Clinical Trials Register

Summary
EudraCT Number:	2017-000801-19
Sponsor's Protocol Code Number:	MBMET_MEYER2017
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-09
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000801-19

A.3

Full title of the trial

An interventional, open-label, Phase II study, to evaluate safety and efficacy of standard and high-dose chemotherapy associated with craniospinal irradiation in patients with metastatic medulloblastoma and other embryonal tumours

Studio interventistico, in aperto, di Fase II, per valutare la sicurezza e l'efficacia di chemioterapia standard e ad alte dosi associata ad irradiamento craniospinale in pazienti affetti da medulloblastoma metastatico e altri tumori embrionali

A.3.1

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

A clinical study to evaluate safety and efficacy of standard and high-dose chemotherapy associated with radiotherapy in pediatric and young adults patients with metastatic medulloblastoma and other embryonal tumours

Studio clinico per valutare la sicurezza e l'efficacia di chemioterapia standard e ad alte dosi associata a radioterapia in pazienti pediatrici e giovani adulti affetti da medulloblastoma metastatico e altri tumori embrionali

A.3.2

Name or abbreviated title of the trial where available

MBMET_MEYER2017

A.4.1

Sponsor's protocol code number

MBMET_MEYER2017

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	AZIENDA OSPEDALIERO-UNIVERSITARIA MEYER
B.1.3.4	Country	Italy
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	Progetto Neuro-Oncologia Fondazione Meyer
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AZIENDA OSPEDALIERO-UNIVERSITARIA MEYER
B.5.2	Functional name of contact point	CLINICAL TRIAL OFFICE
B.5.3	Address:
B.5.3.1	Street Address	VIALE PIERACCINI 24
B.5.3.2	Town/ city	FIRENZE
B.5.3.3	Post code	50139
B.5.3.4	Country	Italy
B.5.4	Telephone number	0555662425
B.5.5	Fax number	0555662425
B.5.6	E-mail	clinicaltrialoffice@meyer.it

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	Yes
D.2.1.1.1	Trade name	METOTRESSATO TEVA - 100 MG/ML SOLUZIONE INIETTABILE 1 FLACONE DA 50 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	METOTREXATO
D.3.2	Product code	[METOTREXATO]
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METOTREXATO
D.3.9.2	Current sponsor code	HD-MTX
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.10	Strength
D.3.10.1	Concentration unit	gm/m2 gram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	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 TEVA - 1 FLACONE 50 ML 20MG/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA PHARMA B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.2	Product code	[ETOPOSIDE]
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	ETOPOSIDE
D.3.9.2	Current sponsor code	VP-16
D.3.9.3	Other descriptive name	ETOPOSIDE
D.3.10	Strength
D.3.10.1	Concentration unit	gm/m2 gram(s)/square meter
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	ENDOXAN BAXTER - 500 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONE VETRO TIPO III 500 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CICLOFOSFAMIDE
D.3.2	Product code	[CICLOFOSFAMIDE]
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	CICLOFOSFAMIDE
D.3.9.2	Current sponsor code	HD-EDX
D.3.9.3	Other descriptive name	CYCLOPHOSPHAMIDE
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	800
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	CARBOPLATINO ACTAVIS - 10 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO 50 MG/5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACTAVIS ITALY S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CARBOPLATINO
D.3.2	Product code	[CARBOPLATINO]
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	CARBOPLATINO
D.3.9.2	Current sponsor code	CBCDA
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	800
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	TEPADINA - 100 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO(VETRO) - 10MG/ML 1 FLACONCINO DA 100 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ADIENNE S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	TIOTEPA
D.3.2	Product code	[TIOTEPA]
D.3.4	Pharmaceutical form	Powder 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	TIOTEPA
D.3.9.2	Current sponsor code	HD-TT
D.3.9.3	Other descriptive name	THIOTEPA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	NAVELBINE - 10 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONE 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	PIERRE FABRE PHARMA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	VINORELBINA
D.3.2	Product code	[VINORELBINA]
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	VINORELBINA
D.3.9.2	Current sponsor code	VINORELBINA
D.3.9.3	Other descriptive name	VINORELBINE
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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	CECENU
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	LOMUSTINA
D.3.2	Product code	[LOMUSTINA]
D.3.4	Pharmaceutical form	Capsule, hard
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	LOMUSTINA
D.3.9.2	Current sponsor code	CCNU
D.3.9.3	Other descriptive name	LOMUSTINE
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	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

Metastatic medulloblastoma and other embryonal tumours

Medulloblastoma metastatico e altri tumori embrionali (classificazione WHO 2007)

E.1.1.1

Medical condition in easily understood language

Brain tumours

Neoplasie cerebrali

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10027107
E.1.2	Term	Medulloblastoma
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate safety of standard and high-dose chemotherapy associated with craniospinal irradiation in pediatric and young adult patients with metastatic MB or other embryonal tumours.

Valutare la sicurezza della somministrazione di chemioterapia standard e ad alte dosi associata ad irradiamento craniospinale con boost sul letto chirurgico nella terapia di prima linea in pazienti pediatrici e giovani adulti affetti da MB metastatico e altri tumori embrionali

E.2.2

Secondary objectives of the trial

To evaluate the effectiveness of treatment in terms of progression-free survival, overall survival and responses to therapy.
To evaluate neuropsychological and psychological aspects, endocrinological and visual sequelae.

Valutare l'efficacia del trattamento mediante determinazione della sopravvivenza libera da progressione di malattia, della sopravvivenza globale e delle risposte al trattamento.
Valutare gli aspetti neuropsicologici e psicologici e l'incidenza di eventuali complicanze endocrinologiche e visive

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed, newly diagnosed, no previously treated patients with metastatic MB and other embryonal tumours (supratentorial primitive neuro-ectodermal tumors (sPNET) and pinealoblastoma, anaplastic large cell or partial resecate medulloblastoma (residue volume > 1,5 cm2), according to WHO 2007 classification. Patients underwent surgery
2. Males and females aged >3 years and <21 years;
3. Life expectancy = 4 weeks
4. Karnofsky / Lansky = 40%
5. Adequate hematological function (leucocyte = 2.0 x 10^9/l - Hemoglobin = 10 g/dl - platelet = 50 x 10^9 /l);
6. Adequate liver function (total bilirubin = 2.5 x ULN - ALT/AST = 5.0 x ULN);
7. Adequate renal function (serum creatinine = 1.5 x ULN);
8. Written informed consent obtained from the patient/parents or legal representative;
9. Availability to trial treatment and ability to be compliant with the protocol

1. Pazienti con MB metastatico e altri tumori embrionali (PNET sovratentoriali (sPNET) e pinealoblastomi, , medulloblastomi anaplastici/a grandi cellule o parzialmente resecati (volume residuo >1,5cm2), secondo classificazione WHO 2007, di prima diagnosi non precedentemente trattati (con chemio e radioterapia) e trattati solo chirurgicamente
2. Maschi e femmine di età compresa fra i 3 e i 21 anni
3. Aspettativa di vita = 4 settimane
4. Karnofsky/Lansky = 40 %
5. Funzione ematologica adeguata (Conta assoluta dei leucociti = 2.0 x 10^9/l, Emoglobina = 10 g/dl, Conta delle piastrine = 50 x 10^9 /l)
6. Funzione epatica adeguata (Bilirubina totale = 2.5 x ULN, ALT/AST = 5.0 x ULN)
7. Funzione renale adeguata (Creatinina sierica = 1.5 x ULN)
8. Consenso informato scritto da parte del paziente se maggiorenne, dei genitori o dei tutori legali
9. Disponibilità del paziente durante il trattamento e capacità di attenersi al protocollo

E.4

Principal exclusion criteria

1. Any disease or condition that contraindicates the use of the study treatment (es. serious mental retardation, brain palsy, congenital syndrome, cardiomyopathy)
2. Administration of anti-cancer therapy concomitantly to the study enrolment
3. Concomitant partecipation to other clinical trial
4. Pregnancy or breastfeeding
5. Non adequate contraception
6. Hypersensibility to active principles or excipients
7. Severe bone-marrow depression
8. Concomitant use of yellow fever vaccine or other live vaccines
9. Other contraindications reported in the SmPC

1. Evidenza di qualsiasi altra malattia o condizioni gravi che rappresentino una controindicazione alla terapia in studio (e.g. grave ritardo mentale, grave paralisi cerebrale, gravi sindromi congenite, cardiopatie)
2. Esecuzione di un ciclo di chemioterapia di 1° linea contemporaneamente all’inizio dello studio
3. Concomitante partecipazione ad altre sperimentazioni
4. Stato di gravidanza o allattamento
5. Utilizzo di metodi contraccettivi inadeguati sia da parte di pazienti di sesso femminile che maschile
6. Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti
7. Grave mielodepressione
8. Uso concomitante di vaccino per la febbre gialla o di altri vaccini vivi
9. Altre controindicazioni riportate nel RCP dei vari farmaci

E.5 End points

E.5.1

Primary end point(s)

- Percentage of subjects with neurological symptoms >=G3, evaluated according to CTCAE 4.0, not present at the beginning of postoperative chemoradiotherapy and not related to the recurrence / progression of the disease - Percentage of subjects with SAE - Percentage of subjects with SAE leading to withdrawal from the study - Mortality due to adverse events

- Proporzione di soggetti con sintomatologia neurologica >=G3, valutata secondo la CTCAE 4.0, non presente all’inizio del trattamento chemioradioterapico postoperatorio e non riconducibile a recidiva/progressione di malattia - Proporzione di soggetti con SAE e relativa tipologia - Proporzione di soggetti con SAE che determinano il ritiro dallo studio - Mortalità per eventi avversi

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months from the end of the treatment (end of follow-up)

24 mesi dalla fine del trattamento (fine follow-up).

E.5.2

Secondary end point(s)

- Progression free survival (PFS) defined as time frame between the date of the enrolment and the date tumour progression ; Overall survival (OS) defined as time frame between the date of the enrolment and the death to any cause; Difference in scoring for neuropsychological (Griffiths, Rey, BVN tests, educational learning) and psycological (PedsQL, CBCL) scales; Rate of treatment response:
- CR, complete response the complete disappearance of all radiographic and/or cytological evidence of tumor;
- PR, partial response >= 50% reduction in the product of the perpendicular diameters of the tumor with negative cytology
- SD, stable disease <= 25%reduction in tumor size
- PD, progressive disease >= 25% increase in tumor size or the appearance of tumor in previously uninvolved areas; Incidence of endocrinological and visual sequelae

- PFS definita come il tempo tra la data di arruolamento e la data di progressione o la data di morte; OS definita come il tempo tra la data di arruolamento e la data di decesso per qualsiasi causa ; Differenze nei punteggi alle scale per le valutazioni neuropsicologiche (test di Griffiths, Rey, BVN, apprendimento scolastico) e psicologiche (PedsQL, CBCL); Proporzione di risposta al trattamento:
- CR, risposta completa: completa scomparsa di segni evidenti di malattia all'esame citologico e/o radiologico
- PR, risposta parziale: riduzione >= 50% dell¿area neoplastica, misurata come prodotto dei diametri perpendicolari maggiori, con esame citologico negativo
- SD, malattia stabile: riduzione <= 25% della massa tumorale
- PD, progressione malattia: aumento >= 25% della massa tumorale o comparsa di nuove lesioni di malattia; Incidenza delle complicanze endocrinologiche e visive

E.5.2.1

Timepoint(s) of evaluation of this end point

MRI scan assessment; MRI scan assessment; Before radiotherapy, at the end of the chemioterapy and at the end of the follow-up; After induction phase and at the end of the treatment; 24 months from the end of the treatment (end of follow-up)

Ad ogni rivalutazione con RMN; Ad ogni rivalutazione RMN; Prima della radioterapia, alla fine del trattamento e alla fine del follow-up; Dopo la fase di induzione e a fine trattamento; 24 mesi dalla fine del trattamento (fine follow-up).

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

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

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

Yes

E.8.1.7.1

Other trial design description

Singolo braccio

Single arm

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.8.2.4

Number of treatment arms in the trial

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.8.4.1

Number of sites anticipated in 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

Information not present in EudraCT

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

LVLS

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.1.1.1

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)

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

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

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

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 will carry out regular clinical follow-up

I pazienti effettueranno controlli regolari secondo pratica clinica

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

2017-02-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-28

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

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