Clinical Trials Register

Summary
EudraCT Number:	2014-004194-16
Sponsor's Protocol Code Number:	IRFMN-BRC-6591
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-05-20
Trial results	View 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

2014-004194-16

A.3

Full title of the trial

A multicenter, single-arm, phase II study to evaluate the activity of
pre-operative zoledronate in triple negative breast cancer patients, according to p53 level

A.3.1

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

Clinical study aimed to assess in patients with triple-negative operable breast cancer the activity of the drug zoledronate administered before surgery, according to the the tumor aggressiveness (determined by the level of expression of the p53 protein)

Studio clinico che valuta l’attivita del farmaco zoledronato somministrato prima dell’intervento di asportazione del tumore in pazienti con tumore del seno triplo negativo operabile, in base alla aggressività del tumore (determinata dal livello di espressione della proteina p53)

A.3.2

Name or abbreviated title of the trial where available

TRIPLE NEGATIVE

A.4.1

Sponsor's protocol code number

IRFMN-BRC-6591

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	IRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
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	Associazione Italiana per la Ricerca sul Cancro
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	IRCCS-Istituto di Ricerche Farmacologiche Mario Negri
B.5.2	Functional name of contact point	Laboratorio Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Giuseppe La Masa 19
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039 02 39014695
B.5.5	Fax number	0039 02 33200231
B.5.6	E-mail	irene.floriani@marionegri.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	Yes
D.2.1.1.1	Trade name	ZOMETA - 4 MG POLVERE E SOLVENTE PER SOLUZIONE PER INFUSIONE ENDOVENOSA 1 FLACONCINO + 1 FIALA SOLVENTE 5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS EUROPHARM LTD
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.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	No
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

Newly diagnosed, untreated, operable triple negative breast cancer

Tumore mammario triplo negativo appena diagnosticato, operabile e non trattato

E.1.1.1

Medical condition in easily understood language

Newly diagnosed, untreated, operable triple negative breast cancer

Tumore del seno triplo negativo appena diagnosticato, operabile e che non ha ricevuto nessuna terapia

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
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 is primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with triple negative breast cancer selected according to the p53 expression (high vs low p53 expression).

L’obiettivo primario dello studio è valutare l’attività antitumorale del trattamento pre-operatorio con zoledronato nel tumore della mammella triplo negativo attraverso l’analisi della espressione del biomarker della proliferazione cellulare Ki67 e in funzione dei livelli di espressione di p53.

E.2.2

Secondary objectives of the trial

To investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed at the time of diagnosis (core biopsy) and at definitive surgery (breast cancer resection).

To study the safety profile of zoledronate, evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions.

Analisi della espressione di geni e proteine correlate a p53 ed al pathway del mevalonato, al momento della diagnosi (biopsia) e dopo il trattamento con zoledronato, al momento della asportazione definitiva della massa tumorale, condotta come segue:
• valutazione delle proteine p53/PIN1 e YAP/TAZ mediante immunoistochimica (IHC)
• analisi molecolare dell’espressione dei geni p53/PIN-1 e YAP/TAZ mediante RT-PCR

Valutazione del profilo di sicurezza del trattamento, determinato in accordo con i National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) versione 4.0 ed attraverso l’occorrenza degli eventi avversi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients with newly diagnosed, untreated, operable triple negative breast cancer (TNBC), intended to definitive breast surgery and suitable for pre-operative therapy with zol.
Patients must meet all the following criteria for study entry:
- Histologically confirmed diagnosis of non-metastatic operable TNBC subjected to diagnostic core biopsy
- TNBC defined as HER2/ER/PgR negative receptors
- Age ≥ 18 years old
- ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
- Ki67 and p53 expression determined by IHC
- Availability of paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for IHC and RT-PCR molecular determinations
- Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months (female patients) and 6 months (male patients) after discontinuation of treatment.
- Written informed consent signed prior to enrolment according to ICH/GCP.

Pazienti che hanno appena ricevuto una diagnosi di tumore mammario triplo negativo, operabile e non ancora trattato, destinati all’intervento di asportazione chirurgica definitiva del tumore e idonei al trattamento pre-operatorio con lo zoledronato.
Per l’inclusione nello studio, i pazienti devono possedere tutti i seguenti requisiti:
-Diagnosi istologica di tumore mammario triplo negativo, operabile e non- metastatico
- Età ≥ 18 anni
- ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
- Espressione di Ki67 e p53 determinata attraverso IHC
- Disponibilità di un campione di tumore fissato in paraffina (FFPE) proveniente dalla biopsia utilizzata per la diagnosi, per le analisi molecolari ed immunoistochimiche
- Le pazienti di sesso femminile in età fertile, devono avere test di gravidanza negativo entro 7 giorni dall’inizio del trial. I pazienti di entrambi i sessi devono acconsentire all’uso di idonei metodi contraccettivi durante il periodo di trattamento e nei 3 mesi (pazienti donne) e 6 mesi (pazienti uomini) successivi alla fine dello stesso.
- In accordo alle norme dettate nelle ICH/GCP consenso informato scritto prima del reclutamento.

E.4

Principal exclusion criteria

Patients who meet any of the following criteria will be excluded from study entry:
- Presence of metastatic disease
- Clinical indication of debulking neo-adjuvant treatment
- Previous investigational treatment for any condition within four weeks prior to study registration
-Treatment with bisphosphonates, denosumab or other drug that, in the Investigator’s judgment, affects bone metabolism
-Treatment with statins or other drugs that, in the Investigator’s judgment, potentially affect the mevalonate pathway
- Any previous treatment for the currently diagnosed breast cancer, including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy
- Inadequate bone marrow, hepatic or renal function including the following:
• Hb< 9.0 g/dL, absolute neutrophil count < 1.5 x 109/L, platelets <100 x 109/L
• Total bilirubin > 1.5 x ULN, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
• AST (SGOT), ALT (SGPT) > 2.5 x ULN
• Creatinine > 1.2 x ULN, calcium < 8.6 mg/dL
- Co-existing active infection or concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study
- Co-existing dental diseases that form a contraindication to the use of zol
- Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures
- Known hypersensitivity to any excipients of zoledronate
- Anticipation of need for major surgical procedure during the course of the trial
- Pregnant or breast feeding women.

I pazienti che possiedono i seguenti requisiti non potranno prender parte allo studio:
- Presenza di tumore metastatico
- Indicazione clinica di trattamento neo-adiuvante
- Trattamenti sperimentali per altre patologie nelle 4 settimane antecedenti alla registrazione allo studio
- Trattamento con bifosfonati, denosumab o, a giudizio del medico sperimentatore, farmaci che agiscono sull’osso
- Trattamento con statine o con farmaci che, a giudizio del medico sperimentatore, hanno potenzialmente un impatto sul pathway del mevalonato
- Qualsiasi trattamento precedente, incluse radioterapia, chemioterapia, terapia con farmaci biologici e/o terapie ormonali correntemente utilizzate in caso di diagnosi di tumore al seno
- Alterazioni della funzionalità del midollo osseo, epatica e renale, di seguito elencate:
• Hb< 9.0 g/dL, conta totale dei neutrofili< 1.5 x 109/L, piastrine <100 x 109/L
• Bilirubina totale > 1.5 x ULN, ad eccezione dei casi in cui gli elevate valori di bilirubina siano attribuibili alla Sindrome di Gilberts
• AST (SGOT), ALT (SGPT) > 2.5 x ULN
• Creatinina > 1.2 x ULN, calcio < 8.6mg7dL
- Infezioni attive concomitanti o gravi patologie concorrenti che possano costituire una controindicazione all’inclusione del paziente nello studio
- Qualsiasi condizione medica o non, che secondo l’opinione del medico sperimentatore renda il paziente non adatto a questo studio per via di un rischio troppo alto
- Disordini psichiatrici o stato mentale alterato che precludano la comprensione del consenso informato e/o il completamento delle valutazioni e delle procedure necessarie per lo studio
- Nota ipersensibilità ad uno degli eccipienti dell’Acido Zoledronico
- Necessita di ricevere cure odontoiatriche
- Stato di gravidanza o allattamento.

E.5 End points

E.5.1

Primary end point(s)

The study is primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate (zol), measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with TNBC selected according to the p53 expression (high vs low p53 expression). Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis. Prior to enrolment, the FFPE diagnostic core biopsy specimens will be analyzed by the study pathologist to determine the presence of invasive TNBC and the Ki67/p53 values. The ki67/p53 evaluation will be then repeated after treatment at the time of definitive surgery.

L’obiettivo primario dello studio è valutare l’attività antitumorale del trattamento pre-operatorio con lo zoledronato attraverso l’analisi della espressione del biomarker della proliferazione cellulare Ki67, nel tumore della mammella triplo negativo, in funzione dei livelli di espressione di p53. L'ipotesi da testare è che la percentuale dei responder al trattamento con zoledronato nel gruppo di pazienti ad elevato livello di espressione di p53 sarà del 75% e nel gruppo con basso livello di espressione di p53 sarà del 20%. Prima dell’arruolamento, i campioni di tessuto tumorale fissati in paraffina (FFPE) provenienti della biopsia saranno analizzati dal patologo per determinare la presenza di TNBC invasivo ed i valori di Ki67/p53. La valutazione dell’espressione di Ki67/p53 sarà ripetuta dopo il trattamento, al momento dell’intervento chirurgico.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint (proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis) will be evaluated after the definitive breast surgery planned seven days after study treatment (i.e. Zometa administration).

L'endpoint primario, ovvero la percentuale di pazienti responder, definiti come la percenuale di pazienti in cui l’espressione di Ki67 risulta ridotta di almeno il 30% nel campione di tessuto tumorale prelevato alla chirurgia rispetto alla biopsia, sarà valutato dopo l'intervento chirurgico di rimozione del tumore previsto sette giorni dopo il trattamento in studio (somministrazione Zometa).

E.5.2

Secondary end point(s)

To investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed at the time of diagnosis (core biopsy) and at definitive surgery (breast cancer resection). After enrolment, the FFPE core biopsy will be tested for critical genes/proteins expression (by RT-PCR and IHC), including p53/PIN1 and YAP/TAZ. The same evaluations will be performed after treatment, at the time of definitive surgery. To study the safety profile of zoledronic acid, evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions.

Analisi della espressione di geni e proteine correlate a p53 ed al pathway del mevalonato, al momento della diagnosi (biopsia) e dopo il trattamento con Zometa, al momento della asportazione definitiva della massa tumorale, condotta come segue: • valutazione delle proteine p53/PIN1 e YAP/TAZ mediante IHC • analisi molecolare dell’espressione dei geni p53/PIN-1 e YAP/TAZ mediante RT-PCR. Valutazione del profilo di sicurezza del trattamento,determinato in accordo con i National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) versione 4.0 ed attraverso l’occorrenza degli eventi avversi

E.5.2.1

Timepoint(s) of evaluation of this end point

The evaluation of critical genes/proteins expression (by RT-PCR and IHC), including p53/PIN1 and YAP/TAZ will be performed on the core biopsy and after treatment, at the time of definitive surgery, planned seven days after study treatment. Zometa safety profile will be evaluated through the duration of the study and post treatment at 30 and 60 days following definitive surgery.

L’obiettivo secondario ovvero l'analisi della espressione di geni e proteine correlate a p53 ed al pathway del mevalonato, verrà valutato al momento della diagnosi (biopsia) e dopo il trattamento con zoledronato, al momento dell' intervento chirurgico di asportazione definitiva della massa tumorale, previsto sette giorni dopo la somministrazione di Zometa. Il profilo di sicurezza di Zometa verrà valutato durante il trattamento e nel periodo di follow-up a 30 e 60 giorni dopo l'intervento chirurgico.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

A braccio singolo

Single arm

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.3.1

Comparator description

Single arm

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

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

Last visit of the last subject undegoing the trial.

Ultima visita dell'ultimo soggetto registrato nello studio.

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:

F.2 Gender

F.2.1

Female

Yes

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Treatment and care of subjects who have ended the participation in the trial is not different from the expected normal treatment of that condition.

Il trattamento dei pazianti che hanno terminato lo studio non sarà diverso da quello previsto dalla 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

2014-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-06-08

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