Study of Diagnostic Performance of [18F]CTT1057 in BCR

Study Overview
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Brief Summary
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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. 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.

Detailed Description
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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.

Official Title
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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)]

Conditions
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Prostate Cancer, Recurrence, Prostatic Neoplasms

Intervention / Treatment
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* Drug: [18F]CTT1057
* Drug: [68Ga]Ga-PSMA-11


Participation Criteria
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Eligibility Criteria
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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 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. 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 reason (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 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 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 Patient with small cell or neuroendocrine PCa in more than 50% of biopsy tissue Prior salvage surgery or salvage radiation therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Sequential Assignment
Interventional Model Description: 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PET/CT imaging with [18F]CTT1057 followed by [68Ga]Ga-PSMA-11 or vice versa<br>All eligible participants will 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 | Drug: [18F]CTT1057<br>* Single intravenous dose of approximately 370 Mega-Becquerel (MBq) and subsequent PET/CT scan<br>Drug: [68Ga]Ga-PSMA-11<br>* Single intravenous dose of approximately 150 MBq and subsequent PET/CT scan<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Region-level correct localization rate (CLR) of [18F]CTT1057 | Region-level correct localization rate (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. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level positive predictive value (PPV) (with anatomical localization) of [18F]CTT1057 | Patient-level positive predictive value (PPV) is defined as the proportion of patients who have 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, out of all patients who are PET/CT scan positive. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-level sensitivity of [18F]CTT1057 | Patient-level sensitivity is defined as the proportion of patients that test positive on [18F]CTT1057 and CTS (True Positive (TP)) among those that are CTS positive (True Positive (TP) or False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level specificity of [18F]CTT1057 | Patient-level specificity is defined as the proportion of patients that test negative on [18F]CTT1057 and CTS (True Negative (TN)) among those that are CTS negative (True Negative (TN) or False Positive (FP)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level negative predictive value of [18F]CTT1057 | Patient-level negative predictive value is defined as the proportion of patients who are both [18F]CTT1057 and CTS negative (True Negative (TN)) among those who test negative on [18F]CTT1057 (True Negative (TN) or False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level accuracy of [18F]CTT1057 | Patient-level accuracy is defined as the proportion of patients that are CTS and [18F]CTT1057 positive (True Positive (TP)) and negative (True Negative (TN)) among those patients that identified on [18F]CTT1057 (True Positive (TP), True Negative (TN), False Positive (FP) or False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level correct detection rate (CDR) | Patient-level correct detection rate (CDR) is defined as the proportion of patients who have 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, out of all patients who are scanned. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level detection rate | Patient-level detection rate is defined as the proportion of patients who have at least one PET positive lesion, regardless of True Positive (TP) or False Positive (FP) findings, out of all patients who are scanned. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT). | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Region level sensitivity of [18F]CTT1057 | Region level sensitivity is defined as the proportion of regions that test positive on both [18F]CTT1057 and CTS (True Positive (TP)) among those regions that are CTS positive (True Positive (TP) or False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients post-prostatectomy and patients after prostate radical radiotherapy (RT). | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Region level specificity of [18F]CTT1057 | Region level specificity is defined as the proportion of regions that test negative on both [18F]CTT1057 and CTS (True Negative (TN)) among those regions that are CTS negative (False Positive (FP) or True Negative (TN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients post-prostatectomy and patients after prostate radical radiotherapy (RT). | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Region level negative predictive value of [18F]CTT1057 | Region level negative predictive value is defined as the proportion of regions that are CTS and [18F]CTT1057 negative (True Negative (TN)) among those regions that test negative on [18F]CTT1057 (True Negative (TN) or False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients post-prostatectomy and patients after prostate radical radiotherapy (RT). | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Region level accuracy of [18F]CTT1057 | Region level accuracy is defined as the proportion of regions that are CTS and [18F]CTT1057 positive (True Positive (TP)) and negative (True Negative (TN)) among those regions that identified on [18F]CTT1057 (True Positive (TP), True Negative (TN), False Positive (FP) and False Negative (FN)). The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Patient-level positive predictive value related to PSA levels | Patient-level positive predictive value related to PSA levels is defined as the percentage of patients who have at least one True Positive (TP) lesion (exactly anatomically localized correspondence between [18F]CTT1057 PET imaging and the reference standard), regardless of any co-existent False Positive (FP) findings, out of all patients who are [18F]CTT1057 positive, stratified by PSA levels. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Characterize the safety and tolerability of [18F]CTT1057 | The distribution of adverse events (AEs) within 14 days after each PET tracer administration will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. | From first dosing (Day 1) up to 14 days post dosing | 
| [18F]CTT1057 scan inter-reader variability | Inter-reader variability is defined as the agreement among three readers determination of [18F]CTT1057 images. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| [18F]CTT1057 scan intra-reader variability | Intra-reader variability is defined as the within-reader agreement for two different time points of [18F]CTT1057 images. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT) | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| 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 detection of PSMA-positive lesions (location and number) using central reads. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT). | [18F]CTT1057 PET imaging acquired at Day 1 or Day 15 assessed against Composite Truth Standard (CTS) obtained within 8 weeks (before or after) of 18F-CTT PET scan or during follow-up (up to 90 days after radiotherapy for PSA level assessment) | 
| Change in patient management plans attributed to the [18F]CTT1057 PET/CT scan | Change in patient management plans attributed to the PET/CT scan is defined as the percentage of patients who underwent a change in intended treatment plan attributed to the [18F]CTT1057 PET/CT scan as assessed by pre and post imaging questionnaires. The endpoint will be analyzed overall in the Efficacy Analysis Set (EFF population) and in each of the following subgroups: Patients with prior Radical Prostatectomy and patients with prior curative intent Radiation Therapy (RT). | From randomization up to 14 days after obtaining the results of the [18F]CTT1057 PET imaging | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PET/CT, BCR, [18F]CTT1057, [68Ga]Ga-PSMA-11, Positron Emission Tomography/Computerized Tomography, Radioligand, Imaging, Biochemical recurrence, Composite Truth Standard, CTS, Prostate Cancer, PCa