Clinical Trials Register

Summary
EudraCT Number:	2012-003066-40
Sponsor's Protocol Code Number:	CLDE225C2301
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:	2013-01-23
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

2012-003066-40

A.3

Full title of the trial

A Phase III, multi-center, open-label, randomized, controlled study of the efficacy and safety of oral LDE225 versus temozolomide in patients with Hh-pathway activated relapsed medulloblastoma

Estudio fase III, multicéntrico, abierto, aleatorizado, controlado, que evalúa la seguridad y eficacia de LDE225 oral frente a temozolomida en pacientes con meduloblastoma en recidiva que tengan activación de la vía Hh

A.3.1

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

A clinical study to test the efficacy and safety of LDE225 compared to temozolomide in patients with a specific type of brain tumour

Estudio clínico para evaluar la eficacia y seguridad de LDE225 en comparación con temozolomida en pacientes con un tipo específico de tumor cerebral.

A.4.1

Sponsor's protocol code number

CLDE225C2301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/192/2012

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	Novartis Pharma Services
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica S.A.
B.5.2	Functional name of contact point	Javier Malpesa
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les Corts Catalanes,764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34933064464
B.5.5	Fax number	34933064290
B.5.6	E-mail	eecc.novartis@novartis.com

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.3.2	Product code	LDE225
D.3.4	Pharmaceutical form	Powder and solvent for oral suspension
D.3.4.1	Specific paediatric formulation	Yes
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	Not available
D.3.9.1	CAS number	1218778-77-8
D.3.9.2	Current sponsor code	LDE225
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	50
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	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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	Temozolomida
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	Temozolomida
D.3.9.4	EV Substance Code	SUB10889MIG
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	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	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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	temozolomide
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	TEMOZOLOMIDE
D.3.9.4	EV Substance Code	SUB10889MIG
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	20
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	No
D.IMP: 4
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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	temozolomide
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	TEMOZOLOMIDE
D.3.9.4	EV Substance Code	SUB10889MIG
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)	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	No
D.IMP: 5
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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	temozolomide
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	TEMOZOLOMIDE
D.3.9.4	EV Substance Code	SUB10889MIG
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	140
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	No
D.IMP: 6
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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	Temozolomida
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	Temozolomida
D.3.9.4	EV Substance Code	SUB10889MIG
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	180
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	No
D.IMP: 7
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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule
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	temozolomide
D.3.9.1	CAS number	85622-93-1
D.3.9.3	Other descriptive name	TEMOZOLOMIDE
D.3.9.4	EV Substance Code	SUB10889MIG
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	250
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	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

Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation

Recaída Meduloblastoma caracterizada por Hedgehog (Hh)- activación de la vía.

E.1.1.1

Medical condition in easily understood language

Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation

Recaída Meduloblastoma caracterizada por Hedgehog (Hh)- activación de la vía.

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	10066594
E.1.2	Term	Medulloblastoma recurrent
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess efficacy of LDE225 with respect to the Overall Response Rate (ORR) according to independent central review (ICR)

El objetivo principal de la parte aleatorizada de este ensayo es comparar la eficacia de LDE225 frente a TMZ con respecto a la tasa de respuesta global según la revisión central independiente (RCI).
El objetivo secundario principal de la parte aleatorizada de este ensayo es evaluar LDE225 frente a TMZ con respecto a la supervivencia libre de progresión (SLP) según el RCI.
El objetivo principal de la parte no aleatorizada de este ensayo es evaluar la eficacia de LDE225 con respecto a la tasa de respuesta global según el RCI.

E.2.2

Secondary objectives of the trial

To assess the efficacy of LDE225 with respect to:
- ORR according to local investigator assessment
- Progression free survival (PFS) according to both ICR and local investigator assessment
- Duration of response (DoR) according to both ICR and local investigator assessment
- Overall survival (OS)

To further characterize the safety and tolerability of LDE225 treatment

To further characterize the pharmacokinetics of LDE225 and any relevant metabolites

Otros objetivos secundarios son:
Para la parte aleatorizada
Comparar la eficacia de LDE225 frente a TMZ con respecto a la TRG y la SLP según la evaluación del investigador local
Evaluar la eficacia de cada tratamiento en la duración de la respuesta (DR) según la evaluación de la RCI y de la investigador local
Evaluar el efecto de cada tratamiento en la supervivencia global (SG)
Caracterizar mejor la seguridad y tolerabilidad de cada tratamiento
Caracterizar mejor la farmacocinético de LDE225 y de cualquier metabolito relevante
Para la parte no aleatorizada
Evaluar la eficacia de LDE225 con respecto a:
La TRG según la evaluación del investigador
La SLP y la DR según la evaluación de la RCI y del investigador local
La supervivencia global
Caracterizar mejor:
La seguridad y la tolerabilidad de LDE225
La farmacocinética de LDE225 y de cualquier metabolito relevante

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients aged >= 4 months
- Patients with histologically confirmed diagnosis of MB, who have experienced relapse or progression
- Only patients with a test result, using the 5-gene Hh signature assay, indicating Hh-pathway activated MB are eligible for this study.
- At least one measurable lesion
- Adequate renal function
- Adequate liver function
- Adequate bone marrow function
- Serum CK <= 1.5 ULN

Other protocol defined inclusion criteria may apply.

Criterios de inclusión para los grupos 1 y 2 aleatorizados
Pacientes con edad ? 4 meses
Pacientes con diagnóstico histológicamente confirmado de MB, que hayan experimentado recaída o progresión después de terapia estándar, incluyendo radioterapia, sin exposición previa a terapia con TMZ.
Pueden incluirse pacientes con cualquier número de recaídas previas siempre que presenten tumores que tengan activación de la vía de señalización Hh, evaluado utilizando el ensayo de firma de Hh de 5 genes.
Por lo menos una lesión medible definida como lesión(es) que puede(n) ser medida(s) de forma precisa al menos en dos dimensiones y sea ? 10 mm en cada dimensión con RM con gadolinio (Gd), independientemente del grosor de sección/intervalo de reconstrucción, para lesiones del SNC y TC o RM (con o sin contraste) para las lesiones que no sean del SNC.
Criterios de inclusión principales para los grupos 3 y 4 no aleatorizados
Las edades de los pacientes para cada grupo se definen a continuación;
La inclusión en el grupo 3 estará limitada a aquellos pacientes con MB en recidiva con Hh+ con edad > 4 meses y ? 6 años que no hayan recibido tratamiento previo con RT ± TMZ
La inclusión en el grupo 4 está abierta para pacientes con MB en recidiva con Hh+ con edad ? 4 meses que hayan recibido RT y TMZ previas.
Pacientes con diagnóstico histológicamente confirmado de MB, que hayan experimentado recaída o progresión y que no hayan recibido tratamiento previo con RT ± TMZ (sólo niños- grupo 3) o que hayan recibido tratamiento previo con RT y TMZ (niños o adultos ?Grupo 4).
Pueden incluirse pacientes con cualquier número de recaídas previas siempre que presenten tumores que tengan activación de la vía de señalización Hh, evaluado utilizando el ensayo de firma de Hh de 5 genes.
Por lo menos una lesión medible definida como lesión(es) que puede(n) ser medida(s) de forma precisa al menos en dos dimensiones y sea ? 10 mm en cada dimensión con RM con gadolinio (Gd), independientemente del grosor de sección/intervalo de reconstrucción, para lesiones del SNC y TC o RM (con o sin contraste) para las lesiones que no sean del SNC.

E.4

Principal exclusion criteria

- Prior treatment with a Smoothened inhibitor
- Systemic anticancer treatment within 2 weeks before first dose of study treatment
- Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment.
- Patients who have neuromuscular disorders that are associated with elevated CK
- Any concurrent severe and/or uncontrolled medical conditions that in the investigator?s opinion could put the patient at greater risk for treatment-related toxicities or confound the interpretation of clinical outcomes.
- Impaired cardiac function
- Clinically significant heart disease
- Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C
- Impairment of GI function or GI disease
- Major surgery, serious illness, or traumatic injury within 2 weeks of first dose of study treatment.
- Unresolved toxicity greater than CTCAE grade 1 from previous anticancer therapy
- Patients anticipated to require major surgery within the first 8 weeks of treatment
- Patients who require a nasogastric tube for drug administration
- Patients on concomitant treatment with drugs that are recognized to cause rhabdomyolysis
- Patients receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9.
- Patients receiving unstable or increasing doses of corticosteroids
- Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 2 weeks before first dose of study treatment, and for the duration of the study
- Investigational agents within 4 weeks or ? 5 x t1/2 (whichever is longer) before first dose of study treatment.
- Pregnant females.
- Patients who are not willing to apply highly effective contraception.
- Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment.

Other protocol defined exclusion criteria may apply.

Criterios de exclusión principales para los grupos 1 y 2 aleatorizados
Tratamiento previo con un inhibidor de la Smoothened
Pacientes que presenten alteraciones neuromusculares que estén asociadas con elevación de la CK (por ejemplo, miopatías inflamatorias, distrofia muscular, esclerosis lateral amiotrófica, atrofía muscular espinal).
Pacientes en tratamiento concomitante con fármacos que se reconoce que causan rabdomiolisis, como inhibidores de la HMG CoA (estatinas), clofibrato y gemfibrozil y que no pueda ser suspendido por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio. Si es imprescindible que el paciente mantenga el tratamiento con una estatina para controlar la hiperlipidemia, sólo puede utilizarse pravastatina con máxima precaución.
Pacientes que reciban tratamiento con medicaciones que se conoce que son inhibidores o inductores potentes de CYP3A4/4 o que sean metabolizados por CYP2B6 y CYP2C9, con estrechos índices terapéuticos que no puedan ser suspendidos por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio y durante todo el estudio.
Pacientes que reciban dosis crecientes e inestables de corticosteroides. Si los pacientes reciben corticosteroides para deficiencias endocrinas o síntomas asociados con el tumor, la dosis deberá haber permanecido estable (o reducida) por lo menos 5 días antes de la primera dosis del tratamiento del estudio.
Pacientes que reciban tratamiento con algún anticonvulsivante inductor enzimático que no pueda ser suspendido por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio y durante todo el estudio. Los pacientes con anticonvulsivantes no inductores enzimáticos son elegibles.
Criterios de exclusión principales para los grupos 3 y 4 no aleatorizados
Tratamiento previo con un inhibidor de la Smoothened
Pacientes que presenten alteraciones neuromusculares que estén asociadas con elevación de la CK (por ejemplo, miopatías inflamatorias, distrofia muscular, esclerosis lateral amiotrófica, atrofía muscular espinal).
Pacientes en tratamiento concomitante con fármacos que se reconoce que causan rabdomiolisis, como inhibidores de la HMG CoA (estatinas), clofibrato y gemfibrozil y que no pueda ser suspendido por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio. Si es imprescindible que el paciente mantenga el tratamiento con una estatina para controlar la hiperlipidemia, sólo puede utilizarse pravastatina con máxima precaución.
Pacientes que reciban tratamiento con medicaciones que se conoce que son inhibidores o inductores potentes de CYP3A4/4 o que sean metabolizados por CYP2B6 y CYP2C9, con estrechos índices terapéuticos que no puedan ser suspendidos por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio y durante todo el estudio.
Pacientes que reciban dosis crecientes e inestables de corticosteroides. Si los pacientes reciben corticosteroides para deficiencias endocrinas o síntomas asociados con el tumor, la dosis deberá haber permanecido estable (o reducida) por lo menos 5 días antes de la primera dosis del tratamiento del estudio.
Pacientes que reciban tratamiento con algún anticonvulsivante inductor enzimático que no pueda ser suspendido por lo menos 2 semanas antes de la primera dosis del tratamiento del estudio y durante todo el estudio. Los pacientes con anticonvulsivantes no inductores enzimáticos son elegibles.

E.5 End points

E.5.1

Primary end point(s)

ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR).

Tasa de respuesta global (TRG) definida como el porcentaje de pacientes con mejor respuesta global de respuesta completa (RC) o de respuesta parcial (RP). (Según las pautas de respuesta del tumor y los criterios para meduloblastoma, véase Suplemento 1)

E.5.1.1

Timepoint(s) of evaluation of this end point

every 8 weeks

cada 8 semanas

E.5.2

Secondary end point(s)

- PFS (progression free survival)
- DoR (duration of response)
- OS (overall survival)
- Adverse and serious adverse events, clinically significant changes in hematology and chemistry values, assessment of physical and/or neurological examinations, vital signs, electrocardiograms, bone x-rays, dental x-rays, and dental exams (as appropriate for age)
- PK (Cmin)

La SLP se define como el tiempo desde la fecha de la aleatorización hasta la fecha del evento definido como la primera progresión documentada o muerte por cualquier causa

E.5.2.1

Timepoint(s) of evaluation of this end point

As defined in table 7-1 of the protocol.
Adverse events: continuously.

Ver tabla 7-1 del Protocolo.

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

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

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

Yes

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

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

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

Australia

Belgium

Brazil

Canada

Czech Republic

France

Germany

Hungary

Italy

Netherlands

Poland

Spain

Switzerland

United Kingdom

United States

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

Last patient last visit (LPLV)

Última visita del último paciente (LPLV)

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

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

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

Children >= 4 months of age

Niños >= 4 meses de edad

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

F.4.2.2

In the whole clinical trial

109

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)

Expected normal treatment of that condition.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-01-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-10-05

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Orphan Designation Number:
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