Clinical Trials Register

Summary
EudraCT Number:	2018-004458-14
Sponsor's Protocol Code Number:	PROvING
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-004458-14

A.3

Full title of the trial

Phase III clinical trial Oligometastatic and Oligorecurrent PROstate Cancer: enhancing patients’ selection by new ImagiNG biomarkers

Studio clinico di fase III sul carcinoma prostatico oligometastatico e oligoricorrente: migliorare la selezione dei pazienti con nuovi biomarcatori per la diagnostica per immagini

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase III clinical trial Oligometastatic and Oligorecurrent PROstate Cancer: enhancing patients’ selection by new ImagiNG biomarkers

Studio clinico di fase III sul carcinoma prostatico oligometastatico e oligoricorrente: migliorare la selezione dei pazienti con nuovi biomarcatori per la diagnostica per immagini

A.3.2

Name or abbreviated title of the trial where available

PROvING

A.4.1

Sponsor's protocol code number

PROvING

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AZIENDA OSPEDALIERO-UNIVERSITARIA PISANA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AIRC
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliero-Universitaria Pisana
B.5.2	Functional name of contact point	Nuclear Medicine Regional Center
B.5.3	Address:
B.5.3.1	Street Address	Via Roma 67
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39050992115
B.5.5	Fax number	+39050992115
B.5.6	E-mail	paola.erba@unipi.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	68Ga-complex of Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC
D.3.2	Product code	[68GaPSMA-11]
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	68Ga-complex of Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC
D.3.9.2	Current sponsor code	[68Ga]PSMA-11
D.3.9.3	Other descriptive name	68GA-PSMA HBED-CC
D.3.9.4	EV Substance Code	SUB171041
D.3.10	Strength
D.3.10.1	Concentration unit	Bq/kg becquerel(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1800000 to 2200000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	Yes
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Fluorocolina Curium Italy
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Fluorocolina
D.3.2	Product code	[18FFMCH]
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	fluorometilcolina (18F) cloruro
D.3.9.1	CAS number	475572-73-7
D.3.9.2	Current sponsor code	[18F]FMCH
D.3.9.3	Other descriptive name	fluoromethylcholine
D.3.9.4	EV Substance Code	SUB30954
D.3.10	Strength
D.3.10.1	Concentration unit	Bq/kg becquerel(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2800000 to 7000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	Yes
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prostate cancer

Carcinoma prostatico

E.1.1.1

Medical condition in easily understood language

Prostate cancer

Tumore della prostata

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10036911
E.1.2	Term	Prostate cancer recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007453
E.1.2	Term	Carcinoma of the prostate metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007454
E.1.2	Term	Carcinoma of the prostate recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10036909
E.1.2	Term	Prostate cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the changes induced by the use of [68Ga]PSMA-11 PET/CT in restaging and in treatment decision making of patients with biochemical failure PCa by comparing the diagnostic performances of [68Ga]PSMA-11 PET/CT (arm A) to the standard approach of [18F]FMCH PET/CT (arm B) at different PSA levels (PSA level of 0.2-0.5; 0.51-1;1.1-2; 2.1-6 ng/mL).

Valutare i cambiamenti indotti dall’uso di [68Ga]PSMA-11 nella PET/CT nella ristadiazione e nella scelta del trattamento dei pazienti con carcinoma della prostata (PCa) con sospetta recidiva biochimica nel confronto tra la performance diagnostica del [68Ga]PSMA-11 PET/CT (braccio A) e quella dell’approccio standard con [18F]FMCH PET/CT (braccio B) a diversi livelli di PSA (livello di PSA di 0.2-0.5; 0.51-1;1.1-2; 2.1-6 ng/mL).

E.2.2

Secondary objectives of the trial

1. To define the clinical outcomes of patients with oligometastatic PCa (up to 3 active synchronous metastasis) treated with [68Ga]PSMA-11 PET/CT and [18F]FMCH PET/CT-guided SBRT.
2. To identify new biomarkers to advance the understanding of oligometastatic PCa:
a. Exosomes as novel intercellular communication vehicles in prostate cancer biology
b. imaging biomarkers by Radiomics Advanced analysis (Radiomics) of the MRI images, [68Ga]PSMA-11 PET/CT and [18F]FMCH PET/CT images in patients with oligometastatic (up to 3 active synchronous metastasis) and multimetastatic disease (more than 3 synchronous metastasis).
3. To create an advanced normogram for oligometastatic patients.

1. Definire gli esiti clinici dei pazienti con PCa oligometastatico (con un massimo di 3 metastasi contemporanee) trattati con radioterapia stereotassica corporea (stereotactic body radiotherapy, SBRT) guidata con [68Ga]PSMA-11 PET/CT e con [18F]FMCH PET/CT.
2. Identificare nuovi biomarcatori per migliorare la comprensione del carcinoma oligometastatico quali:
a. gli Esosomi, come nuovi veicoli di comunicazione intercellulare nella biologia del carcinoma prostatico;
b. i biomarcatori di Imaging attraverso la Analisi Avanzata Radiomica (Radiomics) delle immagini di MRI, di [68Ga]PSMA-11 PET/CT e di [18F]FMCH PET/CT in pazienti con malattia oligometastatica (fino a 3 metastasi attive contemporaneamente) e multimetastatica (più di 3 metastasi attive contemporaneamente).
3. Creare un normogramma avanzato per i pazienti oligometastatici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Related to PCa:
1. Histologically documented castration resistant PCa treated with radical prostatectomy or loco-regional EBRT.
2. BCR PCa demonstrated by two consecutive PSA determinations
3. Life expectancy of more than 6 months.
Related to the patient:
4. Male patients aged >18 years without upper age limit.
5. Ability to understand and willingness to sign a written informed consent document.
6. Written informed consent obtained according to international guidelines and local laws.
7. Compliant to the study procedures, based on the Investigator point of view.

Relativi al PCa:
1. PCa resistente alla castrazione documentato istologicamente trattato con prostatectomia radicale o EBRT loco-regionale.
2. Recidiva biochimica di PCa dimostrata con 2 misurazioni consecutive dei valori di PSA.
3. Aspettativa di vita superiore a 6 mesi.
Relativi al paziente:
4. Pazienti di sesso maschile di età>18 anni senza limite superiore di età.
5. In grado di comprendere e firmare volontariamente un consenso informato scritto.
6. Consenso informato scritto ottenuto secondo le linee guida internazionali e la normativa locale.
7. Adempienti alle procedure dello studio sulla base del giudizio dello Sperimentatore.

E.4

Principal exclusion criteria

Related to the PCa
1. Other malignancies
Related to the patient:
1. Patient not willing to sign a written informed consent document.
2. Patient with severe chronic renal disease (according to the KDOQI/CTCAE eGFR or CrCl< 15 ml/min/1.73m2).

Relativi al PCa
1. Presenza di altre patologie tumorali maligne
Relativi al paziente:
1. Paziente che rifiuta di firmare il consenso informato scritto.
2. Paziente con insufficienza renale cronica severa (secondo il KDOQ/CTCAE eGFR o il CrCl<15 ml/min/1.73m2).

E.5 End points

E.5.1

Primary end point(s)

Rate of positive patients, at different PSA levels (PSA level of 0.2-0.5; 0.51-1;1.1-2; 2.1-6 ng/mL), with oligometastatic and plurimetastatic disease in [68Ga]PSMA-11 PET/CT group as compared to [18F]FMCH PET/CT group.

Tasso di pazienti positivi, ai diversi livelli di PSA (livello di PSA di 0.2-0.5; 0.51-1;1.1-2; 2.1-6 ng/mL), con malattia oligometastatica e plurimetastatica nel Gruppo [68Ga]PSMA-11 PET/CT rispetto al gruppo [18F]FMCH PET/CT.

E.5.1.1

Timepoint(s) of evaluation of this end point

0 (endpoint is evaluated at the same time as the IMP administration since it is a diagnostic radiopharmaceutical for PET/CT imaging)

0 (l'endpoint viene valutato lo stesso giorno della somministrazione dell'IMP in quanto radiofarmaco diagnostico per imaging PET/CT)

E.5.2

Secondary end point(s)

1. PSA control (defined as Delta PSA = the decline between baseline PSA pre-SBRT and PSA value 6 weeks after treatment (¿PSA)), OS and DFS (estimated by the Kaplan-Meier method) of patients with oligometastatic PCa up to (up to 3 active synchronous metastasis) treated with [68Ga]PSMA-11 PET/CT and [18F]FMCH PET/CT-guided SBRT at 1 year of FU. In addition, biochemical progression-free survival, distant progression-free survival, local control, time to next intervention, ADT-free survival will be evaluated.; 2. Identification of circulating exosomes related mRNA in PCa recurrence in oligometastatic and multimetastatic patients as prognostic biomarkers (Kaplan–Meier plots, log-rank test to assess patient prognosis; Multivariate Cox proportional hazards regression analysis to evaluate independent prognostic factors associated with survival, and gene signature, metastatic tumor stage, and pathologic characteristics as covariates).; 3. Identification of the texture signature of the MRI images, [68Ga]PSMA-11 PET/CT and [18F]FMCH PET/CT images in patients with oligometastatic (up to 3 active synchronous metastasis) and multimetastatic disease (more than 3 synchronous metastasis).; 4. Selection of the variables for the advanced normogram, based on the previous statistical analysis. .

1. Controllo del PSA, (definito come Delta PSA = la differenza fra il PSA di base pre-SBRT e il valore di PSA dopo 6 settimane di trattamento (¿PSA)) della overall survival (OS) e della disease free survival (DFS) (stimate col metodo Kapla-Meier) dei pazienti con PCa oligometastatico (fino a 3 metastasi attive contemporaneamente) trattati con SBRT guidata con [68Ga]PSMA-11 PET/CT e [18F]FMCH PET/CT a 1 anno di follow-up. In aggiunta saranno valutati: la sopravvivenza libera da progressione biochimica, la sopravvivenza libera da ADT, il controllo locale tempo prima dell’intervento successivo.; 2. Identificazione degli mRNA circolanti correlati con gli esosomi nella recidiva del PCa in pazienti oligometastatici e multimetastatici come biomarkers prognostici (Kaplan-Meier plots, log-rank test per stabilire la prognosi dei pazienti; analisi Multivariata Cox della regressione proporzionale dei rischi per valutare i fattori prognostici indipendenti associati alla sopravvivenza e come covariate la gene signature, lo stage del tumore metastatico e le caratteristiche patologiche).; 3. Identificazione della texture signature delle immagini ottenute con MRI, [68Ga]PSMA-11 PET/CT e [18F]FMCH PET/CT in pazienti con malattia oligometastatica (fino a 3 metastasi attive contemporaneamente) e multimetastatica (più di 3 metastasi attive contemporaneamente).; 4. Selezione delle variabili per il normogramma avanzato, basato sulle analisi statistiche precedenti.

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year; After the end of radiotherapy (6 weeks after SBRT, three months after the end of external beam radiotherapy) or at the first evaluation after the beginning of systemic therapy (3 months after the beginning of systemic therapy).; 0 (endpoint is evaluated at the same time as the IMP administration since it is a diagnostic radiopharmaceutical for PET/CT imaging); 0 (endpoint is evaluated at the same time as the IMP administration since it is a diagnostic radiopharmaceutical for PET/CT imaging)

1 anno; Al termine della radioterapia (6 settimane dopo la SBRT, 3 mesi dopo la EBRT) o alla prima valutazione dopo l'inizio della terapia sistemica (3 mesi dopo l'inizio della terapia sistemica).; 0 (l'endpoint viene valutato lo stesso giorno della somministrazione dell'IMP in quanto radiofarmaco diagnostico per imaging PET/CT); 0 (l'endpoint viene valutato lo stesso giorno della somministrazione dell'IMP in quanto radiofarmaco diagnostico per imaging PET/CT)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

185

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

246

F.4.2

For a multinational trial

F.4.2.1

In the EEA

246

F.4.2.2

In the whole clinical trial

246

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

clinical practice

pratica clinica

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-11-05

P. End of Trial
P.	End of Trial Status	Ongoing

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Orphan Designation Number:
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