Clinical Trials Register

Summary
EudraCT Number:	2013-004864-69
Sponsor's Protocol Code Number:	HSJD-HR-NB-Ch14.18
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-04-01
Trial 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

2013-004864-69

A.3

Full title of the trial

Phase II single arm institutional study to assess Dinutuximab combined with the cytokines granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma not eligible to other immunotherapy trials

Ensayo Clínico de Fase II unicéntrico, no controlado, de Dinutuximab con las citoquinas factor estimulante de colonias de granulocitos y macrófagos (GM-CSF) e IL-2, en pacientes con neuroblastoma de alto riesgo que no son candidatos para otros ensayos de inmunoterapia

A.3.1

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

Phase II clinical trial of dinutuximab in high risk neuroblastoma.

Ensayo clínico fase II de dinutuximab en neuroblastoma de alto riesgo.

A.4.1

Sponsor's protocol code number

HSJD-HR-NB-Ch14.18

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	Fundació Sant Joan de Deu de Barcelona
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundació Sant Joan de Deu
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MFAR
B.5.2	Functional name of contact point	Dpto Investigacion
B.5.3	Address:
B.5.3.1	Street Address	Secretari Coloma 64-68 esc B entlo 5
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08024
B.5.3.4	Country	Spain
B.5.4	Telephone number	34934344412119
B.5.5	Fax number	34932531168
B.5.6	E-mail	investigacion@mfar.net

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	Dinutuximab
D.3.2	Product code	Ch14.18
D.3.4	Pharmaceutical form	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	DINUTUXIMAB
D.3.9.3	Other descriptive name	DINUTUXIMAB
D.3.9.4	EV Substance Code	SUB130362
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	3.5
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	Yes
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	Yes
D.2.1.1.1	Trade name	Leukine
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis
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.3.1	Product name	Leukine
D.3.2	Product code	PR2
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.2	Current sponsor code	PR2
D.3.9.3	Other descriptive name	PR2
D.3.9.4	EV Substance Code	SUB10450MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	Yes
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	Yes
D.2.1.1.1	Trade name	Leukine
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis
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.3.1	Product name	Leukine
D.3.2	Product code	PR2
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.2	Current sponsor code	PR3
D.3.9.3	Other descriptive name	PR3
D.3.9.4	EV Substance Code	SUB10450MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(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	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	Yes
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

High-risk neuroblastoma

Neuroblastoma de alto riesgo

E.1.1.1

Medical condition in easily understood language

High-risk neuroblastoma

Neuroblastoma de alto riesgo

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10029260
E.1.2	Term	Neuroblastoma
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 evaluate safety of the triple COG immunotherapy schema with the monoclonal antibody Dinutuximab + cytokines (GM-CSF and IL2) and isotretinoin (13-cis-retinoic acid, or RA) in patients with high-risk neuroblastoma who have achieved a CR or VGPR of the macroscopic disease in our institution.

Evaluar la seguridad del esquema de inmunoterapia triple de COG con el anticuerpo monoclonal Dinutuximab + citoquina (GM-CSF y IL-2) e isotretionina (13 cis -ácido retinoico) en pacientes con neuroblastoma de alto riesgo que hayan alcanzado RC o muy buena respuesta parcial (VGPR) de la enfermedad macroscópica en nuestra institución.

E.2.2

Secondary objectives of the trial

To assess response of minimal residual disease (MRD) of the anti-GD2 monoclonal antibody Dinutuximab combined with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma (NB). More precisely, to apply real-time quantitative RT-PCR to test the hypothesis that minimal residual
disease content of BM after the first treatments with Dinutuximab/GM-CSF has significant prognostic impact on relapse-free survival.

Determinar respuesta en términos de enfermedad residual mínima (MRD) del anticuerpo monoclonal Dinutuximab combinado con el factor estimulante de colonias de macrófagos (GM-CSF) e IL-2 en pacientes con neuroblastoma de alto riesgo. Mas precisamente, aplicar RT-PCR para probar la hipótesis que la enfermedad residual mínima contenida en la médula ósea después del primer tratamiento con Dinutuximab/GM-CSF tiene un impacto pronóstico significativo en la supervivencia liblre de recaída.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnosis of neuroblastoma as defined by international criteria by histopathology or bone marrow metastases.
2. Neuroblastoma, as defined by risk-related treatment guidelines and the International Neuroblastoma Staging System, stage 4 with (any age) or without (>18 months) MYCN-amplification, or MYCN-amplified neuroblastoma other than stage 1, or high-risk neuroblastoma defined based on the 3-gene molecular profile.
Group 1 patients have neuroblastoma (as defined above) resistant to standard therapy, as evidenced by incomplete response in bone marrow, but no MIBG-avid soft tissue or bone tumor and no progressive disease.
Group 2 patients have no evidence of measurable disease, i.e., are in CR/VGPR from neuroblastoma (as defined above).
3. Signed informed consent indicating awareness of the investigational nature of this program.

1. Diagnóstico de neuroblastoma según lo definido por los criterios internacionales por histopatología o metástasis de médula ósea.
2. Neuroblastoma (según la definición de las directrices de tratamiento relacionado con el riesgo y el International Neuroblastoma Staging System), estadio 4 con amplificación MYCN (cualquier edad) o sin amplificación MYCN (> 18 meses), o neuroblastoma MYCN-amplificado distinto al estadio 1, o neuroblastoma de alto riesgo definido basado en el patrón de expresión de 3 genes.
Grupo 1, los pacientes tienen neuroblastoma (como se define anteriormente) resistente a la terapia estándar, evidenciado por respuesta incompleta en médula ósea, pero no tumores MIBG-avid en tejido blando o hueso y sin enfermedad progresiva.
Grupo 2, los pacientes no tienen evidencia de enfermedad medible, es decir, están en CR / VGPR de neuroblastoma (como se define anteriormente).
3. Consentimiento firmado que indica el conocimiento de la naturaleza de investigación de este programa

E.4

Principal exclusion criteria

1. Existing severe major organ dysfunction, i.e., renal., cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity >/= grade 3.
2. Progressive disease or MIBG-avid soft tissue/bone tumor.
3. Active life-threatening infection.
4. Inability to comply with protocol requirements.
5. Patient is elegible for SIOP HR-NB-01 protocol.

1. Disfunción orgánica mayor o severa, es decir, renal, cardíaca, hepática, neurológica, pulmonar, gastrointestinal o toxicidad de grado >/= 3.
2. Enfermedad progresiva o tumor MIBG-avid de tejido blando/hueso.
3. Infecciones activas potencialmente mortales.
4. Incapacidad para cumplir con los requisitos del protocolo.
5. El paciente es elegible para el protocolo SIOP HR-NB-01.

E.5 End points

E.5.1

Primary end point(s)

Safety, toxicities: The safety and tolerability of the treatment will be determined by means of type, incidence, severity, timing, seriousness, and relatedness; of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI-CTCAE v 4.0.

Seguridad, toxicidad: La seguridad y tolerabilidad del tratamiento a estudio se evaluará por medio de la descripción de los efectos adversos que incluirá tipo, incidencia, severidad, momento de aparición, gravedad y relación con el tratamiento de los acontecimientos adversos reportados, exámenes físicos y determinaciones de laboratorio. La toxicidad será tabulada según la versión 4.0 del NCI-CTCAE.

E.5.1.1

Timepoint(s) of evaluation of this end point

Every patient visit, during his/her participation in the clinical trial

En cada visita del paciente durante su participación en el ensayo clínico.

E.5.2

Secondary end point(s)

Rate of BM response for patients with detectable minimal residual disease in the BM after the first treatment with Dinutuximab/GM-CSF and relation with relapse-free survival. Relapsed-free survival: Defined as the time from the day of start of treatment to the first evidence of progression as defined by International Response Criteria (Brodeur et al., 1993) or death from any cause. If the patient does not have a documented date of progression or death, then PFS will be censored at the date of last adequate assessment.

Tasa de respuesta BM para los pacientes con enfermedad residual mínima detectable en el BM después del primer tratamiento con Dinutuximab/GM-CSF y su relación con la supervivencia libre de recaída. Supervivencia libre de recaída: Se define como el tiempo desde el día de inicio del tratamiento hasta la primera evidencia de progresión según la definición de los criterios internacionales de respuesta (Brodeur et al, 1993) o muerte por cualquier causa. Si el paciente no tiene una fecha documentada de progresión o muerte, entonces PFS será censurado en la fecha de la última evaluación adecuada.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. BM studies at end of cycles 2 and 4 and after the 6th cycle of RA. Subsequently, BM studies are repeated in conjunction with MIBG or PET scan through 2 years in patients with history of BM or cortical bone involvement, but are repeated ~every 6 months in other patients (e.g., patients who were stage 4 by virtue of metastases in
distant lymph nodes).
2. CT or MRI of primary site approximately every 3 months through 1 year.
3. 99mTc-MDP-bone approximately every 3 months while on study until normal.
4. MIBG or PET scan approximately every 3 months through 2 years.

1. Estudios de MO al final de los ciclos 2, 4 y después del sexto ciclo de RA. Posteriormente, los estudios MO se repitetirán en conjunto con MIBG o PET durante 2 años en pacientes con antecedentes de MO o afectación ósea cortical, pero se repiten ~ cada 6 meses en los demás casos (por ejemplo, los pacientes que se encontraban en estadio 4, en virtud de las metástasis en ganglios linfáticos distantes).
2. TC o RM de sitio primario aproximadamente cada 3 meses, hasta 1 año.
3. 99mTc-MDP-hueso aproximadamente cada 3 meses, durante el estudio hasta prueba de imagen normal.
4. MIBG o PET aproximadamente cada 3 meses, por 2 años.

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

The study will be considered closed from a normative point of view after data on primary and secondary variables are sufficiently prepared for its initial publication.

El ensayo se considerará cerrado desde el punto normativo, una vez los datos de la variable primaria y secundaria estén lo suficientemente maduros para su publicación inicial.

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

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

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.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

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

The highest incidence of neuroblastoma is in the first 2 years of life, 80% before 5 years of age, less than 2% over 18 years old. Subjects usually are incapable of giving consent personally in this study.

La mayor incidencia de neuroblastoma se da en los 2 primeros años de vida, el 80% antes de los 5 años y menos del 2% en mayores de 18 años. Los sujetos habitualemente estarán incapacitados para dar el consentimiento personalmente en este estudio.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Normal practise for the disease under study

Práctica habitual en la enfermedad a estudio

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

2014-05-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-10

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
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