Clinical Trials Register

Summary
EudraCT Number:	2019-000744-10
Sponsor's Protocol Code Number:	P.64Cu.003.01
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:	2020-10-08
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

2019-000744-10

A.3

Full title of the trial

Higher diagnostic accuracy of 64Cu PET/CT compared to standard 18F-choline PET/CT in the detection rate of metastasis from prostate cancer.
Phase III multicenter, sponsored, interventional "open-label" clinical study, with prospective enrollment.

Maggior accuratezza diagnostica della PET/CT con 64CuCl2 rispetto alla PET/CT con 18F-colina nella diagnosi di metastasi in pazienti con carcinoma della prostata

Studio clinico di fase III multicentrico, sponsorizzato, interventistico “open-label”, ad arruolamento prospettico.

A.3.1

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

better diagnostic accuracy and ability to detect multiple metastases of the PET exam with a new experimental radiopharmaceutical (64CuCl2) in the diagnosis of metastases in patients with prostate cancer compared to the PET / CT examination performed with 18F-choline.

migliore accuratezza diagnostica e capacità di rilevare più metastasi dell’esame PET con un nuovo radiofarmaco sperimentale (64CuCl2) nella diagnosi di metastasi in pazienti con carcinoma della prostata, rispetto all'esame PET/CT eseguito con 18F-colina.

A.3.2

Name or abbreviated title of the trial where available

64CuCl2 PET/CT VS 18F-choline PET/CT in prostate cancer

64CuCl2 PET/CT VS 18F-colina PET/CT in pazienti affetti da carcinoma prostatico

A.4.1

Sponsor's protocol code number

P.64Cu.003.01

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	SPARKLE SRL
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sparkle srl
B.5.2	Functional name of contact point	Ufficio sperimentazioni
B.5.3	Address:
B.5.3.1	Street Address	Località cavallino
B.5.3.2	Town/ city	Montecosaro
B.5.3.3	Post code	62010
B.5.3.4	Country	Italy
B.5.4	Telephone number	0733560354
B.5.5	Fax number	0733560352
B.5.6	E-mail	sperimentazione@sparklepet.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	64-Rame Cloruro
D.3.2	Product code	[64Cu(II)Cl2]
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	Rame cloruro (64CuCl2)
D.3.9.2	Current sponsor code	(64Cu)CuCl2
D.3.10	Strength
D.3.10.1	Concentration unit	MBq/ml megabecquerel(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	925
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 at risk of developing metastatic lesions

carcinoma prostatico a rischio di sviluppo lesioni metastatiche

E.1.1.1

Medical condition in easily understood language

prostate cancer with the risk of developing metastasis

tumore della prostata con rischio di sviluppare metastasi

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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

The study design is based on a co-primary endpoint, where is considered of the same level of importance, both the diagnostic accuracy (sensitivity and specificity of the 64Cu PET/CT to identify metastatic patients) and the capacity to detect more sites of metastasis.
In particular, it will be evaluated:
• higher diagnostic accuracy of 64Cu PET/CT compared to 18F-choline PET/CT in the diagnosis of metastatic patients;
• higher diagnostic accuracy of 64Cu PET/CT compared to 18F-choline PET/CT in the diagnosis of metastatic lesions evaluated both on rate of patients overstaged and higher number of lesion identified.

La progettazione dello studio si basa su un obbiettivo co-primario, dove viene considerato allo stesso livello di importanza, sia l'accuratezza diagnostica (sensibilità e specificità della PET/CT 64Cu per identificare i pazienti metastatici) che la capacità di rilevare più siti di metastasi.
In particolare saranno valutate:
• la maggiore accuratezza diagnostica di 64Cu PET/CT rispetto a 18F-colina PET/CT nella diagnosi di pazienti metastatici;
• la maggiore accuratezza diagnostica di 64Cu PET/CT rispetto a 18F-colina PET/CT nella diagnosi di lesioni metastatiche valutate sia sulla percentuale di pazienti sovrastadiati sia sul numero più elevato di lesioni identificate.

E.2.2

Secondary objectives of the trial

1. Evaluate difference on diagnostic accuracy (sensitivity, specificity) between the two PET /CT (64Cu and 18Fcholine) on region (thorax, abdomen, pelvis) and lesion (bone, node, lung and other organs) levels 2. Evaluation of inter and intra-observer reproducibility
3. Correlate 64Cu and 18Fcholine sensitivity at different PSA levels
4. Evaluate the rate of patient who changed the stage (oligometastatic vs. polymetastatic patient) using 64Cu PET/CT
5. Evaluate the 64Cu PET/CT impact on decision thinking (impact of the test versus pre-test probability) by positive and negative predictive values and multidisciplinary reports of clinical strategy and therapeutic decision
6. Evaluate the impact of 64Cu PET/CT result on clinical outcome by patient follow-up data and in particular the consequences of incorrect diagnosis (treatment delay or unnecessary interventions)

1. Valutare la differenza sull'accuratezza diagnostica (sensibilità, specificità) tra le due PET/CT (64Cu e 18F colina) su base regione del corpo (torace, addome, bacino) e su base lesione (osso, linfonodi, polmone e altri organi),2. Valutare la riproducibilità inter e intra-osservatore,3. Correlare la sensibilità 64Cu e 18F colina a diversi livelli di PSA,
4. Valutare il rateo di pazienti in cui viene cambiato lo stadio (M0 vs. M1) l’estensione di malattia (paziente oligometastatico vs. polimetastatico) utilizzando 64Cu PET/CT,
5. Valutare l'impatto di 64Cu PET/CT sul pensiero decisionale (impatto del test rispetto alla probabilità pre-test) mediante valutazione dei valori predittivi positivi e negativi e valutazione delle variazioni di strategia clinica e decisione terapeutica mediante i report multidisciplinari, 6. Valutare l'impatto del risultato PET/CT a 64Cu sull'esito clinico dai dati di follow-up del paziente e in particolare le conseguenze di una diagnosi errata

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age >=45 years at the enrollment time
2. Documented hystologically diagnosis of PCa
3. Clinical indication to staging or restaging
4. Imaging of MRI and/or TAC and/or bone scintigraphy not older than 30 days
5. Previous execution of 18F-FCH not older than 30 days
6. Patient at risk of developing metastasis during their illness according symptoms presence or EAU criteria of risk as follows:
• At diagnosis : PSA > 20 or GS > 7 or cT2c; or any PSA –any Gs cT3-4 or cN+;
• At restaging after primary treatment: PSA > 1 ng/ml;
• After-staging for biochemical progression during treatment: 3 PSA assay demonstrating an increase > 50% respect to nadir and a PSA > 2 ng/ml.
7. No other concomitant or previous malignant tumors, except for non-melanoma skin cancers
8. Karnofski index ¿ 80%
9. No other relevant disease (cfr exclusion criteria)
10. Ability to understand the contents of the information material for the subject
11. Ability to sign the Informed consent

1. età>=45 anni al momento dell’arruolamento
2. pregressa diagnosi istologica, documentabile, di adenocarcinoma primitivo della prostata
3. Indicazione clinica sulla stadiazione o alla ristadiazione
4. Esami di Imaging MRI e/o TAC e/o di scintigrafia ossea non più vecchi di 30 giorni
5. Precedente escuzione di 18F-FCH-PET non più vecchi di 30 giorni
1. Pazienti a rischio di sviluppare metastasi durante la loro malattia in base alla presenza di sintomi o ai criteri di rischio EAU come segue:
a) Alla diagnosi: PSA> 20 o GS> 7 o cT2c; o qualsiasi PSA -anche Gs cT3-4 o cN +
b) Alla ristadiazione dopo il trattamento primario: PSA> 1 ng / ml
c) Alla ristadiazione per la progressione biochimica durante il trattamento: 3 test del PSA che dimostrano un aumento> 50% rispetto al nadir e un PSA> 2 ng / ml
2. storia clinica negativa per altre patologie neoplastiche pregresse od in atto, con l’eccezione di carcinomi cutanei non-melanoma
3. indice di Karnofski = 80%
4. assenza di altre comorbillità rilevanti (cfr: criteri di esclusione)
5. piena capacità di comprendere le informazioni riportate nella documentazione illustrativa per il Soggetto
6. piena capacità di sottoscrivere il consenso informato

E.4

Principal exclusion criteria

1. Anemia (Hb<9 gr/dl)
2. Symptoms or signs of sepsis and / or evidence of acute infections
3. AST >1.5 higher than normal range
4. ALT >1.5 higher than normal range
5. Total bilirubin > 1.5 higher than normal range
6. Copper metabolism disease (m.di Menkes, m.di Wilson)
7. Previous participation in trials with exposure to ionizing radiation for therapeutic purposes
8. Any condition, material, logistics, or Subjective, which, even in the opinion of the Principal Investigator, may condition the subject's compliance with the execution of the procedures established by the Protocol
9. Inability to understand the contents of the information documentation for the subject

1. Anemia con Hb<9 gr/dL
2. Presenza di sintomi o segni di sepsi e/o evidenza di infezioni acute
3. AST >1.5 volte il limite superiore del range di normalità
4. ALT >1.5 volte il limite superiore del range di normalità
5. Bilirubina totale > 1.5 volte il limite superiore del range di normalità
6. Malattie del metabolismo del rame (m.di Menkes, m.di Wilson)
7. Precedente partecipazione a trials clinici con esposizione a radiazioni ionizzanti a scopo terapeutico
8. Qualsiasi condizione, materiale, logistica, o Soggettiva, che, anche a giudizio dello Sperimentatore Principale, possa condizionare la compliance del Soggetto alla esecuzione delle procudure previste dal Protocollo
9. Incapacità a comprendere il contenuto della documentazione informativa per il Soggetto

E.5 End points

E.5.1

Primary end point(s)

Evaluate sensitivity and specificity of the two compared PET methods for the same patient in the identification of metastatic patients and the number of metastases.
18F-FCH PET/CT and 64CuCl2 PET/CT will be evaluated as positive (PET +) in case of evidence of pathological focal uptake at the site s compatible with metastasis (lymph node, skeleton, lung, other viscera), otherwise it is judged negative (PET-) when no pathological focal uptake is evident.
The (PET +) cases will be considered as TP (true positive) (standard of truth +) and the(PET-) cases will be considered TN (true negative) (standard of truth -)

Valutare la sensibilità e la specificità delle due metodiche PET messe a confronto nello stesso paziente nella identificazione dei pazienti metastatici e del numero di metastasi.
La PET F-Cholina e la PET con 64CuCl2-PET verranno valutate come positive (PET+) in caso di evidenza di uptake focale patologico in corrispondenza di sede/i compatibile con metastasi (linfonodo, scheletro, polmone, altri visceri; viene altrimenti giudicata negativa (PET-) quando non sono evidenziabili uptake focali patologici.
Verranno considerati VP (veri positivi) i casi (PET+) (standard of truth +) e VN (veri negativi) i casi (PET- ) (standard of truth -).

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of trial

a fine studio

E.5.2

Secondary end point(s)

1. Calculation for each patient of the diagnostic accuracy (sensitivity, specificity) and area under the curve (AUC) of the two PET / CT (64Cu and 18F choline) based on the body region (thorax, abdomen, pelvis) and on base lesion (bone, lymph nodes, lung and other organs),
2. Evaluation of inter and intra-observer reproducibility of the 64Cu PET / CT,
3. Correlation of 64Cu PET and 18F-choline sensitivity with PSA levels with optimal cut-off identification using the ROC curve,
4. Evaluation of the rate of patients in which the stage is changed, ie the rate of patients M0 vs. M1 patients with each PET method. Furthermore, evaluation of the different rate of oligometastatic and plurimetastatic patients identified with the two PET / CT. The patient with a maximum of three bone or lymph node metastases will be defined as oligometastatic,
5. Evaluation for each patient of the different impact determined by the two PETs on decisional thinking (impact of the test compared to the pre-test probability) with calculation of positive and negative predictive values and evaluation of changes in clinical strategy,
6. Assessment for each patient of the impact determined by the PET / CT on the clinical outcome by the patient's follow-up data and in particular the consequences of a misdiagnosis (treatment delay or unneeded interventions) will be recorded.

1. In ciascun paziente verrà calcolata l'accuratezza diagnostica (sensibilità, specificità) e area sotto la curva (AUC) delle due PET/CT (64Cu e 18F colina) in base alla regione del corpo (torace, addome, bacino) e su base lesione (osso, linfonodi, polmone e altri organi),
2. Verrà valutata la riproducibilità inter e intra-osservatore della 64Cu PET/CT,
3. La sensibilità 64Cu PET e 18F-colina verrà correlata ai livelli di PSA con identificazione di cut-off ottimale mediante curva ROC,
4. Verrà valutato il rateo di pazienti in cui viene cambiato lo stadio cioè il rateo di pazienti M0 vs. M1 con ciascuna metodica PET. Inoltre verrà valutato il diverso rateo di pazienti oligometastatici e plurimetastatici identificati con le due PET/CT. Verrà definito oligometastatico il paziente con un numero massimo di tre metastasi ossee o linfonodali,
5. In ciascun paziente verrà valutato il diverso impatto determinato dalle due PET sul pensiero decisionale (impatto del test rispetto alla probabilità pre-test) con calcolo dei valori predittivi positivi e negativi e valutazione delle variazioni di strategia clinica,
6. In ciascun paziente verrà valutato l’impatto determinato dalla 64Cu PET/CT sull'esito clinico mediante i dati di follow-up del paziente e in particolare saranno registrate le conseguenze di una diagnosi errata (ritardo del trattamento o interventi non necessari).

E.5.2.1

Timepoint(s) of evaluation of this end point

at the end of trial

a fine studio

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

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

18F-colina

18F-choline

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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:

111

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

111

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

111

F.4.2

For a multinational trial

F.4.2.1

In the EEA

111

F.4.2.2

In the whole clinical trial

111

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)

according to clinical practice routin

come da 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

2019-06-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-26

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

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