Clinical Trials Register

Summary
EudraCT Number:	2008-008697-31
Sponsor's Protocol Code Number:	CRAD001W2301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-11-25
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

Spain - AEMPS

A.2

EudraCT number

2008-008697-31

A.3

Full title of the trial

Estudio Fase III, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de everolimus administrado diariamente en combinación con trastuzumab y vinorelbina, en mujeres pretratadas con cáncer de mama metastásico o localmente avanzado con sobreexpresión de HER2/neu

A.3.2

Name or abbreviated title of the trial where available

BOLERO-3

A.4.1

Sponsor's protocol code number

CRAD001W2301

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Farmaceutica S.A
B.1.3.4	Country	Spain
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	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	everolimus / RAD001
D.3.2	Product code	RAD001
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	everolimus
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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.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	HERCEPTIN 150 mg polvo para concentrado para solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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 injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	TRASTUZUMAB
D.3.9.1	CAS number	180288-69-1
D.3.9.3	Other descriptive name	TRASTUZUMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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.IMP: 3
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	Information not present in EudraCT
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	Information not present in EudraCT
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	VINORELBINE
D.3.9.1	CAS number	71486221
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

cáncer de mama metastásico con sobreexpresión de HER2/neu previo tratamiento con trastuzumab

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	PT
E.1.2	Classification code	10055113
E.1.2	Term	Breast cancer metastatic

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Comparar la combinación de everolimus, vinorelbina y trastuzumab con vinorelbina y trastuzumab en monoterapia con respecto a la supervivencia libre de progresión en mujeres con cáncer de mama metastásico o localmente avanzado que sobreexpresa HER2/neu que son resistentes a trastuzumab y que han sido tratadas previamente con un taxano.

E.2.2

Secondary objectives of the trial

Objetivos secundarios principales
Comparar los dos grupos de tratamiento con respecto a la supervivencia global (SG)
Otros objetivos secundarios
Evaluar los dos grupos de tratamiento con respecto a
Tasa de respuesta objetiva (ORR)
Periodo de tiempo hasta el deterioro del estado funcional del ECOG
Seguridad
Cambios en las puntuaciones de la calidad de vida (QoL) a lo largo del tiempo
Tasa de beneficio clínico (CBR)
Duración de la respuesta (DoR)
Tiempo hasta la respuesta
Evaluar el impacto de la coadministración de everolimus en la farmacocinética de vinorelbina en presencia de trastuzumab en un subgrupo de pacientes.
Evaluar el impacto de la coadministración de everolimus en la farmacocinética de trastuzumab en presencia de vinorelbina en un subgrupo de pacientes.
Evaluar las concentraciones de everolimus predosis (Cmin) y a las 2 horas después de la dosis (C2h) cuando se coadministra con vinorelbina y trastuzumab en un subgrupo de pacientes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Consentimiento informado por escrito obtenido antes de realizar cualquier procedimiento relacionado con el estudio.
Mujeres ≥ 18 años de edad
Carcinoma invasivo confirmado histológica o citológicamente con evidencia radiológica o localmente recurrente de enfermedad metastásica. La enfermedad localmente recurrente no deberá ser apta para resección con intento curativo;
Estado de HER2+ definido como tinción IHC 3+ o hibridización in situ positiva. El informe patológico que confirme el estado de HER2+ deberá estar disponible en el centro de estudio antes de la aleatorización;
Pacientes con resistencia a trastuzumab, definida como:
Recurrencia durante el tratamiento con trastuzumab o durante los 12 meses después de la última infusión, en pacientes que recibieron trastuzumab como tratamiento adyuvante.
Progresión durante o en las 4 semanas después de la última infusión de trastuzumab en pacientes que recibieron trastuzumab para la enfermedad metastásica.
Terapia previa con taxanos:
Nota: Las pacientes deberán haberse recuperado a grado 1 de cualquier acontecimiento adverso (excepto alopecia) relacionado con la terapia previa, antes de la aleatorización
Pacientes con estado funcional del ECOG de 0-2;
Pacientes con enfermedad medible según los criterios RECIST;
Documentación de prueba de embarazo negativa en pacientes físicamente fértiles antes de la inclusión durante los 7 días previos a la aleatorización. Las mujeres premenopáusicas sexualmente activas deberán utilizar medidas anticonceptivas adecuadas, excluyendo anticonceptivos que contengan estrógenos; mientras participen en el estudio;
Las pacientes deberán cumplir los siguientes criterios de laboratorio en un plazo de 21 días antes de la aleatorización
Hematología
Recuento de neutrófilos absoluto (ANC) ≥ 1500 /mm3 o 1.5 × 109/L;
Plaquetas ≥ 100,000 /mm3 o 100 × 109/L;
Hemoglobina ≥ 90 g/L o 5.6 mmol/L;
INR ≤ 2;
Bioquímica
AST/SGOT y ALT/SGPT ≤ 2.5 × por encima del límite de normalidad (ULN) (o ≤ 5.0 × ULN, si el aumento de las transaminasas es debido a metástasis hepáticas)
Bilirrubina sérica total ≤ 1.5 × ULN (en pacientes con síndrome de Gilbert conocido, bilirrubina total ≤ 3 × ULN, con bilirrubina directa ≤1.5 × ULN);
Colesterol sérico en ayunas ≤ 300 mg/dl o 7.75 mmol/L y triglicéridos en ayunas ≤ 2.5 × ULN (con fármacos hipolipemiantes permitidos);
Creatinina sérica ≤ 1.5 × ULN;
Evaluación de la fracción de eyección ventricular izquierda (ecocardiograma o MUGA) realizada durante las 4 semanas previas a la aleatorización, que muestre un valor de LVEF ≥ LLN.

E.4

Principal exclusion criteria

Inhibidores de la mTOR o agentes alcaloides de la vinca previos para el tratamiento del cáncer;
Más de tres líneas de quimioterapia previas para la enfermedad avanzada;
Nota: Si la recurrencia ocurrió durante la terapia adyuvante o ≤ 6 meses desde la última administración de la terapia adyuvante (con la excepción de tratamientos endocrinos), la terapia adyuvante se considerará como un régimen previo de quimioterapia sistémica para la enfermedad avanzada;
Pacientes que hayan recibido radioterapia previa para ≥ 25% de la médula ósea durante las últimas 4 semanas previas a la aleatorización;
Antecedentes de metástasis del sistema nervioso central;
Pacientes que reciban agentes inmunosupresores concomitantes o uso crónico de corticosteroides en el momento del iniciar el estudio excepto en los casos descritos a continuación:
Se permiten aplicaciones tópicas (por ejemplo, erupción), inhaladores (por ejemplo, enfermedades obstructivas de las vías respiratorias), colirios o inyecciones locales (por ejemplo, intraarticulares);
Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de everolimus oral;
Ulcera activa del tracto gastrointestinal superior;
Neuropatía periférica ≥ grado 2 en la aleatorización;
Enfermedad cardíaca activa que incluya algo de lo siguiente:
Angina de pecho que precise el uso de medicación antianginosa;
Arritmias ventriculares excepto para contracciones ventriculares prematuras benignas;
Arritmias nodales y supraventriculares que precisen un marcapasos o no controladas con medicación;
Anormalidad de conducción que precise un marcapasos;
Enfermedad valvular con compromiso documentado en la función cardíaca;
Pericarditis sintomática;
Antecedentes de disfunción cardíaca que incluya algo de lo siguiente:
Infarto de miocardio documentado con enzimas cardíacos elevados o anomalías persistentes regionales de la motilidad de la pared en la evaluación de la función LV;
Antecedentes de insuficiencia cardíaca congestiva documentada (clasificación III-IV funcional de la Asociación de Cardiología de Nueva York);
Cardiomiopatía documentada;
Infección por virus de la inmunodeficiencia humana conocida
Otras condiciones médicas incontroladas y/o severas concurrentes (por ejemplo, diabetes mellitus incontrolada, infección incontrolada o no tratada activa incluyendo infecciones fúngicas sistémicas, enfermedad pulmonar restrictiva crónica u obstructiva crónica incluyendo disnea en reposo por cualquier causa) que pudiese causar riesgos de seguridad inaceptables o comprometer el cumplimiento con el protocolo;
Cualquier enfermedad maligna dentro de los 5 años previos a la aleatorización, con la excepción de carcinoma in situ del cuello del útero adecuadamente tratado, carcinoma de células basales o escamosas o cáncer cutáneo no melanomatoso;
Hipersensibilidad conocida a cualquier medicación del estudio;
Diátesis hemorrágica activa o con medicación antivitamina K oral (excepto dosis bajas de warfarina y aspirina o equivalente, siempre que el INR ≤ 2.0);
Acumulación clínicamente significativa de líquido en el tercer espacio (es decir, ascitis que precise punción o efusión pleural que precise punción o esté asociada con falta de aliento);
Mujeres embarazadas o en periodo de lactancia

E.5 End points

E.5.1

Primary end point(s)

La variable principal en este estudio es la supervivencia libre de progresión (SLP), definida como el momento desde la fecha de aleatorización hasta la fecha de la primera progresión del tumor radiológicamente documentada o muerte por cualquier causa. Si una paciente no ha presentado un evento, la SLP se censurará en la fecha de la última evaluación del tumor aceptable. La progresión se determinará con evaluación local según los criterios RECIST, véase Suplemento 1.
Remítase al Apartado 10 de estadística para más detalles.

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

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

Pls refer to protocol

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

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-11-25.

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Pls refer to protocol section 11 Administrative Procedures, Informed Consent

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

130

F.4.2.2

In the whole clinical trial

572

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)

Pls refer to protocol

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

2010-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-01-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-11

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