Clinical Trials Register

Summary
EudraCT Number:	2005-004263-35
Sponsor's Protocol Code Number:	CFEM345D2411
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2007-01-10
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

2005-004263-35

A.3

Full title of the trial

A randomized, multi-center Phase IIIb, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer

Studio randomizzato, multicentrico, di fase IIIb, in aperto, di confronto tra letrozolo e anastrozolo nel trattamento adiuvante di donne in postmenopausa con carcinoma della mammella con recettori ormonali e linfonodi positivi

A.4.1

Sponsor's protocol code number

CFEM345D2411

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	NOVARTIS FARMA
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
B.5.2	Functional name of contact point

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*30CPR RIV 2,5MG
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA *
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	Film-coated 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	Letrozole
D.3.9.1	CAS number	112809-51-5
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	2.5
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
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	ARIMIDEX*28CPR 1MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTRAZENECA SpA *
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	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	Anastrozole
D.3.9.1	CAS number	120511-73-1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	1
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

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

Hormone receptor positive breast cancer in postmenopausal women

Carcinoma della mammella con recettori ormonali positivi in donne in postmenopausa

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	14.1
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

To compare the rate of disease free survival (DFS) at 5 years in postmenopausal women with hormone receptor and lymph node positive breast cancer randomized between letrozole and anastrozole

confrontare il tasso di sopravvivenza libera da malattia a 5 anni in donne in postmenopausa con carcinoma della mammella con recettori ormonali e linfonodi positivi randomizzate al trattamento con letrozolo o anastrozolo

E.2.2

Secondary objectives of the trial

-To compare the general safety between the two treatment arms -To compare the two treatment groups in a descriptive manner with the other indicators of efficacy including overall survival, breast cancer specific survival, time to development of distant metastases and time to development of contra lateral breast cancer -Compare percent change in BMD between the two arms -Compare the effects of treatment on serum lipid profiles in both treatment arms -Compare the incidence of clinical fractures between the two treatment arms

•Confrontare la sicurezza dei due gruppi di trattamento •Confrontare in modo descrittivo i due gruppi di trattamento per cio' che riguarda gli altri indicatori di efficacia,inclusi la sopravvivenza globale,la sopravvivenza specifica per il carcinoma della mammella,il tempo di comparsa di metastasi a distanza e il tempo di comparsa di carcinoma della mammella controlaterale •Confrontare la variazione percentuale della densita' minerale ossea tra i due gruppi di trattamento •Confrontare gli effetti del trattamento sul profilo lipidico sierico in entrambi i gruppi di trattamento •Confrontare l'incidenza di fratture ossee tra i due gruppi di trattamento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-provision of written informed consent -undergone a total mastectomy, a lumpectomy, or a quadrantectomy for primary breast cancer -the date of randomization must be no more than: 4 weeks from completion of surgery or 4 weeks after completion of adjuvant chemotherapy Note adjuvant radiation and endocrine therapy e.g. letrozole and anastrozole can be given at the same time as radiotherapy due to non-overlapping toxicity profile -presence of node positive disease -receptor-positive tumors, defined ER ≥10 fmol/mg cytosol protein; or ≥10% of the tumor cells positive by immunocytochemical evaluation -postmenopausal whether induced by surgery, radiotherapy or chemotherapy, or by being naturally amenorrheic, for 1 year or more if younger than 50 and for 6 months if 50 or older -postmenopausal levels of FSH/LH/E2 (follicle stimulating hormone, luteinizing hormone, estrogen) according to the definition of 'postmenopausal range' for the laboratory involved -WBC ≥ 3.0 x 109/L, granulocytes ≥ 1.5 X 109/L and platelets ≥ 100 x 109/L -AST/SGOT or ALT/SGPT ≤ 3 times ULN -serum creatinine ≤ 2 times ULN

-Consenso informato scritto -Pregresso intervento di mastectomia, quadrantectomia o escissione di carcinoma della mammella -La data della randomizzazione non deve superare: •4 settimane dalla fine dell'intervento chirurgico o •4 settimane dal termine della chemioterapia adiuvante Nota: letrozolo o anastrozolo possono essere somministrati contemporaneamente alla radioterapia perche' non c'e' sovrapposizione nel profilo di tossicita' -Linfonodi positivi -Il tumore deve essere positivo per i recettori ormonali, e cioe': recettori per gli estrogeni (ER) ≥10 fmol/mg di proteine citosoliche, o numero di cellule tumorali positive alla valutazione immunoistochimica ≥10% -La paziente deve essere in postmenopausa, indotta mediante intervento chirurgico, radioterapia o chemioterapia, oppure in amenorrea, da 1 anno o piu' per le donne di eta' < 50 anni, e da sei mesi se di eta' ≥ 50 anni -Livelli postmenopausali di FSH/LH/E2 in accordo alla definizione di 'range postmenopausale' del laboratorio coinvolto -Numero di leucociti ≥ 3,0 x 109/L, granulociti ≥ 1,5 x109/L e piastrine ≥ 100 x 109/L -AST/SGOT o ALT/SGPT inferiore o uguale a tre volte il limite superiore di normalita' -Creatinina sierica inferiore o uguale a due volte il limite superiore di normalita'

E.4

Principal exclusion criteria

-presence of metastatic disease -concomitant or prior bilateral breast cancer -previous or concomitant other (non-breast cancer) malignancy within the previous 5 years -presence of other non-malignant systemic diseases which may prevent prolonged follow-up -if no history of previous coronary heart disease but has at least two other coronary heart disease risk factors: LDL ≥160 mg/dL OR if fewer than two other coronary heart disease risk factors: LDL ≥190 mg/dL -total fasting cholesterol ≥ 240 mg/dL -patients on lipid-lowering agents, diet, or other measures for hyperlipidemia at baseline -progressed on neoadjuvant endocrine therapy -hormone replacement therapy (HRT) within 4 weeks before trial treatment was initiated -adjuvant anti-estrogen therapy for more than 1 month immediately following surgery, radiotherapy and/or chemotherapy -Breast cancer chemoprevention with anti-estrogens if less than 18 months between stopping and diagnosis of breast cancer -Severe hepatic dysfunction defined as Child-Pugh grade C

-Presenza di malattia metastatica -Carcinoma della mammella bilaterale concomitante o precedente -Altra neoplasia maligna concomitante o nei 5 anni precedenti -Presenza di altra patologia sistemica non neoplastica che possa impedire un follow up prolungato -In assenza di precedente coronaropatia ma con almeno altri due fattori di rischio per coronaropatia: LDL ≥ 160 mg/dL, oppure, se meno di due altri fattori di rischio per coronaropatia: LDL ≥ 190 mg/dL -Colesterolo totale a digiuno ≥ 240 mg/dL -Terapia con farmaci ipolipemizzanti, regime dietetico o altri trattamenti per iperlipidemia al basale -Progressione della malattia durante terapia endocrina neoadiuvante -Terapia sostitutiva ormonale nelle quattro settimane che precedono l'inizio del trattamento in studio -Terapia adiuvante anti-estrogenica per piu' di un mese immediatamente dopo l'intervento chirurgico, la radioterapia e/o la chemioterapia -Chemioprevenzione del carcinoma mammario con anti-estrogeni, se intercorrono meno di 18 mesi tra la sua interruzione e la diagnosi di carcinoma mammario -Epatopatia grave (Child-Pugh grado C)

E.5 End points

E.5.1

Primary end point(s)

Disease free survival: time from the date of randomisation to the date of the first documentation of re-occurrence of invasive breast cancer in local, regional or distant sites, new invasive breast cancer in the contra-lateral breast, or death from any cause. Patients will be assessed for disease recurrance every 6 months.Upon recurrance/relapse the patient will be discontinued from study medication . Further treatment will be at the investigator's discretion.

•Sopravvivenza libera da malattia: il tempo trascorso dalla data della randomizzazione alla data della prima recidiva di carcinoma mammario (locale, regionale o a distanza), di un nuovo carcinoma mammario controlaterale, o del decesso per qualunque causa. Le valutazioni per accertare la presenza di recidiva di malattia saranno eseguite ogni 6 mesi. Al momento della recidiva il trattamento in studio sara' interrotto e la decisione terapeutica sara' a discrezione dello sperimentatore

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)

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

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

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

Information not present in EudraCT

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	400
F.4.2	For a multinational trial
F.4.2.1	In the EEA	2500
F.4.2.2	In the whole clinical trial	4000

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

2006-02-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-02-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-09-08

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