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    Summary
    EudraCT Number:2011-004868-30
    Sponsor's Protocol Code Number:PNET5MB
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-07-31
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2011-004868-30
    A.3Full title of the trial
    AN INTERNATIONAL PROSPECTIVE STUDY ON CLINICALLY STANDARD-RISK MEDULLOBLASTOMA IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH LOW-RISK BIOLOGICAL PROFILE (PNET 5 MB - LR) OR AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR)
    ESTUDIO PROSPECTIVO INTERNACIONAL DE MEDULOBLASTOMA RIESGO ESTÁNDAR CLÍNICO EN NIÑOS MAYORES DE 3 A 5 AÑOS CON PERFIL BAJO DE RIESGO BIOLÓGICO (PNET 5 MB - LR) O PERFIL-MEDIO DE RIESGO BIOLÓGICO (PNET 5-SR MB)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    AN INTERNATIONAL PROSPECTIVE STUDY ON CLINICALLY STANDARD-RISK MEDULLOBLASTOMA IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH LOW-RISK BIOLOGICAL PROFILE (PNET 5 MB - LR) OR AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR)
    ESTUDIO PROSPECTIVO INTERNACIONAL DE MEDULOBLASTOMA RIESGO ESTÁNDAR CLÍNICO EN NIÑOS MAYORES DE 3 A 5 AÑOS CON PERFIL BAJO DE RIESGO BIOLÓGICO (PNET 5 MB - LR) O PERFIL-MEDIO DE RIESGO BIOLÓGICO (PNET 5-SR MB)
    A.4.1Sponsor's protocol code numberPNET5MB
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02066220
    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 Medical Center Hamburg-Eppendorf
    B.1.3.4CountryGermany
    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 supportDeutsche Kinderkrebsstiftung
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Hamburg-Eppendorf
    B.5.2Functional name of contact pointKatja von Hoff
    B.5.3 Address:
    B.5.3.1Street AddressMartinistr. 52
    B.5.3.2Town/ cityHamburg
    B.5.3.3Post code20246
    B.5.3.4CountryGermany
    B.5.4Telephone number004940741053394
    B.5.5Fax number004940741058300
    B.5.6E-mailk.von-hoff@uke.de
    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 AuthorisationSpain
    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 nameCisplatin
    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 INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCarboplatin
    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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameLomustine
    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 INNLOMUSTINE
    D.3.9.1CAS number 13010-47-4
    D.3.9.4EV Substance CodeSUB08567MIG
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameVincristine
    D.3.4Pharmaceutical form 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 INNVINCRISTINE SULFATE
    D.3.9.1CAS number 2068-78-2
    D.3.9.4EV Substance CodeSUB05101MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCyclophosphamide
    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 INNCyclophosphamide
    D.3.9.1CAS number 6055-19-2
    D.3.9.3Other descriptive nameCYCLOPHOSPHAMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB16414MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number106.9
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    Children with medulloblastoma of standard risk. Medulloblastoma is a highly cellular malignant embryonal neoplasm classified as a Primitive Neuro-ectodermal Tumour [PNET]
    Niños con meduloblastoma de riesgo estándar. El Meduloblastoma (MB) es un tumor embrionario maligno altamente celular clasificado como Tumor Neuro-ectodérmico Primitivo [PNET].
    E.1.1.1Medical condition in easily understood language
    Medulloblastoma is a type of brain tumour that mainly affects children
    El meduloblastoma es un tipo de tumor que afecta principalmente a niños
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10027107
    E.1.2Term Medulloblastoma
    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
    Treatment Arm- LR
    - to confirm that the 3-year Event-Free Survival rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when patients are treated with 18.0 Gy neuraxis irradiation plus boost to the primary tumor, and reduced-intensity chemotherapy
    Treatment Arm - SR
    - to test whether the Event-Free Survival in children and adolescents with standard-risk medulloblastoma having an average-risk biological profile is different for patients treated with or without carboplatin concomitantly with radiotherapy (23.4 Gy neuraxis irradiation plus boost to the primary tumor) followed by a modified maintenance chemotherapy.
    Rama del tratamiento bajo riesgo (LR): Confirmar que la Supervivencia libre de eventos (SLE) de 3 años en los niños y adolescentes con meduloblastoma de riesgo estándar que tiene un perfil de bajo riesgo biológico permanece superior al 80% cuando los pacientes se tratan con 18.0 Gy irradiación neuroeje más refuerzo al tumor primario, y con quimioterapia de intensidad reducida.

    Rama de tratamiento riesgo estándar (SR): Probar si la supervivencia libre de eventos (SLE) en niños y adolescentes con meduloblastoma de riesgo estándar que tiene un perfil biológico de riesgo intermedio es diferente en los pacientes tratados con o sin carboplatino concomitantemente con radioterapia (23,4 Gy neuroeje irradiación más sobreimpresión al tumor primario) seguida de una quimioterapia de mantenimiento modificada.
    E.2.2Secondary objectives of the trial
    Treatment Arm - LR
    - Overall Survival rate, and pattern of relapse
    - late effects of the reduced-dose approach
    - to conduct comprehensive studies in a prospective fashion on the biological basis of WNT-subgroup medulloblastoma, with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in this disease subgroup.
    Treatment Arm - SR
    - Overall Survival Rate, Progression-free survival rates, and pattern of relapse
    - to test the feasibility of carboplatin treatment concomitantly with radiotherapy
    - late effects in the randomized treatment arms
    - to conduct comprehensive studies in a prospective fashion on the biological basis of standard-risk medulloblastoma with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in this disease subgroup.
    Rama del tratamiento LR:
    - Investigar la tasa de supervivencia global (OS), y patrón de recaída
    - Estudiar los efectos tardíos de la utilización de la dosis reducida
    - Llevar a cabo estudios exhaustivos de forma prospectiva de los aspectos biológicos del subgrupo de MB WNT, con el objetivo de identificar, investigar y validar biomarcadores y dianas de medicamentos con potencial terapéutico en este subgrupo de enfermedad.

    Rama de tratamiento SR:
    - Investigar las tasas de supervivencia global (SG), las tasas de supervivencia libre de progresión (SLP), y el patrón de recaída en los brazos de tratamiento aleatorios.
    - Probar la viabilidad del tratamiento de carboplatino concomitante con radioterapia
    - Estudiar los efectos tardíos de la utilización de la dosis reducida
    - Realizar estudios de manera prospectiva sobre las bases biológicas de MB de riesgo estándar, con el objetivo de identificar, investigar y validar biomarcadores y dianas de medicamentos con potencial terapéutico
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudies will only be conducted in Germany.
    E.3Principal inclusion criteria
    LR-arm:
    a) Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 16 years.
    The date of diagnosis is the date on which first surgery/biopsy is undertaken.

    b) Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007):
    classic medulloblastoma desmoplastic/nodular medulloblastoma Pre-treatment central pathology review is considered mandatory.

    c) Standard risk medulloblastoma, defined as:
    - total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual
    tumour on early postoperative MRI, without and with contrast, on central review;
    - no CNS metastasis on MRI (cranial and spinal) on central review; )
    - no tumour cells on the cytospin samples of lumbar CSF
    - no clinical evidence of extra-CNS metastasis.

    Patients with a reduction of postoperative residual tumour through second surgery to less than or equal to 1.5 cm2 are eligible, if timeline for start of radiotherapy can be kept.

    d) Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centers. Submission of blood and CSF is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended.
    e) No amplification of MYC or MYCN (determined by FISH).
    f) Low-risk biological profile, defined as WNT subgroup positivity. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).
    g) No prior therapy for medulloblastoma other than surgery;
    h) Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study
    i) Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy.
    j) CTC grades < 2 for liver, renal, haematological function
    k) No significant sensineural hearing deficit as defined by pure tone audiomentry with bone conduction or air conduction and normal tympanogram showing no impairement ? 20 dB at 1-3 kHz. If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit.
    l) No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome or other reasons as defined by patient?s clinician;
    m) No identified Turcot and Li Fraumeni syndrome.
    n) Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation.
    o) National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).

    SR-arm as above , with the exception of a, f):
    a) Age at diagnosis, at least 3 - 5 years (depending on the country) and and less than 22 years.
    The date of diagnosis is the date on which first surgery/biopsy is undertaken
    f) Average-risk biological profile, defined as WNT subgroup negativity. WNT-negative tumours are defined by (i) ß-catenin nuclear immuno-negativity by IHC (mandatory testing), and the absence of ß-catenin mutation (mandatory testing) and monosomy 6 (optional testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) in the absence of ß-catenin mutation and monosomy 6, or (iii) monosomy 6 in the absence of ß-catenin nuclear immuno-positivity by IHC or ß-catenin mutation.
    WNT subgroup positive tumours arising in patients age ?16.0 years at diagnosis. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).
    Rama de tratamiento LR:
    a) La edad de diagnóstico, por lo menos 3 - 5 años (en el caso de España 4 años) y menos de 16 años. La fecha de diagnóstico es la fecha en que se lleve a cabo la cirugía/biopsia;

    b) Histología probada de meduloblastoma, incluyendo los siguientes subtipos, como se define en la clasificación de la OMS (2007): meduloblastoma clásico, desmoplásico/nodular. La revisión patologíca central pretratamiento se considera obligatoria.

    c) El meduloblastoma de riesgo estándar, definido como;
    -Resección quirúrgica total o casi total con resto tumoral menor de o igual a 1,5 cm2 (medido en el plano axial) sobre la primera MRI postoperatoria, sin y con contraste, en la revisión central;
    - No metástasis del SNC en la RM (craneal y espinal) tras la revisión central;
    - No células tumorales en la cytospin de LCR lumbar
    - Sin evidencia clínica de adicional SNC-metástasis;

    Los pacientes con resto menor o igual a 1,5 cm2 son elegibles, si la segunda cirugía es realizada dentro de los 14 días después de la primera cirugía.

    d) Envío de material biológico de alta calidad, incluyendo muestras de tumor fresco congelado para la evaluación molecular de los marcadores biológicos (tales como la evaluación del estado del número de copias del gen MYC) en el Centro de referencia biológico nacional. Envío de sangre obligatorio para el estudio de DNA en línea germinal de todos los pacientes. Se recomienda envío de líquido cefaloraquídeo.

    e) No presentar amplificación de MYC o MYCN (determinado por FISH);

    f) perfil biológico de bajo riesgo, definido como positividad de subgrupo WNT. El subgrupo WNT está definido por la presencia de (i) mutación de B-catenina (obligatorio), (ii) immunopositividad nuclear de ß-catenina por IHC (obligatorio) y mutación de B-catenina o (iii)B-catenina nuclear positiva por inmunohistoquimica y monosomía del 6 (opcional).

    g) No tratamiento previo para el meduloblastoma distinto de la cirugía;

    h) La radioterapia debe comenzar 28 días después de la cirugía. Si se retrasa más de 40 días después de la cirugía, los pacientes no serán elegibles para el estudio.

    i) Los criterios de inclusión y screening deben completarse durante los 28 días después de la primera cirugía. En caso de una segunda cirugía, se ampliaría a no más de 35 días después de la primera.
    No se pueden incluir pacientes después de los 40 días de la primera cirugía o después del comienzo de radioterapia.

    j) Grados de toxicidad <2 para la función del hígado, renal, y función hematológica.

    k) Ausencia de déficit neurosensorial auditivo significativo definido por audiomentria de tono puro y timpanograma normal, sin mostrar discapacidad de más 20 dB en frecuencias de 1-3 kHz. Si la audiometría no es posible, las emisiones otoacústicas normales después de la operación son aceptables, si no hay antecedentes de déficit de audición.

    l) No hay contraindicación médica para la radioterapia o la quimioterapia, tales como síndromes de rotura de ADN preexistente (por ejemplo, la anemia de Fanconi, síndrome de rotura Nijmegen), síndrome de Gorlin o otras razones médicas;

    m) Ausencia de síndrome de Turcot y Li Fraumeni.

    n) Consentimiento informado escrito (y el asentimiento del paciente en su caso) para el tratamiento de acuerdo con la legislación de cada país participante. Se le debe facilitar al paciente hoja de información de los estudios biológicos (del tumor y de línea germinal), con consentimiento escrito obtenido para su participación.

    o) Aprobación del comité de ética Local y Nacional, de acuerdo con la legislación de cada país participante.

    Rama de tratamiento SR, como arriba, con la excepción de a) y f):
    a) La edad de diagnóstico, por lo menos 3-5 años (en España 4 años) y menos de 22 años. La fecha de diagnóstico es la fecha en que se lleve a cabo la cirugía;

    f) El perfil biológico de riesgo intermedio se define como WNT negativo por (i) B catenina nuclear negativa por IHQ (obligatorio), ausencia de mutación de B catenina (obligatorio) monosomia 6 (opcional) o (ii) B catenina positiva (oblogatoria) con ausencia de B catenina mutada y monosomía 6 o (iii) monosomia 6 en ausencia de B catenina positiva o B catenina mutada.
    Los tumores positivos del subgrupo WNT en pacientes mayores de 16 años al diagnóstico.
    El subgrupo WNT está definido por (i) presencia de B catenina mutada (obligatorio) o (ii) B catenina positiva por IHQ (obligatorio) y B catenina mutada, o (iii) B catenina positiva por IHQ y monosomía 6 (opcional).
    E.4Principal exclusion criteria
    a) One of the inclusion criteria is lacking;
    b) Brainstem or supratentorial primitive neuro-ectodermal tumour;
    c) Atypical teratoid rhabdoid tumour;
    d) Medulloepithelioma; Ependymoblastoma
    e) Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review.
    f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable.
    g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF);
    h) Patient previously treated for a brain tumour or any type of malignant disease;
    i) DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin,Turcot, or Li Fraumeni syndrome
    j) Patients who are pregnant;
    k) Female patients who are sexually active and not taking reliable contraception;
    l) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons;
    m) Patients in whom non-compliance with toxicity management guidelines can be expected.
    a) Fallo de alguno de los criterios de inclusión;
    b) tumor neuroectodérmico primitivo supratentorial o del Tronco cerebral;
    c) tumor teratoide rabdoide atípico;
    d) Meduloepitelioma; Ependimoblastoma.
    e) el meduloblastoma de células grandes, meduloblastoma anaplásico o meduloblastoma con extensa nodularidad (MBEN), confirmado en el examen patológico central.
    f) perfil biológico desfavorable o no determinable, definida como la amplificación de MYC o MYCN, o b-catenina no determinable (estatus WNT no determinable).
    g) meduloblastoma metastásico (RMN de SNC y/o LCR lumbar postoperatorio positivo);
    h) paciente tratado previamente para un tumor cerebral o cualquier tipo de enfermedad maligna;
    i) síndromes de rotura de ADN (por ejemplo, la anemia de Fanconi, síndrome rotura Nijmegen) u otro, o identificados de Gorlin, Turcot, o el síndrome de Li Fraumeni
    j) Embarazo;
    k) Pacientes femenina sexualmente activa sin contracepción adecuada;
    l) Los pacientes que no se pueden realizar un seguimiento adecuado por razones psicológicas, sociales, familiares o geográficas;
    m) pacientes en los que se pueda esperar el incumplimiento de las directrices de manejo de la toxicidad.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is event-free survival (EFSOP) for the treatment arm SR and 3-years EFS rate for the treatment arm LR
    El criterio principal de valoración es la supervivencia libre de eventos (SLEOP) para la rama de tratamiento SR y la supervivencia libre de eventos a los 3 años para el tratamiento de la rama LR
    E.5.1.1Timepoint(s) of evaluation of this end point
    LR-arm: 3 years after last patient in
    SR-arm: after 105 events (relapse) or after an estimated follow-up time of 4 years after last patient in
    Rama de tratamiento LR: 3 años después de la inclusión del último paciente
    Rama de tratamiento SR: después de 105 eventos (recaída) o después de un segumiento de 4 años de duración después de la inclusión del último paciente
    E.5.2Secondary end point(s)
    1) Event-free survival (EFSend)
    2) Overall survival (OSOP)
    3) Overall survival (OSend)
    4) Progression-free survival (PFSOP)
    5) Feasibility of carboplatin treatment
    6) Residual tumor (<1.5 cm2) will be estimated by central MRI review postoperatively
    7) Relapse pattern will be evaluated at the end of therapy
    8) Indirect measures for quality of survival
    9) Ototoxicites
    10) Endocrine function
    11) Neurologic function
    12) Biological tumour markers
    13) Leukoencephalopathy (LEP)
    14) Audit of compliance with protocol defined therapy
    1) Supervivencia libre de eventos
    2) Supervivencia global (OSOP)
    3) Supervivencia global (OSfinal)
    4) Supervivencia libre de progresión
    5) Viabilidad de tratamiento carboplatino concomitante con radioterapia.
    6) El tumor residual (<1.5cm2) será estimado por una revisión centralizada sobre la primera MRI postoperatoria
    7) El patrón de recaída será evaluado al final de la terapia
    8) Medidas indirectas de calidad de vida
    9) Ototoxicidad
    10) Función endocrina
    11) Función neurológica
    12) Marcadores tumorales biológicos
    13) Leucoencefalopatía
    14) Auditoría del cumplimiento de la terapia definida en el protocolo
    E.5.2.1Timepoint(s) of evaluation of this end point
    After an estimated follow-up time of 4 years after last patient in (both arms)
    Después de un seguimiento esperado de 4 años después de la inclusión del último paciente en ámbas ramas del tratamiento
    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 No
    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) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Rama SR: grupo con carboplatino concomitante con radioterapia comparado con grupo sin carboplatino
    SR-arm: group with carboplatin concomitant to radiotherapy compared to group without carboplatin
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last patient, last visit
    Último paciente, última visita
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    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 years9
    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.1.1Number of subjects for this age range: 360
    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: 216
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 108
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-07-31. Yes
    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
    For children and adolescents who are too young to give informed consent, depending on national definitions, informed consent will be obtained in written form from the parents. Patient assent may also be obtained, depending on national requirements.
    Para niños y adolescentes demasiado jóvenes para dar su consentimiento informado, éste será obtenido de sus padres, siguiendo las leyes de cada país. También podrá ser obtenido el asentimiento del paciente, según requerimientos nacionales
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 360
    F.4.2.2In the whole clinical trial 360
    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)
    Due to the severeness and chronic character of the disease and the respective long term sequelae, the patients will undergo further follow-up visits as part of the standard care. Problems and events will be reported.
    Debido a la severidad de la enfermedad, al caracter crónico de la misma y a las secuelas a largo plazo, los pacientes serán sometidos a un régimen de visitas como parte del seguimiento normal del paciente. Los problemas y los eventos serán reportados.
    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 SIOP International Society of Peadiatric Oncology
    G.4.3.4Network Country Switzerland
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Deutsche Gesellschaft für Hämatologie und Onkologie
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation SEHOP Sociedad Española de Hematología Oncología Pediátrica
    G.4.3.4Network Country Spain
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-30
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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