Clinical Trials Register

Summary
EudraCT Number:	2020-004057-71
Sponsor's Protocol Code Number:	BC-P2-2020
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:	2021-05-24
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

2020-004057-71

A.3

Full title of the trial

miRNA100 as predictor of response to anti-endocrine treatment in luminal-HER2 negative breast cancer. a prospective validation clinical trial

STUDIO PROSPETTICO DI VALIDAZIONE DEL RUOLO DELL’ESPRESSIONE DI MICRO-RNA (MIR-)100 COME PREDITTORE DI RISPOSTA AL TRATTAMENTO ENDOCRINO NEL CARCINOMA DELLA MAMMELLA LUMINALE/HER2 NEGATIVO.

A.3.1

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

response evalutation of breast cancer treated with anti-endocrine drugs by means of biological biomarkers (miRNA-100)

valutazione dellla risposta al trattamento del tumore della mammella con farmaci endocrini mediante marcatori biologici (miRNA-100)

A.3.2

Name or abbreviated title of the trial where available

BC-P2-2020

A.4.1

Sponsor's protocol code number

BC-P2-2020

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	FONDAZIONE DEL PIEMONTE PER L'ONCOLOGIA IRCCS
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	FONDAZIONE PIEMONTESE RICERCA SUL CANCRO ONLUS
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	Istituto di Candiolo
B.5.2	Functional name of contact point	Clinical Research Office
B.5.3	Address:
B.5.3.1	Street Address	sp. 142 km 3.95
B.5.3.2	Town/ city	Candiolo
B.5.3.3	Post code	10060
B.5.3.4	Country	Italy
B.5.6	E-mail	cosimo.martino@ircc.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	FEMARA - 30 COMPRESSE 2.5 MG
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.3.1	Product name	letrozolo
D.3.2	Product code	[letrozolo]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LETROZOLO
D.3.9.1	CAS number	112809-51-5
D.3.9.2	Current sponsor code	Letrozolo
D.3.9.3	Other descriptive name	Letrozolo
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2500
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	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

HER2 NEGATIVE/LUMINAL BREAST CANCER

CARCINOMA DELLA MAMMELLA LUMINALE/HER2 NEGATIVO

E.1.1.1

Medical condition in easily understood language

Breast Cancer of luminal subtype negative for HER2 alteration.

tumore della mammella di tipo luminale negativo per il recettore HER2

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	LLT
E.1.2	Classification code	10006283
E.1.2	Term	Breast neoplasm malignant female
E.1.2	System Organ Class	100000004864

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 confirm the role of miR-100 expression as metabolic response marker of patient treated with anti-hormone drugs

Confermare il ruolo dell’espressione di miR-100 come predittore di ormonosensibilità del carcinoma della mammella ormonopositivo.

E.2.2

Secondary objectives of the trial

Define and validate a genomic signature based on miR-100 expression to predict Luminal A subtipe.
Gene expression profiling

Mettere a punto e validare una firma genomica (“signature”) basata sull’espressione di miR-100 predittiva del sottotipo Luminale A e studiarne l’impatto prognostico in database disponibili online.
Valutare i profili di espressione genica globale sul materiale ottenuto mediante la biopsia allo scopo di eseguire studi correlativi miR-gene target atti a scoprire eventuali nuovi biomarcatori di risposta o di resistenza all'ormonoterapia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Ability to provide written informed consent
2. Over 18 years of age
3. Histological diagnosis of invasive breast cancer
4. Radiological evidence (mammography and / or ultrasound) strongly suggestive for the presence of invasive mammary neoplasia (BIRADS 4c or BIRADS 5) with a diameter greater than 15mm
5. Stage I carcinoma (if diameter> 15 mm) or II, operable d'emblée, or
6. Stage II or III cancer, operable following neoaduvant hormonal therapy in patients not eligible for neoadjuvant chemotherapy,
7. Onset stage IV carcinoma, asymptomatic, with operable emblée primary breast cancer or following presurgical therapy, not candidates for combination of letrozole with biological agents (eg. CDK 4/6 inhibitors)
8. Tumor of luminal immunophenotype A or B, according to ESMO guidelines (Luminal A: ER positive, Ki67 <20%, PgR> 20%; Luminal B; ER positive and Ki67=20% or PgR <20%, or both
9. Negativity for HER2
10. Cell proliferation, defined as percentage of Ki67 positive tumor cells,> 5%
11. Postmenopausal state
to. Postmenopausal status is defined by the presence of at least one of the following criteria:
the. age = 60 years
ii. age between 45-59 years as long as one or more of the following criteria are met:
1. amenorrhea = 12 months in the presence of the uterus in place;
2. amenorrhea for less than 12 months and FSH within the postmenopausal range, including patients who have undergone hysterectomy, or in chemotherapy-induced amenorrhea;
3. bilateral adnexectomy at age> 18 years.
12. Ability to take oral therapy, in the absence of known malabsorption syndrome, previous stomach or small bowel surgery
13. Ability to perform the staging and screening exams required by the protocol
14. ECOG Performance status = 0
15. Patients should have normal bone marrow, liver and kidney function as defined by the following biochemical values:
to. Leukocytes = 3,000 / ¿L.
b. Absolute count of neutrophils = 1,500 / ¿L
c. Platelets = 100,000 / ¿L
d. Total bilirubin within normal reference values
is. AST (SGOT) / ALT (SGPT) = 2.5X upper limit of normal
f. Creatinine within normal reference values ¿¿or creatinine clearance = 60mL / min / 1.73m² for patients with creatinine levels above normal

1. Possibilità di fornire consenso informato scritto
2. Età superiore a 18 anni
3. Diagnosi istologica di carcinoma invasivo della mammella
4. Evidenza radiologica (mammografia e/o ecografia) fortemente suggestiva per presenza di neoplasia mammaria invasiva (BIRADS 4c o BIRADS 5) di diametro superiore a 15mm
5. Carcinoma in stadio I (se diametro >15 mm) o II, operabile d’emblée, oppure
6. Carcinoma in stadio II o III, operabile a seguito di terapia neoaduvante ormonale in pazienti non eleggibili per chemioterapia neoadiuvante,
7. Carcinoma in stadio IV d’esordio, asintomatico, con tumore mammario primitivo operabile d’emblée o a seguito di terapia prechirurgica, non candidate ad associazione di letrozolo con agenti biologici (es. CDK 4/6 inibitori)
8. Tumore di immunofenotipo luminale A o B, secondo le linee guida ESMO (Luminale A: ER positivo, Ki67<20%, PgR >20%; Luminale B; ER positivo e Ki67=20% o PgR<20%, o entrambi
9. Negatività per HER2
10. Proliferazione cellulare, definita come percentuale di cellule tumorali Ki67 positive, >5%
11. Stato post-menopausale
a. Stato post-menopausale viene definito dalla presenza di almeno uno dei seguenti criteri:
i. età = 60 anni
ii. età compresa tra i 45-59 anni purché sia soddisfatto uno o più dei seguenti criteri:
1. amenorrea =12 mesi in presenza di utero in sede;
2. amenorrea da meno di 12 mesi e FSH entro il range dei valori della postmenopausa, includendo pazienti che abbiano subito isterectomia, o in amenorrea indotta da chemioterapia;
3. annessiectomia bilaterale in età >18 anni.
12. Capacità di assumere una terapia orale, in assenza di sindrome da malassorbimento nota, precedente chirurgia dello stomaco o del piccolo intestino
13. Capacità di eseguire gli esami di staging e di screening previsti dal protocollo
14. ECOG Performance status = 0
15. Le pazienti dovranno avere una normale funzione midollare, epatica e renale come definito dai seguenti valori biochimci:
a. Leucociti =3.000/¿L
b. Conta assoluta dei Neutrofili =1.500/¿L
c. Piastrine =100.000/¿L
d. Bilirubina totale entro i normali valori di riferimento
e. AST(SGOT)/ALT(SGPT) =2.5X limite superior del valore normale
f. Creatinina entro i normali valori di riferimento oppure creatinine clearence =60mL/min/1.73m² per pazienti con livelli di Creatinina superiori al valore normale

E.4

Principal exclusion criteria

1. Previous treatment for breast cancer with chemotherapy, lapatinib, trastuzumab, letrozole, anastrozole, exemestane or tamoxifen.
2. Indication for neoadjuvant chemotherapy
3. Metastatic disease for which an association of letrozole with biological agents is indicated (eg CDK 4/5 inhibitors)
4. Other malignancies diagnosed within the past 5 years, except basal cell or squamous skin carcinoma, melanoma in situ or cervical cancer in situ.
5. Premenopause
6. Known hypersensitivity to letrozole, or to any of its excipients (for example: women with rare hereditary problems of galactose intolerance, lactase deficiency or glucose / galactose malabsorption).
7. Evidence of severe and poorly controlled systemic disease affecting the lung, heart, liver, kidney that may compromise adherence to treatment or prolonged follow-up.
8. Uncontrolled chronic inflammatory bowel disease (example: Crohn's disease, ulcerative colitis).
9. Active and / or inadequately controlled infections.
10. Altered mental status, senile dementia, or any psychiatric condition that may impair the ability to knowingly sign informed consent.
11. Triple negative breast cancer, i.e. negative for both the overexpression of HER2 and the expression of hormone receptors.

1. Precedente trattamento per tumore della mammella con chemioterapia, lapatinib, trastuzumab, letrozolo, anastrozolo, exemestane o tamoxifene.
2. Indicazione a chemioterapia neoadiuvante
3. Malattia metastatica per la quale sia indicata un’associazione di letrozolo con agenti biologici (es., inibitori di CDK 4/5)
4. Altre neoplasie diagnosticate negli ultimi 5 anni, ad eccezione fatta per il carcinoma basocellulare o squamoso della cute, melanoma in situ o cancro della cervice in situ.
5. Premenopausa
6. Nota ipersensibilità al letrozolo, oppure ad un qualsiasi suo eccipiente (per esempio: donne affette da rari problemi ereditari di intolleranza al galattosio, deficit di lattasi o da mal assorbimento di glucosio/galattosio).
7. Evidenza di una severa e scarsamente controllata malattia sistemica a carico del polmone, del cuore, del fegato, del rene che possa compromettere l’aderenza al trattamento o un prolungato follow-up.
8. Malattia infiammatoria cronica intestinale non controllata (esempio: morbo di Crohn, colite ulcerativa).
9. Infezioni attive e/o non adeguatamente controllate.
10. Alterazione dello stato mentale, demenza senile, o qualsiasi condizione psichiatrica che possa compromettere la capacità di firmare consapevolmente il consenso informato.
11. Carcinoma mammario triple negative, ovvero negativo sia per l’iperespressione di HER2 che per l’espressione dei recettori ormonali.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with complete proliferative response (ki67 value =2.7%) after short treatment in relation to the basal expression of miR-100 dichotomized around the value of =4.343.

Proporzione di pazienti con risposta proliferativa completa (valore ki67 =2.7%) dopo breve trattamento in relazione all’espressione basale di miR-100 dicotomizzata intorno al valore di =4.343.

E.5.1.1

Timepoint(s) of evaluation of this end point

A Ki67 value =2.7 detected after a short treatment with hormonal therapy (21 +/- 3 days) defines the proliferative response to treatment (“complete cell cycle arrest” CCCA). The response will be assessed by measuring the reduction in Ki67 following hormonal treatment according to a schedule defined on the basis of the stage of the disease:
• Patients with operable emblée tumor: at the time of surgery (about 3 weeks)
• Candidate patients for neoadjuvant hormone therapy and patients with stage IV onset of hormone therapy for advanced disease: During the 3rd week from the start of treatment

Un valore Ki67 =2.7 rilevato dopo breve trattamento con terapia ormonale (21 +/- 3 giorni) definisce la risposta proliferativa al trattamento (“complete cell cycle arrest” CCCA). La valutazione della risposta verrà eseguita tramite misurazione della riduzione del Ki67 a seguito del trattamento ormonale secondo una tempistica definita sulla base dello stadio di malattia:
• Pazienti con tumore operabile d’emblée: al momento dell’intervento chirurgico (circa 3 settimane)
• Pazienti candidate a terapia ormonale neoadiuvante e pazienti con stadio IV d’esordio in terapia ormonale per la malattia avanzata: Durante la 3^ settimana dall’inizio del trattamento

E.5.2

Secondary end point(s)

• Comparison of the proliferative response measured as a percentage reduction of Ki67 from baseline, after short treatment, based on miR-100 levels.
• Correlation between the response to hormonal treatment (both complete proliferative response and percentage reduction in Ki67 compared to baseline values) and the expression of miR-100 target genes (mTOR, FOXA1, PLK1, FGFR3 and IGF1R).
• Evaluation of sensitivity and specificity of the gene signature developed in the BC-P1-2013 study in identifying Luminal A tumors defined by PAM50 gene expression tests.

• Confronto della risposta proliferativa misurata come riduzione percentuale del Ki67 rispetto ai valori basali, dopo breve trattamento, in base ai livelli di miR-100.
• Correlazione tra la risposta al trattamento ormonale (sia risposta proliferativa completa che riduzione percentuale del Ki67 rispetto ai valori basali) e l’espressione di geni target di miR-100 (mTOR, FOXA1, PLK1, FGFR3 e IGF1R).
• Valutazione di sensibilità e specificità della signature genica messa a punto nello studio BC-P1-2013 nell’identificare tumori Luminali A definiti tramite test di espressione genica PAM50.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Patients with operable emblée tumor: at the time of surgery (about 3 weeks)
• Candidate patients for neoadjuvant hormone therapy and patients with stage IV onset of hormone therapy for advanced disease: During the 3rd week from the start of treatment

• Pazienti con tumore operabile d’emblée: al momento dell’intervento chirurgico (circa 3 settimane)
• Pazienti candidate a terapia ormonale neoadiuvante e pazienti con stadio IV d’esordio in terapia ormonale per la malattia avanzata: Durante la 3^ settimana dall’inizio del trattamento

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)

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

E.8.1.2

Open

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

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:

177

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

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

237

F.4.2

For a multinational trial

F.4.2.1

In the EEA

237

F.4.2.2

In the whole clinical trial

237

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)

asp er clinical practice

normale 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

2021-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-14

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

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