Clinical Trials Register

Summary
EudraCT Number:	2006-006507-36
Sponsor's Protocol Code Number:	AVF3693g
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:	2007-12-07
Trial results	Removed from public view

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

2006-006507-36

A.3

Full title of the trial

A Phase III Multicenter Randomized Placebo Controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy Regimens in Subjects With Previously Treated Metastatic Breast Cancer

STUDIO DI FASE III, MULTICENTRICO, RANDOMIZZATO, CONTROLLATO DA PLACEBO PER VALUTARE L`EFFICACIA E LA SICUREZZA DEL TRATTAMENTO CON BEVACIZUMAB IN COMBINAZIONE CON IL REGIME CHEMIOTERAPICO IN SOGGETTI CON TUMORE METASTATICO DELLA MAMMELLA PRECEDENTEMENTE TRATTATO.

A.4.1

Sponsor's protocol code number

AVF3693g

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	GENENTECH , INC
B.1.3.4	Country	United States
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	Bevacizumab
D.2.1.1.2	Name of the Marketing Authorisation holder	Genetech Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bevacizumab
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	RO4876646
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Previously treated metastatic breast cancer

Tumore metastatico della mammella precedentemente trattato

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	10006279
E.1.2	Term	Breast neoplasm
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 primary objective of the study is to determine the clinical benefit of the addition of bevacizumab to standard chemotherapy for previously treated metastatic breast cancer (MBC), as measured by progression-free survival (PFS), assessed in a two-step, hierarchical manner as described in the Protocol.

L'obiettivo primario dello studio e' di determinare il beneficio clinico dell'aggiunta del bevacizumab alla chemioterapia standard per il tumore metastatico della mammella (metastatic breast cancer, MBC) precedentemente trattato, determinato come sopravvivenza in assenza di progressione (progression-free survival, PFS), e verificato con modalita' gerarchica come descritto nel Protcollo.

E.2.2

Secondary objectives of the trial

- To estimate the clinical benefit of the addition of bevacizumab to each chemotherapy regimen, with PFS estimates and confidence limits calculated within each chemotherapy stratum for bevacizumab and placebo
- To determinate clinical benefit, as measured by objective response rate, duration of objective response,
one-year survival, and overall survival, of the addition of bevacizumab to standard chemotherapy options compared with standard chemotherapy alone
- To compare the incidence of toxicity, as measured by selected adverse events(see Protocol section 3.3.3)

- Stima del vantaggio clinico dell'aggiunta del bevacizumab a ciascun regime chemioterapico,con valutazioni del PFS e limiti di confidenza calcolati all'interno di ogni strato di chemioterapia,per il bevacizumab e il placebo.
- Determinazione del beneficio clinico,misurato in base alla percentuale di risposta obiettiva,alla durata della risposta obiettiva,alla sopravvivenza a un anno,e sopravvivenza totale,dell'aggiunta del bevacizumab alle opzioni chemioterapiche convenzionali rispetto alla chemioterapia convenzionale da sola.
- Confronto dell'incidenza di tossicita',determinata in base ad eventi avversi selezionati (si veda Protocollo sez.3.3.3)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet the following criteria to be eligible for study entry:
• Signed Informed Consent Form
• ≥ 18 years of age
• Histologically confirmed carcinoma of the breast with measurable or
non-measurable metastatic disease that has progressed
Patients with a history of brain metastasis are eligible for study participation
(U.S. only), as long as their brain metastases have been treated and they have no
evidence of progression or hemorrhage after treatment and no ongoing requirement
for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or
CT scans) during the screening period. CT scan with contrast or MRI scan of the
brain must be performed at least 3 weeks after completion of all therapy to the brain.
Treatment for brain metastasis may include the following: WBRT, SRS
(Gamma knife, LINAC, or equivalent), or a combination as deemed appropriate by
the treating physician. Radiotherapy and stereotactic radiosurgery must be
completed at least 4 weeks prior to Day 0.
Patients may also have neurosurgical resection. Neurosurgery must be completed
at least 6 weeks prior to Day 0, and brain biopsy must be completed at least
4 weeks prior to Day 0.
• Progression of disease during or following administration of one
(non-investigational) chemotherapy regimen, defined as single-agent
chemotherapy administered prior to or during disease progression or a
pre-specified combination or sequence of cytotoxic agents administered in the
first-line settingSubjects whose initial treatment changed prior to progression in the
first-line setting are ineligible unless the change occurred within 30 days
of initial treatment due to toxicity.
• ECOG performance status of 0 or 1 (see Appendix B)
• For women of childbearing potential, use of an effective means of
non-hormonal contraception
• Life expectancy ≥ 3 months
• Willingness and capacity to comply with study and follow-up procedures

I pazienti dovranno soddisfare tutti i seguenti criteri di inclusione:
• Firma del Consenso Informato scritto
• Paziente di eta' ≥ 18 anni
• Carcinoma della mammella confermato istologicamente con lesioni metastatiche misurabili o non misurabili che siano in progressione
• Progressione di malattia durante o dopo la somministrazione di un regime chemioterapico citotossico convenzionale, definito come trattamento con chemioterapia ad agente singolo (single-agent chemotherapy) somministrato prima della progressione della malattia o come combinazione pre-determinata, o sequenza di agenti cito-tossici somministrati nella terapia di prima linea.
Quei soggetti la cui terapia iniziale e' stata modificata prima della progressione nel corso dell'adattamento terapeutico di prima linea, non sono elegibili per lo studio a meno che tale variazione sia avvenuta entro 30 giorni dall'inizio del trattamento iniziale, per motivi di tossicita'.
• ECOG tra 0 e 1
• Per donne in eta' fertile uso di un effettivo metodo di contraccezione non ormonale
• Aspettativa di vita ≥ 3 mesi
• Capacita' di soddisfare le richieste dello studio e le procedure di follow up

E.4

Principal exclusion criteria

Subjects who meet any of the following criteria will be excluded from study entry:
a. Disease Treatment History
• Prior hormonal therapy only as treatment for metastatic disease
without chemotherapy. Patients must have received chemotherapy for their
metastatic disease in the first-line setting. Hormone therapy alone is not allowed.
• For subjects who have received prior anthracycline-based therapy,
documentation of left ventricular ejection fraction < 50% by either
multiple gated acquisition (MUGA) or echocardiogram (ECHO)
• Treatment with more than one prior cytotoxic regimen for MBC
• HER2-positive status
In general, HER2-positive status will be identified by a fluorescence in situ
hybridization (FISH) assay as evaluated at the institution or, if FISH is
unavailable, a 2+ or 3+ immunohistochemistry result (but the method of
identification may vary by region or institution). Patients who have unknown
HER2 status, and for whom determination of HER2 status is not possible,
are eligible for this study.
• Unknown ER and PR status
• Radiation therapy other than for palliation or brain metastasis, biologic therapy,
or chemotherapy for MBC within 21 days prior to Day 0
• Prior therapy with bevacizumab or other VEGF pathway-targeted therapy
See Protocol sec. 4.1.3 for:
b. Bevacizumab Exclusion Criteria
c. General Exclusion Criteria

Soggetti che presentino i seguenti criteri saranno esclusi dalla partecipazione allo studio:

a. Storia del trattamento della malattia
• Precedente terapia ormonale solo come trattamento per le metastasi, senza chemioterapia
• Per soggetti che hanno ricevuto precedente terapia con antracicline, documentazione di frazione di eiezione del ventricolo sinistro < 50% tramite MUGA o ecocardiogramma
• Trattamento con piu' di un regime citotossico per cancro metastatico della mammella
• Pazienti con positivita' per HER2
• Pazienti con status ignoto per recettore degli estrogeni e del progesterone
• Radioterapia tranne come palliativo o per metastasi cerebrali, terapia biologica o chemioterapia per cancro metastatico della mammella entro 21 giotni prima del giorno 0
• Precedenti tepapie con bevacizumab o altra terapia VEGF pathway-targeted
Si veda Protocollo sez. 4.1.3 per:
b. Criteri di Esclusione per Bevacizumab
c. Criteri di Esclusione Generali

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival

Sopravvivenza in Assenza di Progressione

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Terapia Standard

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

Tossicita', problemi legati all'arruolamento o ai dati (si veda protocollo sec. 4.7)

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

Number of subjects for this age range:

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.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

150

F.4.2.2

In the whole clinical trial

700

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)

Terapia Standard

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

2007-06-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-04-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-02-06

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