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    Summary
    EudraCT Number:2019-001068-31
    Sponsor's Protocol Code Number:HR-NBL2/SIOPEN
    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:2021-06-04
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-001068-31
    A.3Full title of the trial
    High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
    Studio 2 per il neuroblastoma ad alto rischio di SIOP-Europa-Neuroblastoma (SIOPEN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    High-Risk Neuroblastoma Study
    Studio per pazienti con neuroblastoma ad alto rischio.
    A.3.2Name or abbreviated title of the trial where available
    HR-NBL2/SIOPEN
    HR-NBL2/SIOPEN
    A.4.1Sponsor's protocol code numberHR-NBL2/SIOPEN
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGUSTAVE ROUSSY
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS “Istituto Giannina Gaslini”
    B.5.2Functional name of contact pointCoordinatore Nazionale
    B.5.3 Address:
    B.5.3.1Street AddressVia G. Gaslini, 5
    B.5.3.2Town/ cityGenova
    B.5.3.3Post code16147
    B.5.3.4CountryItaly
    B.5.4Telephone number01056362410
    B.5.5Fax number01056362714
    B.5.6E-mailalbertogaraventa@gaslini.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCisplatino
    D.3.2Product code [Cisplatino]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATINO
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor codeCisplatino
    D.3.9.3Other descriptive nameCisplatin
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVincristina
    D.3.2Product code [Vincristina]
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINCRISTINA
    D.3.9.1CAS number 57-22-7
    D.3.9.2Current sponsor codeVincristine
    D.3.9.3Other descriptive nameVincristine
    D.3.9.4EV Substance CodeSUB00059MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTiotepa
    D.3.2Product code [Tiotepa]
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTIOTEPA
    D.3.9.1CAS number 52-24-4
    D.3.9.2Current sponsor codeThiotepa
    D.3.9.3Other descriptive nameThiotepa
    D.3.9.4EV Substance CodeSUB10985MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEtoposide
    D.3.2Product code [Etoposide]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.2Current sponsor codeEtoposide
    D.3.9.3Other descriptive nameEtoposide
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVindesina
    D.3.2Product code [Vindesina]
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINDESINA SOLFATO
    D.3.9.1CAS number 53643-48-4
    D.3.9.2Current sponsor codeVindesine
    D.3.9.3Other descriptive nameVindesine
    D.3.9.4EV Substance CodeSUB00061MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCarboplatino
    D.3.2Product code [Carboplatino]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCARBOPLATINO
    D.3.9.1CAS number 41575-94-4
    D.3.9.2Current sponsor codeCarboplatino
    D.3.9.3Other descriptive nameCarboplatino
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCiclofosfamide
    D.3.2Product code [Ciclofosfamide]
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCICLOFOSFAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor codeCiclofosfamide
    D.3.9.3Other descriptive nameCyclophosphamide
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 8
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBusulfano
    D.3.2Product code [Busulfano]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUSULFANO
    D.3.9.1CAS number 55-98-1
    D.3.9.2Current sponsor codeBusulfan
    D.3.9.3Other descriptive nameBusulfan
    D.3.9.4EV Substance CodeSUB05993MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 9
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCiclofosfamide
    D.3.2Product code [Ciclofosfamide]
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCICLOFOSFAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor codeCiclofosfamide
    D.3.9.3Other descriptive nameCyclophosphamide
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 10
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDacarbazina
    D.3.2Product code [Dacarbazina]
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDACARBAZINA
    D.3.9.1CAS number 4342-03-4
    D.3.9.2Current sponsor codeDacarbazine
    D.3.9.3Other descriptive nameDacarbazine
    D.3.9.4EV Substance CodeSUB06882MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 11
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDoxorubicina
    D.3.2Product code [Doxorubicina]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDOXORUBICINA CLORIDRATO
    D.3.9.1CAS number 23214-92-8
    D.3.9.2Current sponsor codeDoxorubicina
    D.3.9.3Other descriptive nameDoxorubicin
    D.3.9.4EV Substance CodeSUB06391MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 12
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIfosfamide
    D.3.2Product code [Ifosfamide]
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.2Current sponsor codeIfosfamide
    D.3.9.3Other descriptive nameIfosfamide
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 13
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMelfalan
    D.3.2Product code [Melfalan]
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELFALAN
    D.3.9.1CAS number 148-82-3
    D.3.9.2Current sponsor codeMelphalan
    D.3.9.3Other descriptive nameMelphalan
    D.3.9.4EV Substance CodeSUB08728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    High-Risk Neuroblastoma
    Neuroblastoma ad alto rischio
    E.1.1.1Medical condition in easily understood language
    High-Risk Neuroblastoma
    Neuroblastoma ad alto rischio
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029261
    E.1.2Term Neuroblastoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    R-I:
    Comparison of the EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma.
    R-HDC:
    Comparison of the EFS rate of single HDC with busulphan and melphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with high-risk neuroblastoma.
    R-RTx:
    Comparison of the EFS rate of 21.6 Gy radiotherapy to the preoperative tumor bed versus 21.6 Gy radiotherapy and a sequential boost up to 36 Gy to the residual tumor in patients with macroscopic residual disease after HDC and surgery.
    R-1:
    Confronto dell’EFS di 2 regimi di induzione, GPOH e RAPID COJEC, in pazienti con neuroblastoma ad alto rischio.
    R-HDC:
    Confronto dell’EFS di HDC singola con busulphan e melphalan (Bu-Mel) rispetto a HDC tandem con Thiotepa seguito da Bu-Mel in pazienti con neuroblastoma ad alto rischio.
    R-RTX:
    Confronto dell’ EFS di 21,6 Gy di radioterapia su massa tumorale pre-chirurgia rispetto a 21,6 Gy di radioterapia con un aumento fino a 36 Gy sul tumore in pazienti con malattia residua macroscopica dopo HDC e chirurgia.
    E.2.2Secondary objectives of the trial
    Describe the EFS and OS from date of randomization of the whole cohort
    Describe the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after the end of induction
    Assess the correlation of the response of metastatic disease during and after induction with survival (EFS and OS)
    Describe the effect of HDC with Bu-Mel versus Thiotepa+Bu-Mel on PFS and OS
    Describe and compare the toxicity associated with RAPID COJEC and GPOH induction therapy
    Describe and compare the acute and long term toxicities of both HDC arms
    Describe the long term toxicities of dinutuximab bet
    Investigate the relationship between the quality of surgical resection of the primary tumor, local control and survival
    Investigate the impact of the radiotherapy dose on local relapse rate
    Collect data on selected circulating biomarkers, biological and genomic features to determine and compare the effect of these on response to treatment, EFS, incidence of relapse/progression and OS
    Descrivere EFS e OS dalla prima data di randomizzazione intera coorte
    Descrivere l'effetto regimi di induzione di RAPID COJEC e GPOH su malattia metastatica durante e dopo fine dell'induzione
    Valutare correlazione della risposta della malattia metastatica durante e dopo induzione con la sopravvivenza (EFS e OS)
    Descrivere effetto di HDC con Bu-Mel contro Thiotepa+Bu-Mel su PFS e OS
    Descrivere e confrontare tossicità associata al terapia induzione RAPID COJEC e GPOH
    Descrivere e confrontare tossicità acute e a lungo termine di entrambi bracci HDC
    Descrivere le tossicità a lungo termine di dinutuximab beta
    Studiare relazione qualità della resezione chirurgica tumore primario, controllo locale e sopravvivenza
    Studiare impatto della dose di radioterapia su frequenza ricaduta locale
    Raccolta dati su biomarcatori circolanti selezionati, caratteristiche biologiche e genomiche per determinare e confrontare loro effetto su risposta al trattamento, EFS, incidenza di recidiva/progressione e OS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    R-I eligibility criteria:
    - Established diagnosis of neuroblastoma according to the SIOPENmodified International Neuroblastoma Risk Group (INRG) criteria, High-risk neuroblastoma defined as:
    Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status*
    or
    L2, M or Ms neuroblastoma with MYCN amplification, any age
    - No previous chemotherapy (except one cycle of Etoposide-Carboplatin)
    - Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
    Sexually active patients must agree to use acceptable and appropriate contraception while on study drug and for one year after stopping the study drug. Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials" (Appendix 11). Female patients who are lactating must agree to stop breast-feeding.
    - Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent.
    - Patient affiliated to a social security regimen or beneficiary of the same according to local requrements.
    - Patients should be able and willing to comply with study visits and procedures as per protocol.

    R-HDC eligibility criteria:
    1) - Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery but will not be eligible for R-HDC and will not be able to pursue the trial.
    OR
    - L2, M or Ms neuroblastoma with MYCN amplification
    2) Age < 21 years
    3) Complete response (CR) or partial response (PR) at metastatic sites:
    -Bone disease: MIBG uptake (or FDG-PET uptake for MIBG-nonavid tumors) completely resolved or SIOPEN score = 3 and at least 50% reduction in mIBG score (or = 3 bone lesions and at least 50% reduction in number of FDG-PET-avid bone lesions for MIBG-nonavid tumors).
    -Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria [Park JR, JCO 2017; Burchill S, Cancer 2017].
    Other metastatic sites: complete response after induction chemotherapy +/- surgery.
    4) Acceptable organ function and performance status
    Performance status = 50%.
    Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
    Cardiac function: Shortening fraction = 28% or ejection fraction = 55% by echocardiogram, no clinical congestive heart failure. Normal pulmonary artery pressure.
    Normal chest X-ray and oxygen saturation.
    Absence of any toxicity = grade 3.
    5) Sufficient collected stem cells available; minimum required: 6 x 106 CD34+ cells/kg body weight stored in 3 separate fractions.
    6) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomization.
    7) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    8) Patients should be able and willing to comply with study visits and procedures as per protocol.

    R-RTx if the following criteria are met:
    1) No evidence of disease progression after HDC/ASCR.
    2) Interval between the last ASCR and radiotherapy start between 60 and 90 days.
    3) Performance status greater or equal 50%.
    4) Hematological status: ANC >0.5x109/L, platelets > 20x109/L.
    5) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization.
    6) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    7) Patients should be able and willing to comply with study visits and procedures as per protocol.
    Criteri di ammissibilità R-I:
    1) Diagnosi di neuroblastoma secondo i criteri dell'International Neuroblastoma Risk Group modificato da SIOPEN, Neuroblastoma ad alto rischio definito come:
    • Neuroblastoma in stadio M superiore a 365 giorni di età alla diagnosi (senza limite di età superiore) e neuroblastoma Stadio Ms 12-18 mesi, qualsiasi stato di MYCN *
    • Neuroblastoma L2, M o Ms con amplificazione di MYCN, a qualsiasi età
    2) Nessuna precedente chemioterapia tranne un ciclo di Etoposide-Carboplatino
    3) I pazienti sessualmente attivi che facciano uso di contraccettivi. Le pazienti in allattamento devono concordare di interrompere l'allattamento.
    4) Consenso informato scritto
    5) Paziente affiliato a un regime di sicurezza sociale o beneficiario dello stesso in base alle richieste locali.
    6) I pazienti devono essere in grado e disposti a rispettare le visite e le procedure di studio secondo il protocollo.

    Criteri di ammissibilità R-HDC:
    1)- Neuroblastoma in stadio M superiore a 365 giorni di età alla diagnosi, qualsiasi stato di MYCN, TRANNE pazienti con stadio M o Ms di età compresa tra 12 e 18 mesi con solo alterazioni cromosomiche numeriche e in risposta completa metastatica alla fine dell'induzione: in questo caso, i pazienti saranno sottoposti a un intervento chirurgico ma non potranno beneficiare di R-HDC e non saranno in grado di proseguire la sperimentazione.
    - Neuroblastoma L2, M o Ms con amplificazione MYCN
    2) Età <21 anni
    3) Risposta completa (CR) o risposta parziale (PR) nei siti metastatici:
    • Malattia ossea: assorbimento di MIBG (o assorbimento di FDG-PET per tumori MIBG-non avidi) completamente risolto o punteggio SIOPEN = 3 e almeno il 50% di riduzione del punteggio di MIBG (o = 3 lesioni ossee e almeno il 50% di riduzione del numero di FDG -Pet lesioni ossee avide per tumori MIBG-non avidi).
    • Malattia del midollo osseo: CR e / o malattia minima (MD) secondo i criteri internazionali di risposta al neuroblastoma [Park JR, JCO 2017; Burchill S, Cancer 2017].
    • Altri siti metastatici: risposta completa dopo chemioterapia di induzione +/- chirurgia.
    4) Funzione accettabile dell'organo e stato delle prestazioni
    • Stato delle prestazioni = 50%.
    • Stato ematologico: ANC> 0,5x109 / L, piastrine> 20x 109 / L
    • Funzione cardiaca: riduzione della frazione = 28% o frazione di eiezione = 55% mediante ecocardiogramma, nessuna insufficienza cardiaca congestizia clinica. Normale pressione arteriosa polmonare.
    • Normale radiografia del torace e saturazione di ossigeno.
    • Assenza di tossicità = grado 3.
    5) sufficienti cellule staminali raccolte disponibili; minimo richiesto: 6 x 106 CD34 + cellule / kg di peso corporeo memorizzati in 3 frazioni separate.
    6) Consenso informato scritto, compreso l'accordo del paziente o dei genitori / tutore legale per i minori, per accedere alla randomizzazione R-HDC.
    7) Paziente affiliato a un regime di sicurezza sociale o beneficiario dello stesso in base alle esigenze locali.
    8) I pazienti devono essere in grado e disposti a rispettare le visite e le procedure di studio secondo il protocollo.

    R-RTx se sono soddisfatti i seguenti criteri:
    1) Nessuna evidenza di progressione della malattia dopo HDC / ASCR.
    2) Intervallo tra l'ultimo ASCR e l’avvio della radioterapia tra i 60 e 90 giorni.
    3) Stato delle prestazioni maggiore o uguale al 50%.
    4) Stato ematologico: ANC> 0,5x109 / L, piastrine> 20x109 / L.
    5) Consenso informato scritto, compreso l'accordo del paziente o dei genitori / tutore legale per i minori, per accedere alla randomizzazione R-RTx.
    6) Paziente affiliato a un regime di sicurezza sociale o beneficiario dello stesso in base alle esigenze locali.
    7) I pazienti devono essere in grado e disposti a rispettare le visite e le procedure di studio secondo il protocollo.
    E.4Principal exclusion criteria
    Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :
    1) Urinary outflow obstruction
    2) severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
    3) severe peripheral neuropathy
    4) demyelinating form of Charcot-Marie-Tooth syndrome
    5) hearing impairment
    6) Concurrent prophylactic use of phenytoin
    7) cardiorespiratory disease that contraindicates hyperhydration

    Non-inclusion criteria common to all randomizations (R-I, R-HDC and R-RTx):
    1) Any negative answer concerning the inclusion criteria of R-I or R-HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomization. However, these patients may remain on study and be considered to receive standard treatment of the respective therapy phase, and may be potentially eligible for subsequent randomizations.
    2) Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood bilirubin > 1.5 x ULN (toxicity = grade 2). In case of toxicity = grade 2, call national principal investigator study coordinator to discuss the feasibility.
    3) Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m² (toxicity = grade 2). If GFR < 60ml/min/1.73m², call national principal investigator to discuss.the feasibility.
    4) Dyspnea at rest and/or pulse oximetry <95% in air.
    5) Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
    6) Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
    7) Participating in another clinical study with an IMP while on study treatment.
    8) Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines.
    9) Patient allergic to peanut or soya.
    10) Chronic inflammatory bowel disease and/or bowel obstruction.
    11) Pregnant or breastfeeding women.
    12) Known hypersensitivity to the active substance or to any of the excipients of study drugs known
    13) Concomitant use with St John’s Wort (Hypericum Perforatum).
    1) Qualsiasi risposta negativa relativa ai criteri di inclusione di R-I o R-HDC o R-RTx
    renderà il paziente non idoneo per la corrispondente randomizzazione della
    fase terapeutica. Tuttavia, questi pazienti possono continuare a essere nello studio
    ed essere considerati in trattamento standard della rispettiva fase terapeutica e
    possono essere potenzialmente idonei per successive randomizzazioni.
    2) Funzione epatica: alanina aminotransferasi (ALT)> 3,0 x ULN e bilirubina
    ematica> 1,5 x ULN (tossicità = grado 2). In caso di tossicità = grado 2, chiamare
    il coordinatore dello studio del ricercatore principale nazionale per discutere
    della fattibilità.
    3) Funzione renale: clearance della creatinina e / o GFR <60 ml / min / 1.73m²
    (tossicità = grado 2). Se GFR <60 ml / min / 1,73 m², chiamare il ricercatore
    principale nazionale per discutere della fattibilità.
    4) Dispnea a riposo e / o pulsossimetria <95% in aria.
    5) Qualsiasi malattia o infezione intercorrente incontrollata che, secondo
    l'opinione dello sperimentatore, comprometterebbe la partecipazione allo
    studio.
    6) Paziente sotto tutela o privato della libertà da una decisione giudiziaria o
    amministrativa o incapace di dare il proprio consenso.
    7) Partecipare a un altro studio clinico con un IMP durante il trattamento in
    studio.
    8) Uso concomitante con vaccino contro la febbre gialla e con virus vivi o vaccini
    batterici.
    9) Paziente allergico alle arachidi o alla soia.
    10) Malattia infiammatoria cronica intestinale e / o ostruzione intestinale.
    11) Donne in gravidanza o in allattamento.
    12) Ipersensibilità nota al principio attivo o ad uno qualsiasi degli eccipienti dei
    farmaci in studio noti
    13) Uso concomitante con l'erba di San Giovanni (Hypericum perforato).
    E.5 End points
    E.5.1Primary end point(s)
    R-I: 3-year EFS from date of R-I randomization
    R-HDC: 3-year EFS from date of R-HDC randomization
    R-RTx: 3-year EFS from date of RTx randomization
    R-I: EFS a 3 anni dalla data di randomizzazione R-I
    R-HDC: EFS a 3 anni dalla data di randomizzazione R-HDC
    R-RTx: EFS a 3 anni dalla data di randomizzazione RTx
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 years
    3 anni
    E.5.2Secondary end point(s)
    For the whole population of high-risk neuroblastoma:
    - 3- and 5-year EFS, PFS and OS calculated from date of randomization
    For each treatment phase:
    - 5-year EFS, 3- and 5-year PFS and OS calculated from date of
    randomization
    - Cumulative incidence of relapse/progression
    - Cumulative incidence of treatment related mortality and of disease
    related mortality
    - Overall response as per the new INRG response criteria [Park JR, JCO
    2017] (including primary tumor after induction), skeletal response on
    MIBG, bone marrow response, local control
    - Therapy-related toxicity
    Per l'intera popolazione di neuroblastoma ad alto rischio:
    • EFS, PFS e OS a 3 e 5 anni calcolati dalla data di randomizzazione
    Per ogni fase del trattamento:
    • EFS a 5 anni, PFS e OS a 3 e 5 anni calcolati dalla data di randomizzazione
    • Incidenza cumulativa di ricaduta / progressione
    • Incidenza cumulativa della mortalità correlata al trattamento e della mortalità correlata alla malattia
    • Risposta globale secondo i nuovi criteri di risposta INRG [Park JR, JCO 2017] (incluso tumore primario dopo induzione), risposta scheletrica su MIBG, risposta midollare, controllo locale
    • Tossicità correlata alla terapia
    E.5.2.1Timepoint(s) of evaluation of this end point
    5 years
    5 anni
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned27
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Croatia
    Czechia
    Denmark
    Finland
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Lithuania
    Netherlands
    New Zealand
    Norway
    Poland
    Portugal
    Serbia
    Slovakia
    Slovenia
    Spain
    Sweden
    Switzerland
    United Kingdom
    Uruguay
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 120
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 140
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Written informed consent will be obtained from the patient or any approved guardian prior to performing any trial related procedure
    Minori, il consenso scritto verrà chiesto ai genitori o un rappresentante legale prima di iniziare qualsiasi procedura legata allo studio
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state300
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 550
    F.4.2.2In the whole clinical trial 800
    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)
    Routine
    Secondo il normale percorso assistenziale
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation SIOPEN
    G.4.3.4Network Country Austria
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-19
    P. End of Trial
    P.End of Trial StatusOngoing
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