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    Summary
    EudraCT Number:2018-004250-17
    Sponsor's Protocol Code Number:RG_18-205,BN3010
    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:2021-08-30
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-004250-17
    A.3Full title of the trial
    An International Prospective Trial on High-Risk Medulloblastoma in Patients Older than 3 Years
    Studio prospettico internazionale su pazienti con età superiore a 3 anni con Medulloblastoma ad Alto Rischio
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    International Trial for Patients with High Risk Medulloblastoma
    Studio internazionale su pazienti con Medulloblastoma ad Alto Rischio
    A.3.2Name or abbreviated title of the trial where available
    SIOP-HRMB
    SIOP-HRMB
    A.4.1Sponsor's protocol code numberRG_18-205,BN3010
    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 SponsorUNIVERSITY OF BIRMINGHAM
    B.1.3.4CountryUnited Kingdom
    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 organisationUniversity of Birmingham
    B.5.2Functional name of contact pointEileen Grimes
    B.5.3 Address:
    B.5.3.1Street AddressCRCTU, School of Cancer Sciences, Vincent Drive
    B.5.3.2Town/ cityEdgbaston, Birmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214147581
    B.5.5Fax number01214149520
    B.5.6E-mailsiop-hrmb@trials.bham.ac.uk
    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.2.5The 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 nameThiotepa
    D.3.2Product code [Thiotepa]
    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 INNTHIOTEPA
    D.3.9.1CAS number 52-24-4
    D.3.9.2Current sponsor codeThiotepa
    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: 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 solfato
    D.3.2Product code [VIncristina solfato]
    D.3.4Pharmaceutical form 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 INNVINCRISTINA SOLFATO
    D.3.9.1CAS number 57-22-7
    D.3.9.2Current sponsor codeVincristina Solfato
    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.2.1.1.1Trade name Lomustine Medac
    D.2.1.1.2Name of the Marketing Authorisation holderMEDAC GMBH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameLomustina
    D.3.2Product code [Lomustine]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLOMUSTINA
    D.3.9.1CAS number 13010-47-4
    D.3.9.2Current sponsor codeLomustina
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 nameCiclofosfamide
    D.3.2Product code [Ciclofosfamide]
    D.3.4Pharmaceutical form Powder 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 INNCICLOFOSFAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor codeCiclofosfamide
    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 nameTemozolomide
    D.3.2Product code [Temozolomide]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEMOZOLOMIDE
    D.3.9.1CAS number 85622-93-1
    D.3.9.2Current sponsor codetemozolomide
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 250
    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.2.5The 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.3.10 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 nameCisplatino
    D.3.2Product code [Cisplatino]
    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 INNCISPLATINO
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor codeCisplatino
    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.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
    Histologically proven high-risk medulloblastoma, with any of the currently defined histological subtypes. High-risk disease is defined as patients with sonic hedgehog (SHH) subgroup or non-SHH/non-wingless-type (WNT) (Groups 3 and 4) medulloblastoma, with at least one additional high risk feature
    Medulloblastoma ad alto rischio istologicamente diagnosticato con uno qualsiasi dei sottotipi istologici attualmente definiti. La malattia ad alto rischio è definita come pazienti con sottogruppo Sonic Hedgehog (SHH) o medulloblastoma non-SHH / di tipo non-wingless (WNT) (Gruppi 3 e 4), con almeno una caratteristica aggiuntiva ad alto rischio
    E.1.1.1Medical condition in easily understood language
    Brain tumour
    Bambini, adolescenti e adulti con diagnosi di Medulloblastoma ad alto rischio (HR-MB), età 3- 21 anni
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate whether outcome in children, young people and adults with high risk medulloblastoma (HR-MB) is improved over standard therapy for those treated with;¿(i) conventional (once a day) radiotherapy¿(ii) hyperfractionated-accelerated radiotherapy (HART), or ¿(iii) high dose chemotherapy with thiotepa followed by conventional radiotherapy. ¿
    • To evaluate whether outcome in HR-MB is different for those treated with two different ¿maintenance chemotherapy therapies (standard four-drug combination given as 8 cycles, alternating between cisplatin, lomustine and vincristine; and cyclophosphamide and vincristine; vs single agent oral temozolomide over 6 cycles)
    • Valutare se l’outcome in bambini, giovani e adulti con HR-MB è migliorato
    rispetto alla terapia standard per quelli trattati con:
    - radioterapia (RT) convenzionale (una volta al giorno - terapia standard),
    - radioterapia accelerata iperfrazionata (HART) o (iii) alte dosi
    terapia (HDT) con tiotepa seguita da RT convenzionale.
    • Valutare se l’outcome in HR-MB è diverso per tutti quelli trattati con due differenti terapie chemioterapiche di mantenimento.
    E.2.2Secondary objectives of the trial
    • To study the late effects of treatment and their impact on quality of survival (QoS), including neurocognitive function, neurological impairment, endocrine impairment, audiological function, and secondary tumours.
    • To conduct comprehensive prospective biological studies in HR-MB, with the aims of (i) understanding the biological basis of HR-MB, (ii) identification and validation of diagnostic and prognostic biomarkers, and (iii) identification and validation of molecular targets with therapeutic potential and associated predictive biomarkers.
    • To conduct prospective QoS, toxicity and pharmacogenomic studies with the aim of exploring clinical, host and tumour factors, and genetic variants, that relate to early and late side-effects of treatment and survival parameters.
    • Studiare gli effetti tardivi del trattamento e il loro impatto sulla qualità della sopravvivenza (QoS), incluse le funzioni neurocognitive, i danni neurologici, i danni a livello endocrinologico, le funzioni audiologiche e i tumori secondari.
    • Condurre studi biologici prospettici in SIOP-HRMB, con gli obiettivi di (i)comprendere le basi biologiche di HR-MB, (ii) identificare e validare biomarcatori prognostici e di diagnostica (iii) identificare e validare i bersagli molecolari con potenziali terapeutici associati a biomarker predittivi.
    • Condurre studi prospettici di QoS, tossicità e farmacogenomica con l'obiettivo di esplorare fattori clinici e varianti genetiche del tumore, che si riferiscono agli effetti collaterali precoci e tardivi dei parametri di trattamento e sopravvivenza.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria for trial entry and R1
    • Histologically proven (centrally reviewed) high-risk medulloblastoma, with any of the currently defined histological subtypes. High-risk disease is defined as patients with sonic hedgehog (SHH) subgroup or non-SHH/non-wingless-type (WNT) (Groups 3 and 4) medulloblastoma, with at least one of the following high risk features:
    o Metastatic disease: Chang Stage M1, M2 and M3.
    o Large cell/Anaplastic MB (as defined by World Health Organisation (WHO) criteria 2016
    o Patients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and other biological risk factors
    o Patients with MYC or MYCN amplified tumours (unless MYCN amplified Group 4 without any other high risk factors)
    o Patients with SHH subgroup tumours harbouring somatic TP53 mutations.
    • Age at diagnosis =3 years. The date of diagnosis is the date on which initial surgery is undertaken.
    • Submission of biological material, including fresh frozen tumour samples and blood, in accordance with national and international schemes for molecular assessment of biological markers, and for associated biological studies.
    • No prior treatment for medulloblastoma, other than surgery, with the exception of one cycle of induction chemotherapy with carboplatin and etoposide may be given prior to trial entry and randomisation where there is clinical urgency to start treatment
    • Adequate hepatic function defined as:
    o Total bilirubin = 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome
    o ALT or AST < 2.5 X ULN for age
    • Adequate renal function defined as creatinine < 1.5 x ULN
    • Adequate haematological function defined as ANC =1 x 109/L; platelets = 100 x 109/L
    • No significant hearing deficit in at least one ear (significant hearing deficit defined as Chang grade 3 or above)
    • Medically fit to receive protocol treatment
    • Documented negative pregnancy test for female patients of childbearing potential
    • Patient agrees to use effective contraception whilst on treatment (patients of childbearing potential)
    • Written informed consent from the patient and/or parent/legal guardian

    Inclusion criteria for Randomisation 2 (R2)
    • Patient entered into the SIOP-HRMB trial at diagnosis
    • Patient treated with:
    o Either Arm A (conventional radiotherapy) or Arm B (HART) as part of R1

    • Diagnosi confermata centralmente di medulloblastoma ad altro rischio con qualsiasi definizione dell’istotipo. La malattia ad alto rischio è definibile nel sottogruppo di pazienti con medulloblastoma con sonic hedgegog (SHH) oppure sottogruppo non-SHH/non-wingless-type (WNT) (Gruppi 3 e 4), quest’ultimo con le seguenti caratteristiche:
    o Malattia metastatica: Chang stage M1, M2 e M3;
    o istologia a grandi cellule o anaplastica (come definito dalla Organizzazione mondiale della sanità WHO secondo i criteri del 2016.
    o Pazienti con significativo residuo di malattia (>1.5 cm2) seguita da una resezione chirurgica primaria del tumore e da altri fattori di rischio biologici.
    o Pazienti con tumori amplificati da MYC o MYCN (a meno che MYCN non abbia amplificato il gruppo 4 senza altri fattori di rischio elevato)
    o Pazienti con tumori del sottogruppo SHH che presentano mutazioni somatiche di TP53.
    • Età alla diagnosi =3 anni. La data della diagnosi corrisponde alla data in cui è stato effettuato l'intervento iniziale
    • Invio di materiale biologico, inclusi campioni di tumore congelato fresco e sangue, in accordo agli schemi nazionali ed internazionali per la valutazione molecolare del biologico e ricerca di marcatori per studi biologici associati.
    • Nessun trattamento precedente per il medulloblastoma, diverso dalla chirurgia, ad eccezione di un ciclo di induzione con carboplatino ed etoposide, che potrà essere somministrato prima dell'ingresso nello studio e prima della randomizzazione
    • Adeguata funzionalità epatica definita come:
    ¿ Bilirubina totale = 1,5 volte il limite superiore della norma (ULN) per l'età, a meno che il paziente non sia noto per avere la sindrome di Gilbert.
    ¿ ALT o AST <2,5 X ULN per l'età
    • Adeguata funzionalità renale definita come creatinina <1,5 x ULN
    • Adeguata funzione ematologica definita come ANC =1 x 109 / L; piastrine = 100 x 109 / L
    • Nessun deficit uditivo significativo in almeno un orecchio (deficit uditivo significativo definito come Chang grado 3 o superiore)
    • Idoneo dal punto di vista medico per ricevere il trattamento del protocollo
    • Test di gravidanza negativo documentato per pazienti di sesso femminile in età fertile
    • Il paziente accetta di utilizzare un metodo contraccettivo efficace durante il trattamento (pazienti in potenziale età fertile)
    • Consenso informato scritto del paziente e / o genitore / tutore legale.
    E.4Principal exclusion criteria
    Exclusion criteria for trial entry and randomisation 1:
    • Patients with proven or with high likelihood of Germline TP53, APC, PTCH, SUFU, PALB2, BRCA2 gene alteration or any other DNA repair defect.
    • Group 4 patients with MYCN amplification and no other high-risk factor
    • Patients with ß-catenin mutation positive WNT medulloblastoma irrespective of other risk factors
    • Patients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and no other biological risk factors.
    • Chang Stage M4 disease
    • Brainstem or embryonal tumours in other sites
    • Patients previously treated for a brain tumour or any type of malignant disease
    • Medical contraindication to radiotherapy or chemotherapy
    • Known hypersensitivity to any of the treatments or excipients
    • Females who are pregnant or breastfeeding
    • Patients who cannot be regularly followed up due to psychological, social, family, geographical or other issues
    • Patients for whom non-compliance with treatment, management guidelines or monitoring is expected.

    Criteri di esclusione • Pazienti con comprovata o con alta probabilità alterazione nelle cellule geminali di: TP53, APC, PTCH, SUFU, PALB2, BRCA2 o qualsiasi altro difetto di riparazione del DNA.
    • Pazienti del gruppo 4 con amplificazione MYCN e nessun altro fattore ad alto rischio
    • Pazienti con medulloblastoma WNT e positivi per la mutazione del gene della ß-catenina indipendentemente da altri fattori di rischio
    • Pazienti con significativo residuo tumorale (> 1,5 cm2) a seguito di resezione chirurgica del tumore primario e nessun altro fattore di rischio biologico.
    • Malattia Stadio Chang M4
    • Tumori in altre sedi, del tronco cerebrale o embrionali.
    • Pazienti precedentemente trattati per un tumore al cervello o qualsiasi tipo di malattia maligna
    • Controindicazione medica alla radioterapia o alla chemioterapia
    • Nota ipersensibilità a uno qualsiasi dei trattamenti o eccipienti
    • Donne in gravidanza o in allattamento
    • Pazienti che non possono essere seguiti regolarmente per motivi psicologici, sociali, familiari, geografici o altri problemi
    • Paziente per il quale è prevista la non conformità al trattamento, alle linee guida di gestione o al monitoraggio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is event-free survival (EFS).
    sopravvivenza libera da eventi (EFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Event Free Survival is defined as the time from the date of randomisation for each randomised question respectively to the date of the event; patients will be censored at date last seen if lost to follow-up.
    Event Free Survival è definito come il tempo dalla data di randomizzazione per ciascuna domanda randomizzata rispettivamente alla data dell'evento; i pazienti saranno censiti alla data dell'ultima visita se persi al follow-up
    E.5.2Secondary end point(s)
    Progression free survuval (PFS); Toxicity (including late effects); QoS; Overall survival (OS)
    Sopravvivenza libera da malattia (PFS); Tossicità (inclusi anche gli effetti tardivi); QoS; Sopravvivenza globale (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall survival and progression free survival are defined as the time from the date of randomisation to the date of death, relapse or progression for PFS or to date of death for OS; patients will be censored at date last seen if lost to follow-up.; will be assessed throughout the trial; will be assessed throughout the trial; Overall survival and progression free survival are defined as the time from the date of randomisation to the date of death, relapse or progression for PFS or to date of death for OS; patients will be censored at date last seen if lost to follow-up.
    La sopravvivenza globale e la sopravvivenza libera da progressione sono definite come il tempo dalla data di randomizzazione alla data di morte, ricaduta o progressione per PFS o fino alla data di morte per OS; i pazienti saranno censurati alla data dell'ultima visita se persi al follow-up.; saranno valutate durante lo studio; saranno valutate durante lo studio; La sopravvivenza globale e la sopravvivenza libera da progressione sono definite come il tempo dalla data di randomizzazione alla data di morte, ricaduta o progressione per PFS o fino alla data di morte per OS; i pazienti saranno censurati alla data dell'ultima visita se persi al follow-up.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 Yes
    E.8.2.3.1Comparator description
    Radioterapia
    Radiotherapy
    E.8.2.4Number of treatment arms in the trial5
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA170
    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
    Austria
    Belgium
    Czechia
    Denmark
    Finland
    France
    Germany
    Ireland
    Italy
    Netherlands
    Norway
    Portugal
    Spain
    Sweden
    Switzerland
    United Kingdom
    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 years11
    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 years11
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 50
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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
    Children
    Minorenni
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state250
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 850
    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)
    Not relevant for this trial. On completion of trial treatment patients will be treated as per local practice.
    Non rilevante per questo studio. Al termine del trattamento di prova i pazienti saranno trattati secondo la pratica locale.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-24
    P. End of Trial
    P.End of Trial StatusOngoing
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