Clinical Trials Register

Summary
EudraCT Number:	2005-002603-16
Sponsor's Protocol Code Number:	CSTI571H2202
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:	2005-11-24
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

2005-002603-16

A.3

Full title of the trial

Estudio fase II, abierto, multicéntrico, no comparativo, que evalúa la eficacia de Glivec® con Hidroxiurea en pacientes con Glioblastoma Multiforme (GBM) en progresión, que reciben fármacos anticonvulsivantes con capacidad de inducción enzimática

A.4.1

Sponsor's protocol code number

CSTI571H2202

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 Farmacéutica, 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	Information not present in EudraCT
D.2.1.1.1	Trade name	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm 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.3.1	Product name	Glivec
D.3.2	Product code	STI571
D.3.4	Pharmaceutical form	Capsule*
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.3.9.1	CAS number	220127-57-1
D.3.9.2	Current sponsor code	STI571
D.3.9.3	Other descriptive name	Glivec
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	100
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
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	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	Information not present in EudraCT
D.2.1.1.1	Trade name	Hidroxiurea
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.3.1	Product name	Hidroxiurea
D.3.2	Product code	Hidroxicarbamida
D.3.4	Pharmaceutical form	Capsule*
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.3.9.2	Current sponsor code	Hidroxiurea
D.3.9.3	Other descriptive name	Hidroxicarbamida
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	500mg BID
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
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	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	Information not present in EudraCT
D.2.1.1.1	Trade name	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm 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.3.1	Product name	Glivec
D.3.2	Product code	STI571
D.3.4	Pharmaceutical form	Capsule*
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.3.9.1	CAS number	220127-57-1
D.3.9.2	Current sponsor code	STI571
D.3.9.3	Other descriptive name	Glivec
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	400
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Glioblastoma multiforme progresivo (GBM) tras fallo a terapia de primera línea definida por cirugía, radioterapia y exposición a un régimen de quimioterapia de Temozolamida (TMZ).

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Objetivos primarios:

Evaluar la eficacia clínica del tratamiento combinado de imatinib más HU basándose en la tasa de respuesta global (RG) objetiva. La tasa de respuesta global objetiva se calcula como la tasa de la mejor respuesta global de la respuesta completa más la respuesta parcial (RC+RP) al tratamiento.

E.2.2

Secondary objectives of the trial

Evaluar la duración de la respuesta global objetiva al tratamiento combinado de imatinib con HU en pacientes con GBM resistente a TMZ.
Evaluar el beneficio clínico del tratamiento combinado de imatinib con HU. El beneficio clínico se evaluará basándose en la respuesta global objetiva más la enfermedad estable (EE) durante más de seis meses (RG + (EE>6 meses)).
Evaluar la supervivencia libre de enfermedad (SLE) a los 6 y 12 meses y la mediana de SLE del tratamiento combinado de imatinib con HU en pacientes con GBM resistente a TMZ.
Evaluar la supervivencia a los 12 y 24 meses del tratamiento combinado con imatinib con HU.
Evaluar el perfil de seguridad de 500 mg dos veces al día de imatinib administrado con 500 mg de HU BID.
Se realizarían sub-investigaciones adicionales para permitir la evaluación de las características moleculares de los tumores GBM en progresión en cada paciente para a su vez entender el mecanismo de las respuestas clínicas al tratamiento con imatinib y HU

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

• Los pacientes deben tener un diagnóstico confirmado histológicamente de GBM primario en progresión basado en el diagnóstico original. Las preparaciones histológicas iniciales deben estar disponibles para una revisión del diagnóstico por el laboratorio central. Podrá incluirse a los pacientes con glioma previo de bajo grado si la reevaluación histológica demuestra la transformación a GBM. Las preparaciones histológicas o la muestra de biopsia más recientes deben estar disponibles para revisión del diagnóstico por el laboratorio central.
• Los pacientes no deben presentar más de un episodio previo de progresión de la enfermedad tras cirugía o radiación previas y sólo una exposición anterior a quimioterapia con temozolomida o nitrosourea. La quimioterapia podría haberse administrado como tratamiento adyuvante o posterior. La aplicación de discos de Gliadel se considerará como régimen quimioterápico con nitrosourea.
• Los pacientes deben presentar una enfermedad mesurable en la RMN potenciada con gadolinio.
• Los pacientes deben estar tomando en la actualidad EIACDs (como carbamazepina, fenobarbital, fenitoína, fosfenitoína, oxcarbamazepina, primadota).
• Pacientes que tomen esteroides: deben llevar ≥ 7 días tomando una dosis estable.
• puntuación de función de ECOG  2
• Hemoglobina ≥ 10g/dl (o hematocrito > 29 %), RAN > 1.500 células/l, plaquetas > 100.000 células/l.
• Creatinina sérica < 1,5 mg/dl, BUN < 25 mg/dl, SGOT sérica y bilirrubina < 1,5 veces el límite superior normal.
• Pacientes, hombres y mujeres, de ≥ 18 años de edad.
• Los pacientes, hombres y mujeres, con actividad sexual deben usar un método anticonceptivo de doble barrera, anticonceptivos orales más anticonceptivo de barrera o deben haberse sometido a una histerectomía total u ovariectomía, o ligadura de trompas, documentadas clínicamente.
• Las mujeres en edad fértil deberán presentar una prueba de embarazo negativa en las 48 horas anteriores a la visita 1 (comienzo del fármaco en estudio).
• Pacientes con una esperanza de vida de al menos 8 semanas.
• Consentimiento informado firmado por el paciente antes de la entrada del paciente y de cualquier procedimiento del estudio.

E.4

Principal exclusion criteria

• Pacientes que hayan recibido imatinib o hidroxiurea antes de entrar en el estudio.
• Pacientes con edema periférico de gd≥2 o derrames pulmonares o pericárdicos o ascitis de cualquier grado.
• Pacientes que se hayan sometido con anterioridad a radiocirugía estereotáctica o radioinmunoterapia a menos que haya una progresión radiográfica clara de la enfermedad fuera del campo de radiación o un tumor recurrente dentro del campo, demostrado por una biopsia
• Los pacientes que presenten un riesgo excesivo de hemorragia intracraneal (definida como accidente cerebrovascular en los 6 meses previos, antecedentes de hemorragia del SNC (excepto la post-operatoria de grado 1) o intraocular.
• Pacientes con infección sistémica no controlada.
• Pacientes con evidencia de hemorragia intratumoral en la imagen de diagnóstico previa al tratamiento, excepto la hemorragia postoperatoria estable de grado 1.Pacientes que se hayan sometido a cirugía mayor en las 4 semanas anteriores a la entrada en el estudio o que todavía no se hayan recuperado de una cirugía mayor previa.Pacientes en los tres meses posteriores a la segunda cirugía para el GBM en progresión, salvo que se haya realizado un escáner postoperatorio que haya mostrado enfermedad medible que esté ahora en progresión.Pacientes que hayan recibido quimioterapia en las 4 semanas anteriores al comienzo del estudio (6 semanas para la nitrosourea) u otros fármacos en investigación (agentes biológicos, inmunoterapéuticos o citostáticos) antes del comienzo del estudio o que no se hayan recuperado de los efectos tóxicos de este tratamiento.Pueden emplearse otros fármacos en investigación o específicos con la quimioterapia mencionada, pero el uso de estos fármacos por separado se considerará como un segundo régimen y llevará a que el paciente no pueda entrar en este protocolo.Pacientes con deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar de forma significativa la absorción de imatinib.Pacientes que estén tomando Cumadina (warfarina sódica).Para la RMN, los pacientes con marcapasos, implantes metálicos ferromagnéticos que no sean los autorizados como seguros para uso en RMN (p.ej., algunos tipos de grapas para aneurismas, fragmentos de metal); pacientes que sufran una claustrofobia incontrolable o físicamente incapaces de introducirse en la máquina (p.ej., obesidad, etc.)Pacientes con otros procesos malignos primarios tratados en los tres años anteriores, excepto el carcinoma escamoso de piel extirpado y lesiones de carcinoma in situ de otros órganos que se haya tratado de forma curativa.
• Pacientes con historial conocido de seropositividad al virus de la inmunodeficiencia humana (VIH); no se requieren pruebas de VIH para entrar en el estudio.
• No se incluirá en el ensayo a aquellos pacientes considerados por el investigador con baja probabilidad de cumplimiento de las normas del estudio, tomen la medicación, se desplacen para las visitas de evaluación necesarias o que tengan otras patologías que puedan interferir con las evaluaciones del estudio.
• No entrarán el protocolo los pacientes que no puedan ofrecer un consentimiento informado fiable y que no tengan un representante legal que tome las decisiones sanitarias en su nombre.

E.5 End points

E.5.1

Primary end point(s)

Eficacia clínica del tratamiento combinado de imatinib más HU basándose en la tasa de respuesta global (RG) objetiva. La determinación de la eficacia del tratamiento incluirá una RMN y una exploración neurológica siguiendo los criterios de MacDonald. (véase el Anexo 3). Todas las RMN se validarán mediante una revisión independiente.

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

Information not present in EudraCT

E.6.11

Pharmacogenomic

Yes

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)

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

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

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

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.8.3

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.8.5

The trial involves multiple Member States

Yes

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

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
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	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Information not present in EudraCT
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 2005-11-24.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
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	8
F.4.2	For a multinational trial
F.4.2.1	In the EEA	65
F.4.2.2	In the whole clinical trial	110

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

2006-01-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-12-15

P. End of Trial
P.	End of Trial Status	Completed

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