other significant adverse events leading to drug interruption, and adverse events 
leading to drug withdrawn. 
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. 


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Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, 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. 
12-lead ECG 
All ECG data will be listed by participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by visit/time.  
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) 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 
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• 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. 
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. 
12.7 
Interim analyses 
Not applicable 
12.8 
Sample size calculation 
Overall, approximately 190 participants will be enrolled to ensure at least 152 participants are 
evaluable (i.e. have both an evaluable [18F]CTT1057 PET/CT scan imaging,  and at least one 
evaluable CTS assessment and have not received any prohibited systemic antineoplastic therapy 
before the completion of PET/CTs and CTS procedures), which will be required for the 


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calculation of the co-primary endpoints. These calculations were made using the software PASS 
11 and R 3.6.1. 
12.8.1 
Primary endpoint(s) 
This study is planned to recruit approximately 190 patients. The sample size calculation is based 
on the co-primary endpoints of region-level CLR and the patient-level PPV of [18F]CTT1057. 
The assumptions for sample size calculations are based on the estimates from data available 
from prior studies. 
The primary endpoint is to evaluate region-level CLR (prostate region, PLN, extra-PLN, 
skeletal, visceral) and patient-level PPV of [18F]CTT1057 PET for detection of tumor location 
confirmed by histopathology/biopsy. Based on the results of previous studies, the following 
distribution of disease across regions are anticipated: Prostate bed: 30%, pelvis: 15%; 
extrapelvic soft tissue: 20%; bone metastases: 35% (Eiber et al 2015, Ceci et al 2015, 
Van Leeuwen et al 2016). It is anticipated that the CLR for the five regions and for all regions 
combined using conventional imaging ranges from 30-60%. An overall CLR for [18F]CTT1057 
PET of at most 50% will be considered as unacceptably low. Hence, the null hypothesis that 
the CLR is at most 50% will be tested against the alternative hypothesis that the CLR is greater 
than 50%. 
The BCR population targeted in this study is expected to have similar PSA values than prior 
studies (Morris et al 2020) of approved diagnostic PET agents for PCa such as [18F]-
fluciclovine, which had a 27% PPV for patients with PSA values that were less than 1.78, as 
noted in their summary basis of approval. Thus, a patient-level PPV of 20% will be considered 
as unacceptably low. The [18F]CTT1057 positive patient rate (detection rate) for the study 
population is 80% based on [18F]-fluciclovine studies. The sample size calculation will be 
performed based on the null and alternative hypotheses as follows. 
• Region-level CLR: 
Correlated binary test results occur in this situation where each experimental unit (patient) 
consists of five correlated regions. Lee and Dubin developed a sample size formula for clustered 
binary data (Lee and Dubin 1994). They propose estimating the binary proportion by assigning 
equal weights to clusters regardless of their sizes to simplify the derivation of their sample size 
formula. The weighted estimator for region-level CLR is approximately Gaussian distributed 
with a variance of a beta distribution (beta-binomial model).  
The null Hypothesis H0: region-level CLR p = 0.5 will be tested against the alternative 
hypothesis H1: p >0.5  Assuming a CLR of 0.58 under the alternative hypothesis, a total sample 
size of 172 enrolled participants would achieve 90% statistical power to detect a change in CLR 
of 0.08 using a one-sided test at a target significance level of 2.5%.This sample size includes 
an adjustment for a dropout rate of 0.20.  
To determine the sample size n such that the type I error of one-sided testing H0 is 0.025 and 
with power 0.9 to reject H0 if alternative H1 is true. By the standard normal approximation, the 
sample size is given 


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where σ2 the variance of a beta distribution, Za is the upper a quantile of the standard normal 
distribution, p0 is the CLR 0.5 under null hypothesis, p1 is 0.58 the achievable CLR. 
Suppose there is no information on the within-cluster correlation of test results. In this case, a 
uniform distribution seems reasonable, setting parameters in the beta distribution alpha=1 and 
beta=1. Then σ2 is 1/12 
Under these assumptions, 137 patients will be necessary to ensure the 90% power, taking into 
account 20% dropout rate, a total of 172 patients will be recruited for this endpoint of the study. 
The lower bound of the 95% CI for CRL should be greater than 0.5 to be considered success. 
• Patient-level PPV 
The null Hypothesis H0: patient-level PPV p = 0.2 will be tested against the alternative 
hypothesis H1: p >0.2  Assuming a patient-level PPV of 0.33 under the alternative hypothesis, 
a total sample size of 190 enrolled participants (which includes 152 [18F]CTT1057 scanned 
patients based on 80% [18F]CTT1057 positive patient rate) would achieve 90% statistical power 
to detect a change in patient-level PPV of 0.13 using a one-sided binomial test at a target 
significance level of 2.5%.This sample size includes an adjustment for a dropout rate of 20%. 
The lower bound of the 95% CI for patient-level PPV should be greater than 0.2 to be considered 
success. 
A total sample size of 190 patients can ensure 92.7% statistical power for region-level CLR and 
90% statistical power for patient-level PPV resulting in an overall study statistical power of at 
least 83.4% (0.927*0.9). 
13 
Ethical considerations and administrative procedures 
13.1 
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 GCP, 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. 
13.2 
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, 


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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. 
13.3 
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.). 
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. 
13.4 
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. 


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14.1 
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 
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 Dec-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. 
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. 
Bott SRJ (2004) Management of recurrent disease after radical prostatectomy. Prostate Cancer 
and Prostatic Dis; 7:211-6. 
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. 
Calais J, Kishan AU, Cao M, et al (2018) Potential Impact of 68Ga-PSMA-11 PET/CT on the 
Planning of Definitive Radiation Therapy for Prostate Cancer. J Nucl Med; 59(11):1714-21. 
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. 
Chantadisai M, Buschner G, Krönke M, et al (2020) Positive predictive value and correct 
detection rate of 18F-rhPSMA-7 PET in biochemically recurrent prostate cancer validated by 
composite reference standard. J Nucl Med; 12:1-38. 
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. 
Cookson MS, Aus G, Burnett AL, et al (2007) Variation in the definition of biochemical 
recurrence in patients treated for localized prostate cancer: the American Urological 
Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and 
recommendations for a standard in the reporting of surgical outcomes. J Urol;177(2):540-5. 
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. 
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. 
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, Goodman JZ, Allen IE, et al (2019) Metaanalysis of 68Ga-PSMA-11 PET 
Accuracy for the Detection of Prostate Cancer Validated by Histopathology. J Nucl Med; 
60(6):786-93. 
Hricak H, Dooms GC, Jeffrey RB, et al (1987) Prostatic carcinoma: staging by clinical 
assessment, CT, and MR imaging. Radiology; 162:331-6. 


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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). 
Isbarn H, Wanner M, Salomon G, et al (2010) Long-term data on the survival of patients with 
prostate cancer treated with radical prostatectomy in the prostate-specific antigen era. BJU Int; 
106:37-43. 
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. 
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. 
Lee EW, Dubin N (1994) Estimation and sample size considerations for clustered binary 
responses. Stat Med; 13:1241-52. 
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. 
Morris MJ, Carroll PR, Saperstein L, et al (2020) Impact of PSMA-targeted imaging with 
18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent 
(BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study 
(CONDOR) [abstract]. J Clin Oncol; 38 (15 Suppl):5501A. 
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. 
Oh WK, Kantoff PW (1999) Treatment of locally advanced prostate cancer: is chemotherapy 
the next step? J Clin Oncol; 17(11):3664-75. 


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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. 
Pernthaler B, Kulnik R, Gstettner C, et al (2019) A Prospective Head-to-Head Comparison of 
18F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in 
PET/CT. Clin Nucl Med; 44(10):e566-e73. 
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. 
Roach M, Hanks G, Thames H, et al (2006) Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized prostate 
cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat 
Oncol Biol Phys;65(4):965-74. 
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. 
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. 
Scher HI, Morris MJ, Stadler WM, et al (2016) Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol; 34(12):1402-18. 
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. 
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. 


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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. 
Szabo Z, Mena E, Rowe SP, et al (2015) Initial Evaluation of [(18)F]DCFPyL for Prostate-
Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol 
Imaging Biol; 17(4):565-74. 
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. 
Van Leeuwen PJ, Stricker P, Hruby G, et al (2016) (68) Ga-PSMA has a high detection rate of 
prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage 
radiation treatment. BJU Int; 117:732-9. 
Van Poppel H, Vekemans K, Da Pozzo L, et al (2006) Radical prostatectomy for locally 
advanced prostate cancer: results of a feasibility study (EORTC 30001). Eur J Cancer; 
42:1062-7. 
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. 
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. 


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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. 
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 68 
gallium-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 
16.1 
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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16.2 
Appendix 2: Response Evaluation Criteria in Solid Tumors 
The latest RECIST guidelines (version 1.1) can be found at the following site: 
[project.eortc.org/recist/wp-content/uploads/sites/4/2015/03/RECISTGuidelines.pdf]  


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16.3 
Appendix 3: PCWG3 
The sections that apply to this trial are the criteria for PSA response and progression, and the 
criteria for bone lesion “prevent/delay end points” (progression). It is based on the PCWG3 
recommendations (Scher et al 2016). 


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16.4 
Appendix 4: Patient Management questionnaire 
A questionnaire on the planned patient management will be filled-in by the treating 
physician/Clinical Study Investigator before (questionnaire 1) and within 14 days after knowing 
the results of the [18F]CTT1057 PET/CT scan (questionnaire 2). 
Options will be given in the questionnaire to capture possible management plan, such as 
• Surgery 
• Radiation alone 
• Radiation alone with change in radiation treatment plan (only applicable for questionnaire 
2) 
• Radiation plus ADT 
• ADT alone 
• Observation/surveillance 
• Other (free text box) 
The results of the [18F]CTT1057 PET/CT scan will be provided to the Study Investigator before 
the patient undergoes the planned treatment by a local nuclear medicine physician or radiologist 
with expertise in reading oncology PET/CT scans, who will be blinded to [68Ga]Ga-PSMA-11 
data but not to other patient data, in order to reproduce as much as possible the real clinical 
context to assess the potential clinical impact of the investigational procedure. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Document type: 
SAP Documentation 
Document status: 
Final  
Release date: 
26-Dec-2023 
Number of pages: 
56 
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 CAAA405A12301 / NCT04838613
 
 
Phase III study for evaluation of the diagnostic performance of 
[18F]CTT1057 PET imaging in
 
patients with prostate cancer with rising
 
 
PSA levels [biochemical
 
recurrence (BCR)] (GuidePath)
Statistical Analysis Plan (SAP)


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SAP Amendment 2 
 
Study No. CAAA405A12301 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
10-
Oct-
2021 
After 
FPFV 
Creation 
of 
final version 
N/A - First version 
NA 
03-
Oct-
2022 
After 
PA01, 
before 
original 
IND 
submission 
Incorporating 
changes 
made in the 
protocol 
amendment 
v01. 
1. Clarification added to the targeted 
population, i.e. prostate cancer 
patients diagnosed with biochemical 
recurrence 
(BCR) 
after 
initial 
definitive therapy (with either RP or 
curative intent RT). 
2. Clarification of the different CTS 
levels will be applied hierarchically 
at lesion level for efficacy analyses 
added. 
3. Addition of a new option named 
“Radiation alone with change in 
radiation 
treatment 
plan” 
for 
questionnaire 2. 
4. Clarification added that the 
secondary 
endpoint 
(based 
on 
central 
imaging 
reads) 
and 
 
for concordance 
between 
[18F]CTT1057 
and 
[68Ga]Ga-PSMA-11 for detection of 
PSMA-positive lesions (in terms of 
number of lesions detected and their 
location) will be assessed at lesion 
level, not patient level.  
5. Updated the definition of efficacy 
analysis set to align with PA01. 
6. Updated the 2 subgroups for 
subgroup analyses to patients with 
prior RP and patients with prior 
curative intent RT.  
7. 
Modified 
analyses 
to 
be 
performed 
regarding 
patient 
Section 
1.1, 
1.2, 2.1.1, 2.2, 
2.3.1, 
2.5.6, 
2.6, 2.7, 2.12, 
3 and Section 
5.  


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
disposition output to fully align with 
SC meeting. 
8. 
Added 
details 
regarding 
a 
supplementary analysis for the 
primary endpoints. 
9. Removed the sentence about 
aggregating results among readers 
for 
the 
intra-reader 
variability 
calculation. 
10. Added COVID-19 related AE 
summaries and two required tables 
by ClinicalTrials.gov.  
11. Added 3-day time window for 
post-baseline lab and vital sign 
assessments.  
 
 
13. Minor typographical corrections, 
removal of duplicated wording and 
minor 
rewording 
implemented 
across the document. 
20- 
Dec-
2023 
After CSR 
dry-run 
review and 
before 
DBL. 
Incorporating 
changes 
identified 
during 
the 
previous SC 
meeting, 
CSR 
TFLs 
amendment 
review, and 
dry-run 
review. 
1. Added clarification to include 
[18F]CTT1057 
([68Ga]Ga-PSMA-
11) treatment-related AEs that occur 
beyond 14-days  after the injection 
of [18F]CTT1057 ([68Ga]Ga-PSMA-
11) as [18F]CTT1057 ([68Ga]Ga-
PSMA-11) TEAE as well and 
moved such definition to Section 
2.7.1. Adverse events.  
2. Added a listing to display the 
information about analysis sets for 
each participant.  
 
4. Updated the patient disposition 
section to include analysis set (if 
different from FAS), and to clarify 
that treatment discontinuation (with 
reasons) and treatment completion 
Section 1.2.1, 
2.1.1, 
2.2, 
2.2.1, 
2.3.1, 
2.3.2, 
2.4.1, 
2.4.2, 
2.5.2, 
2.5.5, 
2.5.6, 
2.6, 
2.6.1, 
2.6.2, 
2.7, 
2.7.1, 
2.7.2, 
2.7.3, 
2.7.4, 
2.12, 4, 5.1, 
5.4.1 and 5.5.  


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
will be displayed by period 1/2 and 
by assigned treatment sequence.  
5. Added grouping information 
when tabulating primary tumor 
clinical stage, biopsy Gleason score, 
radical prostatectomy Gleason score 
(if 
applicable) 
per 
comments 
received from SC meetings.  
6. Description added to include an 
additional summary table of time (in 
days) between two PET scan dates.  
7. 
Added 
clarification 
to 
the 
definition 
of 
concomitant 
medications/therapies/procedures 
for each PET imaging agent. 
8. Added description that patient-
level PPV will be repeated by CTS 
levels. 
9. Added the weighted estimator 
approach for region-level CLR 
under the sensitivity analyses.  
10. Instructions added regarding 
how to display the output for 
covariate-adjusted logistic (random-
effects) model for the co-primary 
endpoints. 
11. Added clarification about the 
analysis set for secondary endpoints, 
wherever applicable.  
12. 
Added 
description 
about 
displaying 
shift 
table 
about  
participants’ treatment plans.  
13. Added detailed instruction on 
the computation of concordance 
between two PET imaging agents on 
lesion-level, overall, and by region 
and M1 regions.   


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
14. 
Removed 
duplicated 
information about pre-/on-/post-
treatment periods under the safety 
analyses section.  
15. Changed the name from AESI to 
STI to align with RLT program 
standard. 
16. Added clarification that on-
treatment death will be tabulated for 
F-SAF and Ga-SAF separately, 
while all deaths analyses will be 
carried out for SAF only.  
17. Added clarification to data that 
will be analyzed for labs and VS.  
20. 
Added 
clarification 
that 
subgroup analyses will be applied to 
co-primary endpoints and secondary 
efficacy endpoints only. 
21. Added minor update to the 
imputation rule when imputed end 
date is < start date, the end date will 
be set to start date. 
21. 
Added 
modelling 
and 
programming details of logistic 
random effects model for the region-
level CLR to the appendix.  


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
22. Minor updates to the estimand 
wording were made as compared to 
the protocol for clarification. 
 
25. Replaced “subject” and “patient” 
with “participant” throughout the 
document, wherever applicable and 
appropriate.  
26. Updated SAP template version.  
27. Minor typographical corrections, 
removal of duplicated wording and 
minor 
rewording 
implemented 
across the document. 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ..................................................................................................................................... 7 
List of figures .......................................................................................................................................... 9 
List of tables ......................................................................................................................................... 10 
List of abbreviations ............................................................................................................................. 11 
1 
Introduction ........................................................................................................................................... 13 
1.1 
Study design ............................................................................................................................ 13 
1.2 
Study objectives, endpoints and estimands ............................................................................. 16 
1.2.1 
Primary estimand(s) .............................................................................................. 19 
2 
Statistical methods ................................................................................................................................ 20 
2.1 
Data analysis general information ........................................................................................... 20 
2.1.1 
General definitions ............................................................................................... 21 
2.2 
Analysis sets ............................................................................................................................ 24 
2.2.1 
Subgroup of interest .............................................................................................. 25 
2.3 
Patient disposition, demographics and other baseline characteristics ..................................... 25 
2.3.1 
Patient disposition ................................................................................................. 25 
2.3.2 
Demographics and other baseline characteristics ................................................. 26 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, compliance) ........... 28 
2.4.1 
Study treatment / compliance ............................................................................... 28 
2.4.2 
Prior, concomitant and post therapies ................................................................... 28 
2.5 
Analysis supporting primary objective(s) ................................................................................ 29 
2.5.1 
Primary endpoint(s) .............................................................................................. 29 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................................... 30 
2.5.3 
Handling of intercurrent events ............................................................................ 31 
2.5.4 
Handling of missing values not related to intercurrent event ............................... 31 
2.5.5 
Sensitivity analyses ............................................................................................... 31 
2.5.6 
Supplementary analyses ....................................................................................... 31 
2.6 
Analysis supporting secondary objectives ............................................................................... 32 
2.6.1 
Secondary endpoint(s) .......................................................................................... 33 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................................... 35 
2.6.3 
Handling of intercurrent events ............................................................................ 38 
2.6.4 
Handling of missing values not related to intercurrent event ............................... 38 
2.6.5 
Sensitivity analyses ............................................................................................... 38 
2.6.6 
Supplementary analyses ....................................................................................... 38 
2.7 
Safety analyses ........................................................................................................................ 38 
2.7.1 
Adverse events (AEs) ........................................................................................... 38 
2.7.2 
Deaths ................................................................................................................... 40 
2.7.3 
Laboratory data ..................................................................................................... 40 
2.7.4 
Other safety data ................................................................................................... 41 


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2.8 
Pharmacokinetic endpoints ...................................................................................................... 42 
2.9 
PD and PK/PD analyses .......................................................................................................... 42 
2.10 
Patient-reported outcomes ....................................................................................................... 42 
2.11 
Biomarkers .............................................................................................................................. 42 
 
 43 
2.13 
Interim analysis ....................................................................................................................... 44 
3 
Sample size calculation ......................................................................................................................... 44 
3.1 
Primary endpoints(s) ............................................................................................................... 44 
4 
Change to protocol specified analyses .................................................................................................. 46 
5 
Appendix ............................................................................................................................................... 46 
5.1 
Imputation rules ....................................................................................................................... 46 
5.1.1 
Study drug ............................................................................................................ 46 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................................... 46 
5.1.3 
Other imputations ................................................................................................. 47 
5.2 
AEs coding/grading ................................................................................................................. 47 
5.3 
Laboratory parameters derivations .......................................................................................... 48 
5.4 
Statistical models ..................................................................................................................... 48 
5.4.1 
Analysis supporting primary objective(s) ............................................................. 48 
5.4.2 
Analysis supporting secondary objective(s) ......................................................... 49 
 
 50 
6 
Reference .............................................................................................................................................. 55 


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List of figures 
Figure 1-1 
Study Design ......................................................................................... 15 
 
 
 


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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 16 
Table 2-1 
Example 2 by 2 Contingency Table for Each Reader ........................... 36 
Table 2-2 
Clinically notable changes in vital signs ............................................... 42 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 46 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 47 
 
 50 
 


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List of abbreviations 
AE 
CRF 
CSR 
DMS 
Adverse Event 
Case Report Form 
Clinical Study Report 
Document Management System 
FAS 
Full Analysis Set 
F-SAF 
[18F]CTT1057 Safety Set 
FDG 
Fluorodeoxyglucose 
FN 
False Negative 
FP 
False Positive 
Ga-SAF 
[68Ga]Ga-PSMA-11 Safety Set 
HR 
Heart Rate  
IA 
Interim Analyses 
ICF 
Informed Consent Form 
MBq 
Mega-Becquerel 
mCi 
Millicurie 
mCRPC 
metastatic-Castration Resistant Prostate Cancer 
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
p.i. 
post-injection 
PCa 
Prostate Cancer 
PCWG3 
Prostate Cancer Working Group 3 
PET 
Positron Emission Tomography 
PLN 
Pelvic Lymph Node 
PPA 
Positive percent agreement  
PPV 
Positive Predictive Value 
PSA 
Prostate Specific Antigen 
PSMA 
Prostate Specific Membrane Antigen 
pTNM 
pathological stage 
PK 
Pharmacokinetics 
PRO 
Patient-reported Outcomes 
RAP 
Reporting & Analysis Process 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP 
Radical Prostatectomy  
RR 
Respiratory Rate  
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SAP 
SAS 
Statistical Analysis Plan 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 


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SC 
Steering Committee  
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
SoT 
Standard of Truth 
STI 
Safety Topic of Interest 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 
 
 
TEAE 
Treatment Emergent Adverse Event 
TN 
True Negative 
TP 
True Positive 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CAAA405A12301, a Phase III study for evaluation of the diagnostic 
performance of [18F]CTT1057 PET imaging in patients with prostate cancer with rising PSA 
levels. 
The content of this SAP is based on protocol CAAA405A12301 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 prospective, open-label, multi center, single-arm Phase III study to evaluate the 
diagnostic performance of [18F]CTT1057 as a PET imaging agent for detection and localization 
of PSMA positive tumors in prostate cancer patients diagnosed with biochemical recurrence 
(BCR) after initial definitive therapy with either radical prostatectomy (RP) or curative intent 
radiation therapy (RT), using a composite truth standard (CTS) as reference. 
Approximately 190 participants will be enrolled to ensure at least 152 participants are evaluable 
for the co-primary endpoints. [18F]CTT1057 PET/CT scan imaging will be centrally read by 3 
independent nuclear medicine physicians who will be blinded to any other participant data. 
See study protocol Section 4.1 and Section 8.3.1 for central read details. 
The CTS to be used as reference will be hierarchical in nature, with 3 levels of Standard of 
Truth (SoT) procedures, that will be applied as follows: 
Level 1 
• Histopathology if available for a lesion (from prospective biopsy or salvage surgery 
performed within 8 weeks after the [18F]CTT1057 PET/CT scan); OR in case that 
histopathology is not available for a lesion, inconclusive (i.e. if biopsy/surgery tissue sample 
is not evaluable for histopathology assessment due to  sample quality or inadequate quantity 
or any other technical causes) or negative (for biopsy only): 
Level 2  
• Imaging diagnostic procedures performed on each participant as clinically indicated per 
SoC, which must include the [68Ga]Ga-PSMA-11 PET/CT scan that is mandatory for all 
participants randomized in the study and at least high resolution CT scan (covering at least 
chest, abdomen, and pelvis and any other region as clinically indicated) with intravenous 
and oral contrast  (or MRI if CT scan with contrast is medically contraindicated).  The high 
resolution CT scan and any other imaging diagnostic procedure clinically indicated as per 
SoC must be acquired within the 8 weeks either prior to or following the [18F]CTT1057 
PET/CT scan. Three-month follow-up imaging (from baseline) will also be used as part of 
the CTS Level 2 in cases where it is clinically required for the diagnosis of particular 
lesion(s); OR if neither of the two above are feasible or deemed appropriate or they are 
inconclusive (i.e. images are not interpretable due to poor or inadequate image quality that 
precludes reliable assessment):  
Level 3  


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• 50% or greater decline in PSA following radiation therapy (as long as no concomitant 
androgen deprivation therapy (ADT) is given) as per PCWG3 criteria (Scher et al 2016).  
In the cases where pathology will be available (CTS Level 1), assessments by the local 
pathologists will be performed as per SoC, and results should be available within 2 weeks after 
surgery. Pathologists will be blinded to the [18F]CTT1057 PET/CT data. In this case, only 
pathology will be used as SoT for the concerned lesion(s).  
In the cases where pathology will not be available for a lesion, the central read results of the 
[68Ga]Ga-PSMA-11 PET/CT scan (performed for all participants randomized) and other 
imaging diagnostic procedures to be performed on each participant for the CTS Level 2 will be 
used as SoT for the co-primary endpoint calculations. See study protocol Section 4.1 for central 
read details. 
All participants will undergo a [68Ga]Ga-PSMA-11 PET/CT as part of the study, for both the 
CTS Level 2 (in case it is required as SoT) and the secondary endpoint of assessment of 
concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of lesions (as 
detailed in the study protocol Section 2). 
In addition to central review, local review of SoC images (including [68Ga]Ga-PSMA-11) will 
be performed to be used by the treating physician/Clinical Study Investigator for participant 
management decisions and overall assessment. See study protocol Section 8.3.1 for assessment 
details and Section 6.4 for blinding requirements. 
A questionnaire on the planned participant management will be filled in by the treating 
physician/Clinical Study Investigator before (questionnaire 1) and within 14 days after 
(questionnaire 2) knowing the results of the [18F]CTT1057 PET/CT scan. A local review of 
[18F]CTT1057 PET/CT images will also be performed by a local nuclear medicine physician or 
radiologist with expertise in reading oncology PET/CT scans and the results will be provided 
to the treating physician/Clinical Study Investigator for completion of questionnaire 2. Options 
will be given in the questionnaire to capture possible management plan, such as Surgery, 
Radiation alone, Radiation alone with change in radiation treatment plan (only applicable for 
questionnaire 2), Radiation plus ADT, ADT alone, Observation/surveillance, Other (free text 
box). Any change in patient management plan between the questionnaire 1 and questionnaire 2 
should not be based only on [18F]CTT1057 PET scan results since this is an investigational 
diagnostic imaging product. Other diagnostic procedures should be performed as per SoC in 
order to confirm and implement the changed management plan. See Figure 1-1 for study design 
schema. 
 
 


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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. All 
procedures described in the Assessment Schedule as per Table 8-1 in the study protocol must 
be carried out, prioritizing laboratory assessments to allow time to obtain the results at least 14 
days prior the planned first 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. 
Once eligibility is confirmed, the participants will be randomized in IRT to be assigned to one 
of the following two PET/CT scan sequences at random in a 1:1 ratio: 
• Sequence 1: [18F]CTT1057 on Day 1 (investigational imaging agent) followed by 
[68Ga]Ga-PSMA-11 at least 14 days apart  (as part of CTS if required, and for secondary 
endpoint) 
• Sequence 2: [68Ga]Ga-PSMA-11 (as part of CTS if required, and for secondary endpoint)  
on Day 1 followed by [18F]CTT1057 (investigational imaging agent) at least 14 days apart 
PET Imaging days 
The 2 PET imaging procedures will be done at least 14 days apart. The day of the first 
PET imaging agent injection will be considered study Day 1. Please refer to the study 
protocol Section 8.3.1 for the steps that will take place on each PET imaging day. 
Both visits will also be considered as the End of Treatment (EOT) visits. 
Safety Checks 
All treated participants will be contacted by phone within 24 to 72 hours following each 
PET scan in order to capture potentially occurring Adverse Events. 
Safety Follow-up 


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Participants will come back to the hospital 14 days (+ 3 day window) after each PET scan day, 
for a safety visit including vital signs, lab and urine analysis. For participants undergoing 
surgery, radiation therapy or initiating any antineoplastic medication (provided all CTS 
procedures have been completed before this initiation) prior to planned safety visit, these safety 
follow-up assessments will need to be performed before the surgery/radiation therapy/initiation 
of antineoplastic medication.  
Additional Follow-up 
Additional follow up period will be applicable where additional diagnostic procedures are to be 
performed. These may include SoC pathology, imaging or other modality disease assessments 
(CTS Levels 1 or 2) up to 8 weeks after [18F]CTT1057 PET scan or three-month follow-up 
imaging (from baseline) where it is clinically required for the diagnosis of particular lesion(s). 
In addition, in cases where the CTS Level 2 is not feasible/appropriate, the CTS Level 3 will 
apply and will include the assessment of PSA levels prior to starting radiotherapy (which should 
commence within 8 weeks of completing [18F]CTT1057 PET scan) and at approximately 90 
days from last day of radiation. 
PSA response per PCWG3 is defined as a 50% or greater decline in PSA on the post-RT 
timepoint compared to PSA prior to RT. If a participant has PSA response, in the absence of 
concomitant androgen deprivation therapy administration, then the irradiated lesion (recorded 
in the concomitant antineoplastic – radiotherapy CRF page) will be considered as a confirmed 
prostate cancer lesion.  
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 region-level correct 
localization rate (CLR) of [18F]CTT1057 
• 
Proportion of regions containing at least one 
TP lesion (anatomically localized 
correspondence between PET imaging and the 
reference standard), regardless of any co-
existent FP findings within the same region, out 
of all regions containing at least one PET-
positive finding by central assessments. See 
Section 1.2.1 for Primary Estimand 
• 
Evaluate the patient-level positive 
predictive value (with anatomical 
localization) of [18F]CTT1057 
• 
Proportion of patients who have at least one 
TP lesion (anatomically localized 
correspondence between PET imaging and the 
reference standard), regardless of any co-
existent FP findings, out of all patients who are 
PET/CT scan positive by central assessments. 
See Section 1.2.1 for Primary Estimand 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Evaluate the patient-level sensitivity of 
[18F]CTT1057 
• 
Proportion of patients that test positive on 
[18F]CTT1057 and CTS (TP) among those that 
are CTS positive (TP or FN) 


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Objective(s) 
Endpoint(s) 
• 
Evaluate the patient-level specificity of 
[18F]CTT1057 
• 
Proportion of patients that test negative on 
[18F]CTT1057 and CTS (TN) among those that 
are CTS negative (TN or FP) 
• 
Evaluate the patient-level negative 
predictive value of [18F]CTT1057  
• 
Proportion of patients who are both 
[18F]CTT1057 and CTS negative (TN) among 
those who test negative on [18F]CTT1057 (TN 
or FN) 
• 
Evaluate the patient-level accuracy of 
[18F]CTT1057  
• 
Proportion of patients that are CTS and 
[18F]CTT1057 positive (TP) and negative (TN) 
among those patients that identified on 
[18F]CTT1057 (TP, TN, FP or FN) 
• 
Evaluate correct detection rate (CDR)  
• 
Proportion of patients who have at least one 
TP lesion (exactly localized correspondence 
between PET imaging and the reference 
standard), regardless of any co-existent FP 
findings, out of all patients who are scanned 
• 
Evaluate detection rate 
• 
Proportion of patients who have at least one 
PET positive lesion, regardless of TP or FP 
findings, out of all patients who are scanned 
• 
Evaluate the region level sensitivity of 
[18F]CTT1057  
• 
Proportion of regions that test positive on both 
[18F]CTT1057 and CTS (TP) among those 
regions that are CTS positive (TP or FN) 
• 
Evaluate the region level specificity of 
[18F]CTT1057  
• 
Proportion of regions that test negative on both 
[18F]CTT1057 and CTS (TN) among those 
regions that are CTS negative (FP, or TN) 
• 
Evaluate the region level negative 
predictive value of [18F]CTT1057  
• 
Proportion of regions that are CTS and 
[18F]CTT1057 negative (TN) among those 
regions that test negative on [18F]CTT1057 (TN 
or FN) 
• 
Evaluate the region level accuracy of 
[18F]CTT1057  
• 
Proportion of regions that are CTS and 
[18F]CTT1057 positive (TP) and negative (TN) 
among those regions that identified on 
[18F]CTT1057 (TP, TN, FP and FN) 
• 
 Evaluate the patient-level positive 
predictive value related to PSA levels  
• 
Percentage of patients who have at least one 
TP lesion (exactly anatomically localized 
correspondence between [18F]CTT1057 PET 
imaging and the reference standard), 
regardless of any co-existent FP findings, out 
of all patients who are [18F]CTT1057 positive, 
stratified by PSA levels 
• 
Characterize the safety and tolerability of 
[18F]CTT1057 
• 
Incidence of AEs. Treatment emergent adverse 
event (TEAE) rate within 14 days after each 
PET tracer 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 
 


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Objective(s) 
Endpoint(s) 
• 
Concordance between [18F]CTT1057 and 
[68Ga]Ga-PSMA-11 for detection of 
lesions at lesion level using central reads 
• 
Concordance between [18F]CTT1057 and 
[68Ga]Ga-PSMA-11  for detection of PSMA-
positive lesions (location and number) using 
central reads 
• 
Evaluate the change in patient 
management plans attributed to the 
PET/CT scan 
• 
Percentage of patients who underwent a 
change in intended treatment plan attributed to 
the PET/CT scan as assessed by pre and post 
imaging questionnaires 
• 
Assess all the above primary and 
secondary objectives independently in the 
subgroup of patients with prior radical 
prostatectomy and the subgroup of   
patients with prior curative intent radiation 
therapy 
• 
All the above primary and secondary endpoints 
independently in the subgroup of patients with 
prior RP and the subgroup of patients with prior 
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1.2.1 
Primary estimand(s) 
The primary clinical question of interest is: What is the probability that a positive [18F]CTT1057 
PET/CT scan truly detects and localizes (PSMA-expressing) tumor recurrence in BCR PCa 
patients? 
The justification for the primary estimands is that we wish to assess the diagnostic performance 
of [18F]CTT1057 PET/CT in detecting and localizing PSMA positivity in PCa patients 
diagnosed of biochemical recurrence (BCR), which represents a stage of prostate cancer where 
there is an increase in PSA levels after initial treatment. Correct identification of disease 
location and extent guides treatment decisions. It is relevant, therefore, to detect smaller lesions 
as early as possible. Sensitivity and specificity of [18F]CTT1057 PET/CT in detecting and 
localizing PSMA positivity using histopathology as SoT will be assessed in an independent 
study in newly diagnosed high-risk PCa patients candidate to surgery. However, in this primary 
staging population a low prevalence and high variability of metastatic lymph nodes has been 
reported (from 4-58%) (Petersen and Zacho 2020). Therefore, an additional study in the 
BCR setting is needed, since this is a relevant patient population which is expected to have an 
adequate representation of metastasis-positive and metastasis-negative patients by any available 
reference standard. In this population, a CTS is needed for reference (for CTS details see 
protocol Section 3 and Section 4.1). Pathology is available in only a limited number of cases, 
and morphological imaging is negative in a substantial number of cases. This makes the 
identification of true and false negative results a challenge, thus complicating the evaluation of 
sensitivity and specificity. Therefore, the region-level correct localization rate (CLR) defined 
as the region-level PPV with anatomical localization and the patient-level PPV with anatomical 
localization are more appropriate co-primary endpoints than sensitivity and specificity in the 
BCR setting. The patient-level PPV with anatomical localization, as the conditional probability 
of positivity given the result of the PET/CT scan is more meaningful than the correct detection 
rate (CDR) defined as the percentage of true-positive patients in the whole population 
(unconditional probability of positivity). Moreover, the CDR has reported to be dependent of 
the PSA levels in the BCR population using another [18F]-PSMA labeled PET agent 
(Chantadisai et al 2020). 
The primary estimands are described by the following attributes: 


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Primary estimand 1: 
1. Population: Patients with biopsy proven prostate adenocarcinoma and rising PSA after 
definitive therapy with RP or curative-intent radiation therapy (external beam or 
brachytherapy), diagnosed of biochemically recurrent prostate cancer. Further details about 
the population are provided in the protocol Section 5. 
2. Variable: Regional-level correct localization rate (CLR), defined as the proportion of 
regions containing at least one true positive lesion (anatomically localized correspondence 
between [18F]CTT1057 PET imaging and the reference standard), regardless of any co-
existent false positive findings within the same region, out of all regions containing at least 
one [18F]CTT1057 PET-positive finding, using central reads. 
3. Treatment of interest: [18F]CTT1057 injected as a single intravenous dose of approximately 
370 MBq and subsequent PET/CT scan. Further details about the investigational treatment 
is provided in the protocol Section 6. 
4. Intercurrent 
events: 
Participants 
who 
received 
the 
investigational 
imaging 
agent [18F]CTT1057 but did not undergo/complete the PET 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: Region-level CLR along with two-sided 95% confidence interval 
estimated using logistic random-effects models taking into account the correlation among 
regions within one participant.  
Primary estimand 2: 
1. Population: the same as primary estimand 1 
2. Variable: Patient-level positive predictive value (PPV), defined as the proportion of 
participants who have at least one true positive lesion (anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the reference standard), 
regardless of any co-existent false positive findings, out of all PET positive participants, 
using central reads. 
3. Treatment of interest: the same as primary estimand 1 
4. Intercurrent events: the same as primary estimand 1 
5. Summary measure:   Patient-level PPV along with two-sided exact binomial 
95% confidence interval. 
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. 
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 data cut-off date. The cut-
off date for the final analysis of study data will be established after all randomized participants 
have completed EOS visit (Last Patient Last Visit). 


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All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on cut-off 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., 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, 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 agents: [18F]CTT1057  
Study Treatment: the administration of at least one of the two PET imaging 
agents: [18F]CTT1057, as a single injection intravenously (i.v.) of approximately 370 MBq 
(range 266 – 407 MBq), and [68Ga]Ga-PSMA-11 as a single injection intravenously (i.v.) of 
approximately 150 MBq (range 111 – 185 MBq), independently of whether the PET/CT scans 
were acquired or not. In this study, the investigational imaging agent of interest is the 
radioligand imaging compound [18F]CTT1057. [68Ga]Ga-PSMA-11 will be used as a 
component of the CTS Level 2 if required, and in all participants for the secondary endpoint of 
assessment of concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of 
lesions (as detailed in the study protocol Section 2). 
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, 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 on or before the date/time of start of study 
treatment [18F]CTT1057 is defined as “baseline” assessment for [18F]CTT1057 safety. 
The last available assessment on or before the date/time of start of study treatment [68Ga]Ga-
PSMA-11 is defined as “baseline” assessment for [68Ga]Ga-PSMA-11 safety. 
If participants have no value as defined above, the baseline result will be set to 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/time before 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 14 days after 
date of actual administration of any study treatment (including the administration date). 
The on–treatment period will be divided into the F-on-treatment period and Ga-on-
treatment period for the respective study treatment of [18F]CTT1057 or [68Ga]Ga-
PSMA-11 
• The F-on-treatment period is from the date of [18F]CTT1057 administration to 
14 days after the date of [18F]CTT1057 administration.  
• The Ga-on-treatment period is from the date of [68Ga]Ga-PSMA-11 
administration to 14 days after the date of [68Ga]Ga-PSMA-11 administration.  
3. post-treatment period: starting 15 days after the date of last administration of study 
treatment. 
 
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 


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post-treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) 
will summarize treatment-emergent AEs only (see Section 2.7.1).   
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, 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 case 
value will be used. Data from all assessments (scheduled and unscheduled), including multiple 
assessments, will be listed. 
 
For participants randomized into sequence 1: [18F]CTT1057 - [68Ga]Ga-PSMA-11 
 
Time Window 
Planned Visit Timing  
Time Window Definition 
On treatment 
 
 
Baseline for 
[18F]CTT1057 
On or before Study Day 1* 
≤ Study Day 1, and time 
prior to [18F]CTT1057 
injection 
 
 
 
Day 1 for [18F]CTT1057 
Study Day 1 
Date of [18F]CTT1057 
injection 
 
 
 
 
 
 
Day 15 for PET for 
[18F]CTT1057 
Study Day 15 
Study Day 15 - 22, and time 
prior to [68Ga]Ga-PSMA-11 
injection 
 
 
 
 
 
 
Baseline (Day 1) for 
[68Ga]Ga-PSMA-11 
On or before [68Ga]Ga-
PSMA-11 injection and after 
[18F]CTT1057 injection 
≥Study Day 15 and ≤ Study 
Day 22, time prior to 
[68Ga]Ga-PSMA-11 
injection 
 
 
 
Day 1 for [68Ga]Ga-
PSMA-11 
On [68Ga]Ga-PSMA-11 
injection  
Date of [68Ga]Ga-PSMA-11 
injection 
 
 
 


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Day 15 for [68Ga]Ga-
PSMA-11 
the date of [68Ga]Ga-PSMA-
11 injection  + 14 days  
Study Day 29- 39 
 
 
 
*Study Day 1 = the date of [18F]CTT1057 injection  
 
For participants randomized into sequence 2: [68Ga]Ga-PSMA-11 - [18F]CTT1057 
 
Time Window 
Planned Visit Timing  
Time Window Definition 
On treatment 
 
 
Baseline  for [68Ga]Ga-
PSMA-11 
On or before Study Day 1* 
≤ Study Day 1, and time 
prior to [68Ga]Ga-PSMA-11 
injection 
 
 
 
Day 1 for [68Ga]Ga-
PSMA-11 
Study Day 1 
Date of [68Ga]Ga-PSMA-
11injection 
 
 
 
Day 15 for PET for 
[68Ga]Ga-PSMA-11 
Study Day 15 
Study Day 15 - 22, time 
prior to [18F]CTT1057 
injection 
 
 
 
Baseline  for 
[18F]CTT1057 
On or before [18F]CTT1057 
and after [68Ga]Ga-PSMA-11 
≥Study Day 15 and ≤ Study 
Day 22, time prior to 
[18F]CTT1057 injection 
 
 
 
Day 1 for [18F]CTT1057 
On [18F]CTT1057 injection 
Date of [18F]CTT1057 
injection 
 
 
 
Day 15 for 
[18F]CTT1057 
the date of [18F]CTT1057 
injection  + 14 days  
Study Day 29-39 
 
 
 
*Study Day 1 = the date of [68Ga]Ga-PSMA-11 injection  
 
For vital signs, post-injection/pre-imaging, and post-imaging assessment will be compared to 
the baseline (pre-injection assessment) in addition to its Day 15 assessment compared to 
baseline. Post-injection/pre-imaging and post-imaging will be performed on the day of imaging.  
2.2 
Analysis sets  
The Full Analysis Set (FAS) includes all randomized participants. 


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The Efficacy Analysis Set (EFF) includes all randomized participants who receive 
the dose of investigational treatment (i.e. [18F]CTT1057), have both an evaluable 
[18F]CTT1057 PET/CT scan imaging and at least one evaluable CTS assessment, and have not 
received any prohibited systemic antineoplastic therapy before the completion of PET/CTs and 
CTS procedures. 
The [18F]CTT1057  Safety Set (F-SAF) includes all participants who received the 
investigational treatment (i.e. [18F]CTT1057). 
The [68Ga]Ga-PSMA-11 Safety Set (Ga-SAF) includes all participants who received 
[68Ga]Ga-PSMA-11. Participants will be analyzed according to the study treatment received. 
The Safety Set (SAF) includes all participants who received at least one of [18F]CTT1057 or  
[68Ga]Ga-PSMA-11. 
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 primary and secondary efficacy endpoints will be summarized by initial definitive therapy 
received: 
• prior radical prostatectomy  
• prior curative intent radiation therapy 
The primary efficacy co-primary endpoints will also be summarized by PSA level at baseline 
(from central laboratory): 
• PSA ≤ 0.5 ng/mL 
• 0.5 ng/mL<PSA≤1 ng/mL 
• 1 ng/mL<PSA≤2 ng/mL 
• 2 ng/mL<PSA≤5 ng/mL 
• PSA > 5 ng/mL 
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 failure and the reasons for screening failure will 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 (based on the ‘Disposition’ page and with % 
based on all screened participants) 
• Number (%) of participants who completed the screening phase and were randomized 
(based on the ‘Disposition’ page and with % based on all screened participants)  


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• Number (%) of participants who did not complete screening (were not randomized) with 
reason (based on the ‘Disposition’ page and with % based on all screened participants) 
o Number (%) of participants who did not complete screening related to COVID-19 
and primary relationships to COVID-19 (based on the ‘Disposition’ page and with % 
based on all screened participants) 
The following summaries will be displayed by assigned treatment sequence and overall: 
• Number (%) of participants who completed treatment period 1 (based on the ‘Disposition’ 
page) 
• Number (%) of participants who discontinued treatment period 1 with reason (based on the 
‘Disposition’ page) 
o Number (%) of participants who discontinued treatment period 1 related to COVID-
19 and primary relationships to COVID-19 (based on the ‘Disposition’ page) 
• Number (%) of participants who completed treatment period 2 (based on the ‘Disposition’ 
page) 
• Number (%) of participants who discontinued treatment period 2 with reason (based on the 
‘Disposition’ page) 
o Number (%) of participants who discontinued treatment period 2 related to COVID-
19 and primary relationships to COVID-19 (based on the ‘Disposition’ page) 
• 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 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 performance 


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status, 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, PSA level at screening from central laboratory for 
subgroup participants who had prior RP and participants who had prior curative intent RT, 
separately) will be summarized by descriptive statistics (N, mean, median, 1st and 3rd quartile, 
standard deviation, minimum and maximum). 
Diagnosis and extent of cancer  
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following for all participants: PSA level at time of initial cancer diagnosis (ng/mL), 
primary tumor clinical stage (i.e. T2c or less, T3, T3a, T3b, T4 and Tx), regional lymph node 
clinical stage, distant metastasis clinical stage, 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), initial definitive therapy received, time since initial diagnosis to first injection (in 
months), time from initial diagnosis to biochemical recurrence diagnosis (in months), the time 
since primary definitive therapy to diagnosis of BCR, time since biochemical recurrence 
diagnosis to the first injection (in days), PSA level at biochemical recurrence diagnosis (ng/mL). 
Note: biopsy Gleason score will be displayed along with the score details for each score 
combination in the listing. 
For participants who underwent radical prostatectomy: primary tumor pathological stage, 
regional lymph node pathological stage, distant metastasis pathological stage, radical 
prostatectomy Gleason score (i.e. ≤ 6, 7 (3+4), 7 (4+3), 8, and 9 or 10), radical prostatectomy 
residual disease status. Note: Radical prostatectomy Gleason score will be displayed along with 
the score details for each score combination in the listing. 
For participants who underwent curative intent radiation therapy: Nadir PSA level (ng/mL) 
Derivations:  
Time since initial diagnosis to the first injection (in months) = (date of the first injection – 
date of first prostate cancer diagnosis + 1) / 30.4375 
Time from initial diagnosis to biochemical recurrence diagnosis (in months) = (biochemical 
recurrence diagnosis - date of first prostate cancer diagnosis + 1) / 30.4375 
Time since biochemical recurrence to the first injection (in days) = date of the first injection – 
biochemical recurrence + 1  
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 (e)CRF will be summarized and listed. Separate summaries will be presented for 
ongoing and historical medical conditions.  The summaries will be presented by primary system 


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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 and [68Ga]Ga-PSMA-11, as reported in 
the study treatment page of the eCRF, will be summarized for the F-SAF and Ga-SAF : 
• Radioactivity dose administered (MBq) 
• Number (%) of participants who were dosed but with extravasation during administration  
• Number of participants with dose administered outside the planned range: 
- for [18F]CTT1057 : < 266 MBq or > 407 MBq  
- for [68Ga]Ga-PSMA-11 : < 111 MBq or > 185 MBq 
• Time (in minutes) from injection to full-body PET imaging acquisition start time 
• Number (%) of participants with additional pelvic PET imaging acquisition, with time from 
injection to additional pelvic PET imaging acquisition start time if applicable 
 
An additional summary of the time (in days) between the [18F]CTT1057 and [68Ga]Ga-PSMA-
11 PET scan dates will be provided using the SAF.    
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. 
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 beam) and setting. 
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 (including regimen 
number, setting and intent), radiotherapy, and surgery. 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.  


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The above summary tables will be performed using the FAS and EFF and listings will be 
provided using the FAS. 
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 within 14 days of [18F]CTT1057 (or 
[68Ga]Ga-PSMA-11) as long as they are prior to [68Ga]Ga-PSMA-11 (or 
[18F]CTT1057) dose (if applicable) 
2. Medications/therapies/procedures starting prior to start of study treatment and 
continuing after the start of study treatment. 
Number of participants (%) who received diuretics (e.g. Furosemide) as concomitant 
medication on the day of PET/CT scans will also be summarized.  
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of first dose of study treatment or starting more than 14 days after the last date of 
study treatment will be flagged in the listing.   Concomitant medication summary tables will be 
provided using the F-SAF and Ga-SAF separately, and listings will be provided for the SAF. 
2.5 
Analysis supporting primary objective(s) 
The primary objectives of the study are to evaluate the region-level CLR of [18F]CTT1057, and 
to evaluate the patient-level PPV (with anatomical localization) of [18F]CTT1057. 
2.5.1 
Primary endpoint(s) 
The co-primary endpoints evaluated for participants in the EFF are the following: 
Region-level CLR: Proportion of regions containing at least one TP lesion (anatomically 
localized correspondence between PET imaging and the reference standard), regardless of any 
co-existent FP findings within the same region, out of all regions containing at least one PET-
positive finding by central assessments. See Section 1.2.1 for Primary Estimand. 
Patient-level PPV: Proportion of participants who have at least one TP lesion (anatomically 
localized correspondence between PET imaging and the reference standard), regardless of any 
co-existent FP findings, out of all participants who are PET/CT scan positive by central 
assessments. See Section 1.2.1 for Primary Estimand. 


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Centralized imaging assessments (CTS Level 2) will be used as reference standard if pathology 
assessment (CTS Level 1) is not available for a lesion, inconclusive or negative (for biopsy 
only).
 
  
2.5.2 
Statistical hypothesis, model, and method of analysis  
For region-level CLR, the observations (regions positive/negative status) are clustered within 
a participant. Observations within participants (clusters) are correlated, which may lead to 
biased estimates of region-level CLR when the correlated nature of the data within each cluster 
is ignored. More important, an analysis ignoring correlation often yields a misleading small 
estimated standard error (and 95% CI) for CLR because it erroneously counts all observations 
as independent observations. Region-level CLR adjusted for correlation among observations 
within participants can be modeled by using a logistic regression model with random effects 
(Gatsonis CA 1995, Verbeke G, Molenberghs G 2000).  
When calculating CLR, the number of TP regions (𝑦𝑦𝑖𝑖), follows the binomial distribution with 
parameter (ni, pi), 
𝑦𝑦𝑖𝑖|𝑏𝑏𝑖𝑖~Binomial(𝑛𝑛𝑖𝑖, 𝑝𝑝𝑖𝑖) 
 
pi denotes the probability of TP among all positive PET regions (TP or FP) for participant i, and 
ni corresponds to the denominator in the CLR definition, i.e. the number of all regions 
containing at least one PET-positive finding by central assessments (TP or FP regions) for 
participant i.   
The number of TP and FP regions overall (i.e. across all five regions, which are prostate region, 
PLN, skeletal, extra-pelvic lymph nodes and visceral) and by region across all participants in 
the EFF will be presented, along with region-level CLR and two-sided 95% CIs estimated using 
the following logistic regression model with random effects.  
 
log ቀ
𝑝𝑝𝑖𝑖
1−𝑝𝑝𝑖𝑖ቁ= μ + bi   
 
where pi is the region-level CLR for participant i, μ is the fixed effect of overall mean, bi is the 
random effect for participants (clusters). bi follows a normal distribution: bi ~ N(0, σ𝑏𝑏
2). 
The lower bound of the 95% CI should be greater than 0.50 to attain the first co-primary 
endpoint.  
 
For patient-level PPV, the number of TP and FP participants, as well as the number of positive 
and  negative (and inconclusive, if applicable) [18F]CTT1057 PET/CT scans, will be presented, 
along with patient-level PPV with two-sided exact binomial 95% CIs (Clopper and Pearson 
1934). 
The lower bound of the 95% CI for patient-level PPV should be greater than 0.20 attain the 
second co-primary endpoint. 


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The same analysis for patient-level PPV will be repeated by CTS Level.  
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 analyses 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 PET/CT scan for any reason (e.g. consent withdrawal, 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 a one-
time imaging assessment. Missing data will not be imputed. 
2.5.5 
Sensitivity analyses  
For participants where CTS Level 1 or 2 is used as the truth standard for the primary analysis, 
the next lower level of CTS will be used to verify positivity or negativity for the sensitivity 
analysis, if available. For instance, if pathology (CTS Level 1) is used for a lesion as the truth 
standard for the primary estimand, the imaging component of CTS (Level 2) will be used as 
truth standard for sensitivity analysis for the primary estimand. Similarly, results of CTS Level 
2 will be replaced by CTS Level 3 if applicable. However, for those using changes in PSA level 
(CTS Level 3) as the truth standard for primary estimand, their positivity status cannot be 
replaced by another component of CTS for sensitivity analysis. 
Region-level CLR along with its 95% CI will also be computed based on the weighted estimator 
approach (Lee and Dubin 1994) for each central reader as following: 
𝑝𝑝̂𝑤𝑤± 1.96𝜎𝜎ො/√𝑛𝑛. 
𝑝𝑝̂𝑤𝑤is the point estimator with 𝑝𝑝̂𝑤𝑤= ∑𝑖𝑖=1
𝑛𝑛 𝑝𝑝̂𝑖𝑖 /𝑛𝑛 and 𝑝𝑝̂𝑖𝑖 =  𝑦𝑦𝑖𝑖/𝑛𝑛𝑖𝑖, where 𝑦𝑦𝑖𝑖 and  𝑛𝑛𝑖𝑖 are the same 
as defined in Section 2.5.2 above and 𝑛𝑛 represents the number of participants with at least one 
PET-positive finding by central assessments. 𝜎𝜎ො is the estimated standard deviation of 𝑝𝑝̂𝑖𝑖 .  
2.5.6 
Supplementary analyses 
Supplementary analyses for region-level CLR and patient-level PPV will be performed for the 
following subgroups: 
• Initial definitive therapy received:  
o prior radical prostatectomy  
o prior curative intent radiation therapy  
 
• PSA level at baseline (from central laboratory): 


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o PSA ≤ 0.5 ng/mL 
o 0.5 ng/mL<PSA≤1 ng/mL 
o 1 ng/mL<PSA≤2 ng/mL 
o 2 ng/mL<PSA≤5 ng/mL 
o PSA > 5 ng/mL 
In addition, estimates of region-level CLR and corresponding 95% CI will be obtained from the 
logistic random-effects regression model, adjusting for covariates and taking into account the 
correlation among regions within one participant; while estimates of patient-level PPV and 
corresponding 95% CI will be obtained from the logistic regression model adjusting for 
covariates. Candidate covariates include categorized PSA level at baseline (from central 
laboratory) and the initial definitive therapy received (with either RP or curative-intent RT) as 
given above. The p-values from the Type III tests for each candidate covariate in the full model 
will be provided. The region-level CLR and patient-level PPV (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 there are no statistically significant covariates identified from the full 
model, the region-level CLR (and 95% CI) from the unadjusted logistic random-effects 
regression model and the patient-level PPV (and 95% CI) from the unadjusted logistic 
regression model will be provided. 
2.6 
Analysis supporting secondary objectives  
The following other secondary efficacy objectives are defined for the EFF unless otherwise 
specified:   
• Evaluate the patient-level sensitivity of [18F]CTT1057 
• Evaluate the patient-level specificity of [18F]CTT1057 
• Evaluate the patient-level negative predictive value of [18F]CTT1057  
• Evaluate the patient-level accuracy of [18F]CTT1057  
• Evaluate correct detection rate (CDR) 
• Evaluate detection rate 
• Evaluate the region level sensitivity of [18F]CTT1057  
• Evaluate the region level specificity of [18F]CTT1057  
• Evaluate the region level negative predictive value of [18F]CTT1057  
• Evaluate the region level accuracy of [18F]CTT1057  
• Characterize the safety and tolerability of [18F]CTT1057 
• [18F]CTT1057 scan inter-reader variability  
• [18F]CTT1057 scan intra-reader variability  
• Concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of lesions 
using central reads 
• Evaluate the change in patient management plans attributed to the PET/CT scan 
• Assess all the above secondary objectives independently in the subgroup of patients with 
prior radical prostatectomy (RP) and the subgroup of patients with prior curative intent 
radiation therapy (RT) 


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2.6.1 
Secondary endpoint(s) 
For the following secondary endpoints, centralized imaging assessments (CTS Level 2) will be 
used as reference standard if pathology assessment (CTS Level 1) is not available for a lesion, 
inconclusive or negative (for biopsy only).  
Patient-level sensitivity is defined as the proportion of TP participants among those who are 
TP or FN 
Patient-level specificity is defined as the proportion of TN participants among those who are 
TN 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 
scanned participants (regardless of TP, TN, FP, FN) 
Patient-level correct detection rate is defined as the proportion of TP participants among all 
scanned participants (regardless of TP, TN, FP, FN) 
Patient-level detection rate is defined as the proportion of TP and FP participants among all 
scanned participants (regardless of TP, TN, FP, FN) 
where TP, TN, FP, FN participants are defined as follows:  
• PSMA TP participants are those who have at least one TP lesion (with anatomically 
localized correspondence between [18F]CTT1057 PET imaging and the CTS). 
• PSMA TN participants are those who do not show any pathological [18F]CTT1057 
uptake and will be confirmed as NOT having any lesions with the CTS. 
• PSMA FP participants are those who show at least one pathological [18F]CTT1057 
uptake but will be verified as NOT having any lesions with the CTS or no lesions are  
correctly localized in anatomical location by the CTS. 
• PSMA FN participants are those who do not show any pathological [18F]CTT1057 
uptake but will be confirmed as having at least one lesion with the CTS. 
Number of TP, TN, FP, FN participants will be presented and used to calculate the diagnostic 
performance parameters.  
Two-sided exact binomial 95% CIs will be calculated for patient-level diagnostic performance 
parameters. 
[18F]CTT1057 scan inter-reader variability is defined as agreement among three readers 
determinations and will be assessed by Fleiss' Kappa statistic.  
[18F]CTT1057 scan intra-reader variability is defined as within-reader agreement for two 
different time points and will be assessed by Cohen's Kappa statistic. A subset of imaging 
reading will be performed at two different time points by each reader. See details in imaging 
charter.  
Change in patient management plans attributed to the [18F]CTT1057  PET/CT scan is defined 
as the percentage of participants who undergo a change in intended treatment plan attributed to 


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the PET/CT scan as assessed by pre-imaging questionnaire 1 and post-imaging questionnaire 
2.  
The number and percentage of participants from the F-SAF for each of the following categories 
of treatment plan in each of the two questionnaires will be calculated: surgery, radiation alone, 
radiation alone with change in radiation treatment plan (only applicable for questionnaire 2), 
radiation plus ADT, ADT alone, observation/surveillance, other (free text box). 
Treatment plan change is defined as a change in the pair of categories (one category of 
questionnaire 1, one category of questionnaire 2).  
The number and percentage of participants from the F-SAF with treatment plan change as 
defined above will be calculated. Shift tables comparing treatment plans between questionnaire 
1 and 2 will be displayed. The number (%) of participants with and without a change in 
treatment plans by [18F]CTT1057 local read results (i.e. positive, negative, and inconclusive) 
will be tabulated. 
Region-level sensitivity is defined as the proportion of TP regions among those that are TP or 
FN 
Region-level specificity is defined as the proportion of TN regions among those that are TN or 
FP 
Region-level negative predictive value is defined as the proportion of TN regions among those 
that are TN or FN 
Region-level accuracy is defined as the proportion of TP and TN 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 containing at least one TP lesion (anatomically localized 
correspondence between [18F]CTT1057 PET imaging and the CTS).  
• PSMA TN regions are regions containing no lesions with pathological [18F]CTT1057 
uptake and confirmed by CTS.   
• PSMA FP regions are regions containing lesions with pathological [18F]CTT1057 uptake 
but are verified negative by CTS or none is correctly localized in anatomical location by 
the CTS. 
• PSMA FN regions are regions containing no lesions with pathological [18F]CTT1057 
uptake but are confirmed as having at least one lesion with the CTS. 
Number of TP, TN, FP, FN regions will be presented and used to calculate the diagnostic 
performance parameters.  
Two-sided 95% CIs for (overall) region-level diagnostic performance parameters will be 
calculated using a logistic random-effects models taking into account the correlation among 
regions within a participant.  
For different regions (i.e. prostate region, PLN, extra-pelvic lymph nodes, skeletal, and visceral), 
two-sided exact binomial 95% CIs for region-level diagnostic performance parameters will be 
calculated. 


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Concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detection of lesions and 
positive percent agreement will be calculated to assess the concordance. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
For patient-level diagnostic performance parameters:   
• Patient-level sensitivity  
• Patient-level specificity  
• Patient-level negative predictive value  
• Patient-level accuracy  
• Patient-level correct detection rate  
• Patient-level detection rate 
The number and percentage of TP, TN, FP, and FN participants will be presented and used to 
calculate the diagnostic performance parameters.  
Two-sided exact binomial 95% CIs for patient-level diagnostic performance parameters will be 
calculated. 
[18F]CTT1057 scan inter-reader variability will be assessed by Fleiss' Kappa 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 received (𝑛𝑛= 3), and k the number of outcome categories (𝑘𝑘=
2) into which assignments are made. Participants are indexed by 𝑖𝑖= 1, … , 𝑁𝑁 and categories are 
indexed by 𝑗𝑗= 1, … , 𝑘𝑘. Let 𝑛𝑛𝑖𝑖𝑖𝑖 represent the number of readers who assigned the 𝑖𝑖th participant 
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 be obtained to 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 
can be calculated as: 𝜅𝜅1 ± 1.96𝑠𝑠𝑠𝑠
ෞ(𝜅𝜅1)). An additional table will be presented to show the 


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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 using the F-
SAF. 
[18F]CTT1057 scan intra-reader variability will be assessed by Cohen's Kappa 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 2-1) 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 2-1 
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), 𝑛𝑛𝑖𝑖1 the 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 𝜅𝜅= 
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 2-1) and  𝑝𝑝𝑒𝑒= ∑
𝑛𝑛𝑖𝑖1
𝑁𝑁
𝑛𝑛𝑖𝑖2
𝑁𝑁
𝑘𝑘
𝑖𝑖=1
 
(𝑝𝑝𝑒𝑒=
𝑎𝑎+𝑏𝑏
𝑁𝑁
𝑎𝑎+𝑐𝑐
𝑁𝑁+ 
𝑐𝑐+𝑑𝑑
𝑁𝑁
𝑏𝑏+𝑑𝑑
𝑁𝑁 in Table 2-1).  Intra-reader variability will be calculated for the F-SAF. 
 
For region-level diagnostic performance parameters:   
• Region-level sensitivity  


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• Region-level specificity  
• Region-level negative predictive value  
• Region-level accuracy  
Number of TP, TN, FP, FN regions will be presented and used to calculate the diagnostic 
performance parameters.  
Two-sided 95% CI’s for (overall) region-level diagnostic performance parameters will be 
calculated using a logistic random-effects models taking into account the correlation among 
regions within a participant.  
For different regions (i.e. prostate region, PLN, skeletal, extra-pelvic lymph nodes and visceral), 
two-sided exact binomial 95% CI’s for region-level diagnostic performance parameters will be 
calculated. 
 
Concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 For detection of PSMA-
positive lesions, positive percent agreement (PPA) will be calculated to assess the concordance.  
Logistic random-effects models will be used taking into account the correlation among lesions 
within a participant overall and by region. When calculating PPA, the number of positive lesions 
identified and anatomically co-localized by both [18F]CTT1057 and [68Ga]Ga-PSMA-11 for 
participant i (see 
), 𝑦𝑦𝑖𝑖, follows the binomial 
distribution with parameter (ni, pi),  
 
𝑦𝑦𝑖𝑖|𝑏𝑏𝑖𝑖~Binomial(𝑛𝑛𝑖𝑖, 𝑝𝑝𝑖𝑖) 
 
pi denotes the PPA for participant i, ni corresponds to the denominator in the PPA definition, 
i.e. the number of all positive lesions identified by [68Ga]Ga-PSMA-11 for participant i.  
PPA along with two-sided 95% CIs will be estimated by the logistic regression model with 
random effects below:  
 
log ቀ
𝑝𝑝𝑖𝑖
1−𝑝𝑝𝑖𝑖ቁ= μ + bi 
 
where pi is the lesion-level PPA for participant i, μ is the fixed effect of overall mean, bi is the 
random effect of participants (clusters). bi  follows a normal distribution : bi ~ N(0, σ𝑏𝑏
2).  
The same analysis will be repeated by region and combining skeletal, extra-pelvic lymph nodes, 
and visceral regions (M1).  
The number of PSMA-positive lesions identified on [18F]CTT1057 PET/CT, on [68Ga]Ga-
PSMA-11 PET/CT, on [18F]CTT1057 PET/CT but not on [68Ga]Ga-PSMA-11, on [68Ga]Ga-
PSMA-11 but not on [18F]CTT1057 PET/CT, and the number of PSMA-positive lesions 
identified on both[18F]CTT1057 and  [68Ga]Ga-PSMA-11 PET/CT will be displayed overall, 
by region and by combined M1 region.  


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The above analyses will be provided by each central reader using the F-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 
imaging agent [18F]CTT1057 but do not undergo/complete the PET/CT scan for any reasons 
(e.g. consent withdrawal, PET camera failures, etc.) will not be used for the secondary efficacy 
endpoint analyses, 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 
Supplementary analyses for patient-level and region-level diagnostic performance parameters 
defined in Section 2.6.2 will be performed for the following subgroup: 
• PSA level at baseline (from central laboratory): 
o PSA ≤ 0.5 ng/mL 
o 0.5 ng/mL<PSA≤1 ng/mL 
o 1 ng/mL<PSA≤2 ng/mL 
o 2 ng/mL<PSA≤5 ng/mL 
o PSA > 5 ng/mL 
2.7 
Safety analyses 
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).  Safety summary tables will be presented using the F-SAF and Ga-SAF 
separately, and listings will be provided for the SAF, unless otherwise specified.  
The overall observation period will be divided into three mutually exclusive segments (see 
Section 2.1.1 for details).  
2.7.1 
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. Summary tables for adverse events (AEs) will include only 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 as long as they were prior to the [68Ga]Ga-


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PSMA-11 dose (applicable for Sequence 1), and adverse events that were reported as related to 
[18F]CTT1057 irrespective of time of onset will be regarded as [18F]CTT1057 treatment-
emergent AEs. Similarly, all AEs that started or worsened within 14 days after the [68Ga]Ga-
PSMA-11 dose and as long as they were prior to the [18F]CTT1057 dose (applicable for 
Sequence 2), and adverse events that were reported as related to [68Ga]Ga-PSMA-11 
irrespective of time of onset will be regarded as [68Ga]Ga-PSMA-11 treatment-emergent AEs. 
[18F]CTT1057 TEAEs and [68Ga]Ga-PSMA-11 TEAEs will be summarized. 
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 adverse events and 
deaths (number and % of participants who died, with any AE, any SAE, any dose change, drug 
withdrawn etc.), AEs by SOC, PT and maximum grade, by relationship (all AEs and AEs related 
to study treatment), seriousness (SAEs and non-SAEs), leading to treatment discontinuation, 
leading to dose change, requiring additional therapy, 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. 


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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. 
2.7.1.1 
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 and [68Ga]Ga-PSMA-11. These groupings are 
defined using MedDRA terms, 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 specific tracer ([18F]CTT1057 and [68Ga]Ga-
PSMA-11). For each specified STI, the number and percentage of participants with at least one 
event of the STI occurring during the 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.  The 
analyses related to STIs for [18F]CTT1057 will be carried out using the F-SAF and the analyses 
related to STIs for [68Ga]Ga-PSMA-11 will be carried out using the Ga-SAF. 
2.7.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced. On-treatment death analyses will be presented for the F-SAF and Ga-SAF separately, 
by system organ class and preferred term. All deaths analyses will be presented for the SAF, by 
system organ class, preferred term, and treatment sequence. 
All deaths will be listed, and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened participants. 
2.7.3 
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 within 14 days (+ 3 day-window) after each imaging agent administration 
(and prior to the subsequent imaging agent administration, if applicable). 
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 


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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: 
• 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. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
The number and percentage of participants with an abnormal ECG (clinically significant) at 
screening will be presented. A listing of all ECG assessments will be produced. These analyses 
will be performed for the FAS. 
2.7.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: body temperature, blood pressure, heart rate, respiratory 
rate. 
Data handling 
Vital signs collected prior to (baseline), and within 14 days (+ 3 day-window) after each 
imaging agent administration (and prior to the subsequent imaging agent administration, if 
applicable) will be summarized. Values measured outside of the on-treatment period will be 
flagged in the listings. 


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Data analysis 
For analysis of vital signs, the clinically notable vital sign criteria are provided in Table 2-2 
below. 
Table 2-2 
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 by treatment sequence and notable values 
will be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged.  
2.8 
Pharmacokinetic endpoints   
No pharmacokinetic endpoints are defined in the study.  
2.9 
PD and PK/PD analyses 
No PD and PK/PD analyses are planned in the study.  
2.10 
Patient-reported outcomes 
No patient-reported outcomes analyses are planned in the study.  
2.11 
Biomarkers 
No biomarker analyses are planned in the study.  


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2.13 
Interim analysis 
No interim analysis is planned for this study.  
3 
Sample size calculation 
Overall, approximately 190 participants will be enrolled to ensure at least 152 participants are 
evaluable (i.e. those who have both an evaluable [18F]CTT1057 PET/CT scan imaging,  and at 
least one evaluable CTS assessment and have not received any prohibited systemic 
antineoplastic therapy before the completion of PET/CTs and CTS procedures), which will be 
required for the calculation of the co-primary endpoints. These calculations were made using 
the software PASS 11 and R 3.6.1. 
3.1 
Primary endpoints(s) 
This study is planned to recruit approximately 190 participants. The sample size calculation is 
based on the co-primary endpoints of region-level CLR and the patient-level PPV of 
[18F]CTT1057. 
The assumptions for sample size calculations are based on the estimates from data available 
from prior studies. 
The primary endpoint is to evaluate region-level CLR (prostate region, PLN, extra-pelvic lymph 
nodes, skeletal, and visceral) and patient-level PPV of [18F]CTT1057 PET for detection of 
tumor location confirmed by CTS. Based on the results of previous studies, the following 
distribution of disease across regions are anticipated: Prostate bed: 30%, pelvis: 15%; 
extrapelvic soft tissue: 20%; bone metastases: 35% (Eiber et al 2015, Ceci et al 2015, 
Van Leeuwen et al 2016). It is anticipated that the CLR for the five regions and for all regions 
combined using conventional imaging ranges from 30-60%. An overall CLR for [18F]CTT1057 
PET of at most 50% will be considered as unacceptably low. Hence, the null hypothesis that 
the CLR is at most 50% will be tested against the alternative hypothesis that the CLR is greater 
than 50%. 
The BCR population targeted in this study is expected to have similar PSA values as prior 
studies (Morris et al 2020) of approved diagnostic PET agents for PCa such as [18F]-
fluciclovine, which had a 27% PPV for patients with PSA values that were less than 1.78, as 
noted in their summary basis of approval. Thus, a patient-level PPV of 20% will be considered 
as unacceptably low. The [18F]CTT1057 positive patient rate (detection rate) for the study 
population is 80% based on [18F]-fluciclovine studies. The sample size calculation will be 
performed based on the null and alternative hypotheses as follows. 
 
Region-level CLR 
Correlated binary test results occur in this situation where each experimental unit (participant) 
consists of five correlated regions. Lee and Dubin developed a sample size formula for clustered 
binary data (Lee and Dubin 1994). They propose estimating the binary proportion by assigning 
equal weights to clusters regardless of their sizes to simplify the derivation of their sample size 


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formula. The weighted estimator for region-level CLR is approximately Gaussian distributed 
with a variance of a beta distribution (beta-binomial model).  
The null hypothesis (H0: region-level CLR p = 0.50) will be tested against the alternative 
hypothesis (H1: p > 0.50). Assuming a CLR of 0.58 under the alternative hypothesis, a total 
sample size of 172 enrolled participants would achieve 90% statistical power to detect a change 
in CLR of 0.08 using a one-sided test at a target significance level of 2.5%. This sample size 
includes an adjustment for a dropout rate of 20%.  
The sample size was determined as n to ensure a type I error using a one-sided significance 
level of 2.5% and with 90% power to reject H0 if the alternative H1 is true.  
By the standard normal approximation, the sample size is given as follows: 
 
where σ2 is the variance of a beta distribution, Za is the upper quantile of the standard normal 
distribution, p0 is a CLR of 0.50 under the null hypothesis, and p1 is a CLR of 0.58 under the 
alternative hypothesis. 
Suppose there is no information on the within-cluster correlation of test results. In this case, a 
uniform distribution seems reasonable, setting parameters in the beta distribution of alpha=1 
and beta=1. Then σ2 is 1/12. 
Under these assumptions, 137 participants will be necessary to ensure 90% power. Taking into 
account a 20% dropout rate, a total of 172 participants will be recruited for this endpoint of the 
study. 
The lower bound of the 95% CI for CRL should be greater than 0.50 to be considered a success. 
 
Patient-level PPV 
The null hypothesis (H0: patient-level PPV p = 0.20) will be tested against the alternative 
hypothesis (H1: p > 0.20). Assuming a patient-level PPV of 0.33 under the alternative 
hypothesis, a total sample size of 190 enrolled participants (which includes 152 [18F]CTT1057 
scanned participants based on 80% [18F]CTT1057 positive patient rate) would achieve 90% 
power to detect a change in patient-level PPV of 0.13 using a one-sided binomial test at a 
targeted significance level of 2.5%. This sample size includes an adjustment for a dropout rate 
of 20%.  
The lower bound of the 95% CI for patient-level PPV should be greater than 0.20 to be 
considered a success. 
A total sample size of 190 participants can ensure 92.7% statistical power for region-level CLR 
and 90% statistical power for patient-level PPV resulting in an overall study statistical power 
of at least 83.4% (0.927*0.90). 


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4 
Change to protocol specified analyses 
 
 
The subgroup analyses on participants with prior RP and participants with prior curative intent 
RT will be applied to co-primary and secondary efficacy endpoints only.  
Minor updates to the estimand wording were made as compared to the protocol for clarification. 
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 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   
Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last study treatment date 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 < 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 incomplete date of initial diagnosis of cancer and date of biochemical recurrence 
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. 
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 


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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)  
For region-level CLR, statistical model details are presented in Section 2.5. The GLIMMIX 
procedure in SAS will be used to implement the logistic regression model with random effects. 


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This analysis will be restricted to participants with at least one PET positive region (TP or FP) 
by central assessments in the EFF. In case of problems with fitting the model and estimating 
parameters, the default estimation technique (i.e. residual pseudo-likelihood with a subject 
expansion (METHOD = RSPL)) will be used. This analysis will be applied to each of the three 
central readers via the (BY READER) statement. 
For this model, the SAS code will be: 
 
proc glimmix data=dataset; 
by reader; 
   class subject; 
   model tpcount / poscount= / solution; 
   random intercept / subject=subject; 
run; 
 
• 
tpcount refers to the number of TP regions per participant  
• 
poscount refers to the number of PET positive regions (TP or FP) per participant  
 
The estimated fixed effect 𝜇𝜇̂  and its standard error 𝑆𝑆𝑆𝑆 on the logit scale can be obtained from 
the output. And the (subject-specific) region-level CLR (conditional on the random effect when 
𝑏𝑏𝑖𝑖 = 0) along with the two-sided 95% CI can be computed by applying the inverse link function: 
Point estimate of the region-level CLR: 𝐸𝐸[𝑝𝑝𝚤𝚤|𝑏𝑏𝚤𝚤= 0]
෣
 = 𝐸𝐸ቂ
𝑦𝑦_𝚤𝚤
𝑛𝑛_𝚤𝚤|𝑏𝑏𝚤𝚤= 0ቃ 
෣
= 
exp(𝜇𝜇ෝ)
1+ exp(𝜇𝜇ෝ) 
𝐶𝐶𝐼𝐼𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿= 
exp(𝜇𝜇̂ −𝑧𝑧0.975𝑆𝑆𝑆𝑆)
1 +  exp(𝜇𝜇̂ − 𝑧𝑧0.975𝑆𝑆𝑆𝑆) 
𝐶𝐶𝐼𝐼𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈= 
exp(𝜇𝜇̂ + 𝑧𝑧0.975𝑆𝑆𝑆𝑆)
1 +  exp(𝜇𝜇̂ + 𝑧𝑧0.975𝑆𝑆𝑆𝑆) 
 
For patient-level PPV, an exact binomial confidence interval (implemented using SAS 
procedure FREQ with EXACT statement for one-way tables) will be calculated (Clopper and 
Pearson 1934)  
Efficacy endpoints be summarized in terms of percentage rates with 95% CIs. 
5.4.2 
Analysis supporting secondary objective(s) 
For region-level efficacy endpoints, statistical model details are presented in section 2.6. The 
GLIMMIX procedure in SAS will be used to implement the logistic regression model with 
random effects.  
For patient-level efficacy endpoints, an exact binomial confidence interval (implemented using 
SAS procedure FREQ with EXACT statement for one-way tables) will be calculated (Clopper 
and Pearson 1934)  
Efficacy endpoints be summarized in terms of percentage rates with 95% CIs.  


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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. 
 
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. 
 
Chantadisai M, Buschner G, Krönke M, et al (2020) Positive predictive value and correct 
detection rate of 18F-rhPSMA-7 PET in biochemically recurrent prostate cancer validated by 
composite reference standard. J Nucl Med; 12:1-38. 
 
Clopper, C., & Pearson, E. (1934). The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika, 26(4), 404-413. 
 
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. 
 
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. 
 
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, In: 
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. 
 
Gatsonis CA. Random-effects models for diagnostic accuracy data. Acad Radiol 
1995;2(suppl1):S14–S21; discussion S57–S67, S61–S64. 
 
Lee EW, Dubin N (1994) Estimation and sample size considerations for clustered binary 
responses. Stat Med; 13:1241-52. 
 


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McHugh, M (2012) Interrater reliability: the kappa statistic. Biochemia Medica; 22(3): 276-
282. 
 
Morris MJ, Carroll PR, Saperstein L, et al (2020) Impact of PSMA-targeted imaging with 
18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent 
(BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study 
(CONDOR) [abstract]. J Clin Oncol; 38 (15 Suppl):5501A. 
 
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. 
 
Scher HI, Morris MJ, Stadler WM, et al (2016) Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol; 34(12):1402-18 
 
Van Leeuwen PJ, Stricker P, Hruby G, et al (2016) (68) Ga-PSMA has a high detection rate of 
prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage 
radiation treatment. BJU Int; 117:732-9. 
 
Verbeke G, Molenberghs G. Linear mixed models for longitudinal data. New York, NY: 
Springer, 2000.