Clinical Trials Register

Summary
EudraCT Number:	2006-001489-17
Sponsor's Protocol Code Number:	SIOPENRNET003
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-06-30
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

Greece - EOF

A.2

EudraCT number

2006-001489-17

A.3

Full title of the trial

High Risk Neuroblastoma Study 1.7 of SIOP-Europe (SIOPEN)
R4 randomization for the use of the chimeric anti-GD2 antibody ch14.18

Μελέτη Νευροβλαστώματος Υψηλού Κινδύνου 1.7 της SIOP-EUROPE (SIOPEN).
Τυχαιοποίηση R4 για τη χρήση του χιμαιρικού αντι-GD2 αντισώματος ch14.18

A.3.1

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

High Risk Neuroblastoma Study

Μελέτη Νευροβλαστώματος Υψηλού Κινδύνου

A.3.2

Name or abbreviated title of the trial where available

HR-NBL-1.7/SIOPEN

A.4.1

Sponsor's protocol code number

SIOPENRNET003

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	ST. ANNA KINDERKREBSFORSCHUNG e.V.
B.1.3.4	Country	Austria
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	CHILDREN'S CANCER RESEARCH INSITUTE (CCRI)
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CCRI
B.5.2	Functional name of contact point	Ingrid PRIBILL
B.5.3	Address:
B.5.3.1	Street Address	Zimmermannplatz 10
B.5.3.2	Town/ city	Wien
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	00431404704960
B.5.5	Fax number	00431404707430
B.5.6	E-mail	ingrid.pribill@ccri.at

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	Yes
D.2.5.1	Orphan drug designation number	P/0094/2014
D.3 Description of the IMP
D.3.1	Product name	Chimeric antibody ch14.18/CHO
D.3.2	Product code	ch14.18/CHO
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ch14.18/CHO
D.3.9.1	CAS number	1613303-02-8
D.3.9.2	Current sponsor code	APN311
D.3.9.3	Other descriptive name	CH14.18
D.3.9.4	EV Substance Code	SUB130798
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	4.5
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	Proleukin 18 x 10^6 IU
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS Pharma
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.3.1	Product name	aldesleukin
D.3.4	Pharmaceutical form	Powder for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aldesleukin
D.3.9.1	CAS number	110942-02-4
D.3.9.3	Other descriptive name	ALDESLEUKIN
D.3.9.4	EV Substance Code	SUB05303MIG
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	1.1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	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	ETOPOSIDE/PHARMACHEMIE
D.2.1.1.2	Name of the Marketing Authorisation holder	CHEMIPHARM S.G. DETSAVES & Co.
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	Etoposide
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	Etoposide
D.3.9.1	CAS number	117091642
D.3.9.3	Other descriptive name	ETOPOSIDE PHOSPHATE
D.3.9.4	EV Substance Code	SUB13772MIG
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	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	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	PARAPLATIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Hellas SA
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	Carboplatine
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	Carboplatin
D.3.9.1	CAS number	41575-94-4
D.3.9.3	Other descriptive name	PARAPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
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)	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	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	CISPLATIN/HOSPIRA
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA UK LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	CISPLATIN
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.3	Other descriptive name	CISPLATIN
D.3.9.4	EV Substance Code	SUB07483MIG
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	1
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	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	ENDOXAN
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER HELLAS LTD
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	CYCLOPHOSPHAMIDE
D.3.4	Pharmaceutical form	Powder for solution for injection
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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.3	Other descriptive name	ANHYDROUS CYCLOPHOSPHAMIDE
D.3.9.4	EV Substance Code	SUB121739
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	500 to 1000
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	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	DOXORUBIN
D.2.1.1.2	Name of the Marketing Authorisation holder	CHEMIPHARM S.G. DETSAVES & Co.
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	DOXORUBICINE
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOXORUBICIN
D.3.9.1	CAS number	23214-92-8
D.3.9.3	Other descriptive name	ADRIAMYCIN
D.3.9.4	EV Substance Code	SUB01827MIG
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	2
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: 8
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	VINCRISTINE/PHARMACHEMIE
D.2.1.1.2	Name of the Marketing Authorisation holder	CHEMIPHARM S.G. DETSAVES & Co.
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	VINCRISTINE
D.3.4	Pharmaceutical form	Solution for injection/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	VINCRISTINE
D.3.9.1	CAS number	2068-78-2
D.3.9.3	Other descriptive name	VCR
D.3.9.4	EV Substance Code	SUB05101MIG
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	1 to 2
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: 9
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	BUSILVEX
D.2.1.1.2	Name of the Marketing Authorisation holder	PIERRE FABRE MEDICAMENT
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.3.1	Product name	BUSULFAN
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUSULFAN
D.3.9.1	CAS number	55-98-1
D.3.9.3	Other descriptive name	Busulfex; Busulphan
D.3.9.4	EV Substance Code	SUB05993MIG
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	6
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: 10
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	MELPHALAN
D.2.1.1.2	Name of the Marketing Authorisation holder	ASPEN PHARMA TRADING LTD
D.2.1.2	Country which granted the Marketing Authorisation	Iceland
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	MELPHALAN
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MELPHALAN
D.3.9.1	CAS number	3223-07-2
D.3.9.3	Other descriptive name	MELPHALAN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB126965
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	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: 11
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	HYCAMTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS EUROPHARM LIMITED
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.3.1	Product name	HYCAMTIN
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOPOTECAN
D.3.9.1	CAS number	119413-54-6
D.3.9.3	Other descriptive name	TOPOTECAN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04921MIG
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	1
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: 12
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	A-CNOTREN
D.2.1.1.2	Name of the Marketing Authorisation holder	PHARMATHEN SACI
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	A-CNOTREN
D.3.4	Pharmaceutical form	Capsule, soft
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	ISOTRETINOIN
D.3.9.1	CAS number	4759-48-2
D.3.9.3	Other descriptive name	13-cis RA
D.3.9.4	EV Substance Code	SUB08341MIG
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	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)	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: 13
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	GRANULOKINE
D.2.1.1.2	Name of the Marketing Authorisation holder	AMGEN EUROPE B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Greece
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	GRANULOKINE
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	FILGRASTIM
D.3.9.1	CAS number	121181-53-1
D.3.9.3	Other descriptive name	G-CSF
D.3.9.4	EV Substance Code	SUB07627MIG
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	0.3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	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

Yψηλού Κνδύνου Νευροβλάστωμα

E.1.1.1

Medical condition in easily understood language

Neuroblastoma (the most common extracranial solid cancer in childhood and the most common cancer in infancy)

Νευροβλάστωμα (το νευροβλάστωμα είναι ο συχνότερος εξωκρανιακός όγκος της παιδικής ηλικίας και ο συχνότερος καρκίνος της νεογνικής ηλικίας)

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	19.0
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 test the hypothesis that the modified N7 induction regimen will improve the metastatic response rates or event free survival (EFS) as compared to Rapid COJEC.
• To test the hypothesis that the addition of subcutaneous aldesleukin (IL-2, (Proleukin®)) to immunotherapy with chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO) given as continuous infusion in addition to differentiation therapy with isotretinoin (13-cis-RA) following myeloablative therapy (MAT) and autologous SCR, will improve EFS in patients with high-risk neuroblastoma (stage 4 disease or stages 2 and 3 with MYCN amplification all over the age of one, or infants with MYCN amplification).

• Να ελεγχθεί η υπόθεση ότι η χημειοθεραπευτική αγωγή εφόδου με τροποποιημένο σχήμα Ν7 θα βελτιώσει τα ποσοστά ανταπόκρισης της μεταστατικής νόσου και την ελεύθερη της νόσου επιβίωση (EFS) σε σύγκριση με το χημειοθεραπευτικό σχήμα Rapid COJEC.
• Να ελεγχθεί η υπόθεση πως η προσθήκη υποδόρια χορηγούμενης aldesleukin (IL-2, Proleukin®) στην ανοσοθεραπεία με χιμαιρικό μονοκλωνικό αντίσωμα 14.18 anti-GD2 που παράχθηκε σε κύτταρα ωοθηκών κινέζικου χάμστερ (CHO) (ch14.18/CHO) και που δίδεται ως συνεχής έγχυση, επιπρόσθετα της θεραπείας διαφοροποίησης με isotretinoin (13-cis-RA), έπειτα απο μυελοαφανιστική θεραπεία (ΜΑΤ) και αυτόλογο SCR, θα βελτιώσει την EFS σε ασθενείς με νευροβλάστωμα υψηλού κινδύνου (ασθενείς με νόσο σταδίου 4 ή σταδίου 2 και 3 με ενίσχυση του ογκογονιδίου MYCN και ηλικία μεγαλύτερη του ενός έτους, ή βρέφη με πολλαπλασιασμό MYCN).

E.2.2

Secondary objectives of the trial

• To evaluate BM response to Rapid COJEC and modified N7 with ICH-GD2, AIPF and QRT-PCR.
• To evaluate response to Rapid COJEC and modified N7 induction therapies with mIBG for standardised scoring of skeletal response.
• To determine the effect of response of metastatic disease to induction therapy on EFS and OS
• To investigate the relationship between complete surgical resection of the primary tumour and OS.
• To collect data on selected, validated biological features and to determine the effect of these on EFS, the incidence of relapse/progression and OS.
• To compare the toxicity, in particular episodes of febrile neutropenia and grade 3-4 infection, associated with induction therapy with Rapid COJEC and modified N7.
• To sample PK data to calculate the effect of AUC as achieved according to dosing guidelines.
• To monitor drug levels of MAT and relate them to patients outcome and toxicity.

• Να αξιολογηθεί η ανταπόκριση του μυελού των οστών στο σχήμα εφόδου Rapid COJEC και στο τροποποιημένο σχήμα εφόδου Ν7 με ICH-GD2, AIPF και QRT-PCR.
• Να αξιολογηθεί η ανταπόκριση στη θεραπεία με Rapid COJEC & τροποπ. Ν7, με mIBG σε τυποποιημένη βαθμολόγηση της σκελετικής ανταπόκρισης.
• Να καθοριστεί το αποτέλεσμα της θεραπείας εφόδου στην EFS και την OS.
• Να διερευνηθεί η σχέση μεταξύ πλήρους χειρουργικής εκτομής του πρωτογενούς όγκου και OS.
• Να συλλεχθούν δεδομένα σε επιλεγμένα, έγκυρα βιολογικά χαρακτηριστικά και να καθοριστεί το αποτέλεσμα τους στην EFS, τη συχνότητα των υποτροπιών και την OS.
• Να συγκριθεί η τοξικότητα σε συγκεκριμένα επεισόδια εμπύρετης ουδετεροπενίας και λοιμώξεις 3-4 βαθμού σχετιζόμνες με θεραπεία εφόδου.
• Να συλλεχθούν φαρμακοκινητικά (PK) δεδομένα για τον υπολογισμό της AUC, όπως αυτή επετεύχθη σύμφωνα με τις οδηγίες δοσολογίας.
• Να μετρηθούν τα επίπεδα των φαρμάκων της ΜΑΤ και η σχέση τους με έκβαση ασθενών και τοξικότητα.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Established diagnosis of neuroblastoma according to the International Neuroblastoma
Staging System (INSS).
• Age below 21 years.
• High risk neuroblastoma defined as either:
a) INSS stage 2, 3, 4, and 4s with MYCN amplification, or
b) INSS stage 4 without MYCN amplification aged > 12 months at diagnosis
• Patients who have received no previous chemotherapy except for one cycle of etoposide and carboplatin (VP16 / Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).
• Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met.
• Tumour cell material available for determination of biological prognostic factors.
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
• Provisional follow up of 5 years.

• Επιβεβαιωμένη διάγνωση νευροβλαστώματος σύμφωνα με το Διεθνές Σύστημα Σταδιοποίησης Νευροβλαστώματος (International Neuroblastoma Staging System INSS)
• Ηλικία κάτω των 21 ετών
• Το νευροβλάστωμα υψηλού κινδύνου ορίζεται ως:
α) INSS σταδίου 2, 3, 4 και 4 με πολλαπλασιασμό του MYCN, ή
β) INSS σταδίου 4 χωρίς πολλαπλασιασμό του MYCN με ηλικία > 12 μηνών κατά τη διάγνωση.
• Ασθενείς που δεν έχουν λάβει προηγουμένως χημειοθεραπεία παρά μόνο έναν κύκλο ετοποσίδης και καρβοπλατίνης (VP16 / Carbo). Σε αυτές τις περιπτώσεις οι ασθενείς θα λάβουν σχήμα εφόδου Rapid COJEC και ο πρώτος κύκλος Rapid COJEC μπορεί να αντικατασταθεί απο VP16 / Carbo (ετοποσίδη / καρβοπλατίνη).
• Έντυπο συγκατάθεσης ασθενούς μετά από ενημέρωση, που περιλαμβάνει συγκατάθεση των γονέων ή του νόμιμου κηδεμόνα για τους ανήλικους, για την συμμετοχή σε τυχαιοποιημένη μελέτη, υπό τη προϋπόθεση ότι θα πληρούνται τα κριτήρια τυχαιοποίησης.
• Διαθέσιμο υλικό καρκινικών κυττάρων για τον καθορισμό βιολογικών προγνωστικών παραγόντων.
• Γυναίκες με δυνατότητα τεκνοποίησης πρέπει να έχουν ένα αρνητικό τέστ κυήσεως. Ασθενείς με δυνατότητα τεκνοποίησης πρέπει να συγκατατεθούν να χρησιμοποιούν αποτελεσματική μέθοδο αντισύλληψης. Γυναίκες που θηλάζουν πρέπει να συγκατατεθούν να διακόψουν το θηλασμό.
• Καταχώρηση όλων των στοιχείων επιλεξιμότητας στο Κέντρο Δεδομένων Μελέτης εντός 6 εβδομάδων απο τη διάγνωση.
• Ενδεχόμενο παρακολούθησης εως 5 έτη.

E.4

Principal exclusion criteria

Any negative answer concerning the inclusion criteria of the study, R3 or R4 will render the patient ineligible for the corresponding therapy phase.

Οποιαδήποτε αρνητική απάντηση σχετικά με τα κριτήρια ένταξης της μελέτης, R3 ή R4, καθιστούν τον/την ασθενή μη επιλέξιμο για την αντίστοιχη φάση θεραπείας.

E.5 End points

E.5.1

Primary end point(s)

Randomization 3:
Two co-primary endpoints will be investigated:
1) Metastatic Response after induction treatment
• No skeletal uptake on MiBG
• Negative bone marrow aspirates and trephines
• Αbsence of other metastatic sites
2) Event Free Survival (EFS)
• disease progression or relapse
• death from any cause
• second neoplasm

Randomization 2: Imunnotherapy - Question Ch14/18/CHO with or without aldesleukin (IL-2)

Primary endpoint: 3-year EFS calculated from the date of the second randomization.
The following will be considered as events:
• disease progression
• death from any cause
• second neoplasm

Tυχαιοποίηση 3:
Δύο συμπρωταρχικά καταληκτικά σημεία θα διερευνηθούν:
1) Η ανταπόκριση των μεταστάσεων μετά τη χημειοθεραπεία εφόδου
• Απουσία σκελετικής πρόσληψης στο MiBG
• Αρνητικά δείγματα αναρρόφησης ή τρυπανισμού του μευλού των οστών
• Απουσία άλλων εστιων μετάστασης
2) Ελεύθερη Συμβάντων Επιβίωση (EFS)
• Εξέλιξη ή υποτροπή της νόσου
• Θάνατος από οποιαδήποτε αιτία
• Δεύτερη νεολασία

Τυχαιοποίηση 2: Ανοσοθεραπεία - συμβολή του Ch14/18/CHO με ή χωρίς αλδεσλευκίνη (IL-2)

Κύριο Καταληκτική Σημείο: 3 ετής Επιβίωση Ελεύθερη Συμβάντων (EFS), υπολογιζόμενη από την ημερομηνία της δεύτερης τυχαιοποίησης
Τα ακόλουθα θα θεωρούνται ως συμβάντα:
• Εξέλιξη ή υποτροπή της νόσου
• Θάνατος από οποιαδήποτε αιτία
• Δεύτερη νεολασία

E.5.1.1

Timepoint(s) of evaluation of this end point

The final analysis will be performed 18 months from R1 and R2 and 6 months from R3, after the inclusion of the last patient

Η τελική ανάλυση θα πραγματοποιηθεί 18 μήνες μετά την τυχαιοποίηση R1 και R2 και 6 μήνες μετά την τυχαιοποίηση R3, μετά την ένταξη του τελευταίου ασθενούς

E.5.2

Secondary end point(s)

• Overall Survival (calculated from the date of randomization to the death from any cause)
• Cumulative incidence of disease relapse/progression and deaths without relapse/progression
• Cumulative incidence of treatment-related mortality and of disease-related mortality
• Response [Overall Response (incl. primary tumor after induction0, skeletal response on MiBG, BM response]
• Toxicity (in particular, comparison of the frequency of episodes of FNP and Grade 3-4 infections during induction treatments [modified N7 vs. COJEC)
• Response rates, survival, EFS and the cumulative incidence of relapse/progression will be related to prognostic factors inc.: biological factors [MYCN amplification, SCAs, expression signature] of the neuroblastoma cells in the bone marrow and/or the primary tumor
• Serological factors (serum concentrations at diagnosis of LDH, ferritin, neuron specific enolase)
• Urinary catecholamines at diagnosis (VMA, HVA, dopamine)

• Συνολική Επιβίωση (υπολογιζόμενη από την ημερομηνία τυχαιοποίησης έως την ημερομηνία θανάτου, από οποιαδήποτε αιτία)
• Αθροιστική επίπτωση των υποτροπών/της εξέλιξης της νόσου και των θανάτων απουσία υποτροπής/εξέλιξης της νόσου.
• Αθροιστική επίπτωση της σχετιζόμενης με τη θεραπεία θνητότητας και της σχετιζόμενης με τη νόσο θνητότητας.
• Ανατπόκριση [Συνολική Ανταπόκριση (συμπεριλ. την ανταπόκριση του πρωτοπαθούς όγκου μετά τη χημειοθεραπεία εφόδου), την σκελετική ανατπόκριση στη MiBG, την ανταπόκριση του μευλού των οστών]
• Τοξικότητα (ειδικότερα, σύγκριση της συχνότητας των επεισοδίων εμπύρετης ουδετεροπενίας και Βαθμού 3-4 λοιμώξεων στη διάρκεια της χημειοθεραεπίας εφόδου [τροποποιημένο σχήμα N7 vs. COJEC)
• Τα ποσοστά ανταπόκρισης, τα ποσοστά επιβίωσης και EFS και η αθροιστική επίπτωση υποτροπών/περιπτώσεων εξέλιξης της νόσου θα συσχετιστούν με προγνωστικούς παράγοντες [ενίσχυση του ογκογονιδίου MYCN, SCAs) των κυττάρων του νευροβλαστώματις στο μυελό των οστών ή/κσι στον προωτοπαθή όγκο.
• Ορολογικοί παράγοντες (συγκεντρώσεις πλάσματος κατά τη διάγνωση των LDH, φερριτίνης, ειδικής κυτταρικής ενδολάσης)
•Κατεχολαμίνες ούρων κατά τη διάγνωση (VMA, HVA, ντοπαμίνη)

E.5.2.1

Timepoint(s) of evaluation of this end point

The final analysis will be performed 18 months from R1 and R2 and 6 months from R3, after the inclusion of the last patient

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

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

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

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

Yes

E.8.2.3.1

Comparator description

Xημειοθεραπεία εφόδου Rapid COJEC

Induction chemotherapy Rapid COJEC

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

120

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

Austria

Belgium

Czech Republic

Denmark

Finland

France

Greece

Hungary

Ireland

Israel

Italy

Norway

Poland

Portugal

Serbia

Slovakia

Spain

Sweden

Switzerland

United Kingdom

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

Τhe final analysis will be performed 18 months after the inclusion of the last patient.

To evaluate the difference of EFS between the randomized arms, all randomized patients will be analyzed and the comparison of treatment regimens will be performed on the ITT population.

The 3-year EFS will be estimated by the Kaplan-Meier method.

H τελική ανάλυση θα πραγματοποιηθεί 18 μήνες μετά την ένταξη του τελευταίου ασθενούς

Προκειμένου να αξιολογηθεί η διαφορά των EFS μεταξύ των τυχαιοποιημένων θεαπευτικών σκελών της μελέτης, όλοι οι τυχαιοποιημένοι ασθενείς θα ναλυθούν και η σύγκριση μεταξύ των τυχαιοποιημένων θεραπευτικών σχημάτων θα πραγματοποιηθεί στον πληθυσμό ITT.

Η τριετής επιβίωση EFS θα υπολογιστεί με τη μέθοδο των Kaplan-Meier.

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

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:

2700

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:

530

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

2110

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)

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

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

Παιδιατρικοί ασθενείς

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

2500

F.4.2.2

In the whole clinical trial

2700

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)

Patients are enrolled in a 5-year follow-up period.
No further treatment planned

Oι ασθενείς θα εντάσσονται σε ένα 5-ετές πρόγραμμα παρακολούθησης.
Δεν έχει προγραμματιστεί καμία επιπλέον θεραπεία

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

2016-08-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-26

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

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Orphan Designation Number:
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