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    Summary
    EudraCT Number:2011-004868-30
    Sponsor's Protocol Code Number:PNET5MB
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-21
    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 ConcernedCzech Republic - SUKL
    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)
    Mezinárodní prospektivní studie u dětí starších 3 let s onemocněním meduloblastomem standardního rizika s příznivým (SIOP PNET 5 MB – LR) nebo obvyklým (SIOP PNET 5 MB – SR) biologickým profilem
    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)
    Mezinárodní prospektivní studie u dětí starších 3 let s onemocněním meduloblastomem standardního rizika s příznivým (SIOP PNET 5 MB – LR) nebo obvyklým (SIOP PNET 5 MB – SR) biologickým profilem
    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 AuthorisationCzech Republic
    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 AuthorisationCzech Republic
    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 AuthorisationCzech Republic
    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 AuthorisationCzech Republic
    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 AuthorisationCzech Republic
    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]
    Děti s meduloblastomem standartního rizika. Meduloblastom je vysoce maligní nádor z embryonálních buněk klasifikovaný jako primitivní neuroektodermální nádor (PNET)
    E.1.1.1Medical condition in easily understood language
    Medulloblastoma is a type of brain tumour that mainly affects children
    Meduloblastom je typ mozkového nádoru, který postihuje převážně děti
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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.
    Léčebné rameno - LR
    -potvrdit, že míra přežití 3 roky bez klinické příhody (EFS) u dětí a dospívajících s meduloblastomem standartního rizika s biologickým profilem nízkého rizika zůstane více než 80%, když budou pacienti ozářeni 18,0 Gy na oblast kraniospinální osy, boostem na primární nádor a obdrží chemoterapii nižší intenzity.
    Léčebné rameno - SR
    -zjistit, zda je přežití bez klinické příhody (EFS) u dětí a dospívajících s meduloblastomem standardního rizika a středně rizikovým biologickým profilem odlišné u pacientů léčených s nebo bez karboplatiny souběžně s radioterapií (23,4 Gy na oblast kraniospinální osy plus boost na primárního nádor) následovanou modifikovanou udržovací chemoterapií.
    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.
    Léčebné rameno - LR
    -sledovat míru celkového přežití (OS) a relapsy
    -studovat pozdní účinky snížené dávky
    -provést u meduloblastomu prospektivní komplexní studie na biologickém základě WNT podskupiny ve snaze v této podskupině identifikovat, zkoumat a ověřovat biomarkery a lékové cíle s terapeutickým potenciálem.
    Léčebné rameno - SR
    -prozkoumat parametry celkového přežití (OS), míru přežití bez progrese (PFS), a typ relapsu v randomizovaných léčebných ramenech.
    -testovat proveditelnost léčby karboplatinou souběžně s radioterapií
    -studovat pozdní účinky v randomizovaných léčebných ramenech
    -provést prospektivní studie na biologickém základě meduloblastomu standardního rizika ve snaze v této podskupině identifikovat, zkoumat a ověřovat biomarkery a lékové cíle s terapeutickým potenciálem.
    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.
    Substudie budou prováděny pouze v Německu.
    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).
    Léčebné rameno - LR
    a)věk v době stanovení diagnózy, nejméně 3 – 5 let (závisí od jednotlivé země) a méně než 16 let. Datum stanovení diagnózy je datum operace.
    b)histologicky potvrzený meduloblastom, zahrnující příslušné podtypy dle WHO klasifikace (2007):
    -klasický meduloblastom
    -desmoplastický/nodulární meduloblastom
    Celkové zhodnocení patologického nálezu před léčbou je povinné.
    c)Meduloblastom standartního rizika je definován jako:
    - kompletní nebo téměř kompletní chirurgická resekce zbytkového nádoru ≥ 1,5cm2 (měřeno v axiální rovině) dle časné pooperační MRI bez nebo s
    kontrastem, centrálně přezkoumaná;
    - bez metastáz v CNS dle MRI (lebky a páteře), centrálně přezkoumaná;
    - bez nádorových buněk v mozkomíšním moku za použití cytospinu
    - bez klinických známek metastáz mimo CNS
    Pacienti po druhé operaci s reziduem zbytkového nádoru ≥ 1,5cm2 jsou vhodní, pokud bude dodržen časový harmonogram zahájení radioterapie.
    d)Předložení vysoce kvalitního biologického materiálu včetně čerstvých zmrazených nádorových vzorků pro molekulární posuzování biologických markerů (jako je posouzení počtu kopií genu MYC) v národních biologických referenčních centrech. Poskytnutí krve je povinné pro všechny pacienty, kteří souhlasí se studiemi na zárodečné DNA. Doporučuje se poskytnout mozkomíšní mok.
    e)Není amplifikace MYC nebo MYCN (za použití FISH);
    f)Biologický profil nízkého rizika definován jako podskupina s pozitivitou WNT. WNT podskupina je definována přítomností (i) mutace β-kateninu (povinné testování), nebo (ii), jadernou imunopozitivitou β-kateninu vyšetřenou IHC metodou (povinné testování) a mutací β-kateninu, nebo (iii) jadernou imunopozitivitou dle IHC a monosomíí (dobrovolné testování).
    g)Žádná předchozí terapie meduloblastomu kromě operace;
    h)Radioterapie zahájená ne později než 28 dní po operaci. Pacient, u něhož se předpokládá neschopnost zahájit radioterapii do 40 dnů od operace, je nevhodný pro studii
    i)Screening s dodržením kritérií způsobilosti by měl být ukončen a pacient by měl být zařazen do studie do 28 dnů po prvním chirurgickém zákroku (v případě druhého chirurgického zákroku do 35 dnů po první operaci). Zařazení pacientů není možné po 40. dnu od první operace nádoru, nebo po zahájení ozařování.
    j)CTC stupně < 2 pro jaterní, ledvinné a hematologické funkce
    k)Žádný významný deficit percepce sluchu, při audiometrii definován jako čistý tón s kostním vedením nebo vzduchovým vedením a normální tympanogram nevykazující poškození ≥ 20 dB 1-3 kHz. Není-li při audiometrii po operaci zaznamenána produkce čistého tónu normální otoakustické emise jsou přijatelné, pokud nejsou v anamnéze údaje svědčící pro sluchový deficit.
    l)Žádné kontraindikace radioterapie nebo chemoterapie jako jsou preexistující syndromy s poškozenou DNA (např. Fanconiho anémie, Nijmegenův syndrom lomivosti), Gorlinův syndrom nebo jiné důvody, definované pacientovým lékařem;
    m)Není přítomen Turcot a Li Fraumeni syndrom.
    n)Písemný informovaný souhlas (a svolení pacienta v případě potřeby) s léčbou v souladu s právními předpisy každé zúčastněné země. Pacientovi musí být poskytnuta informace o biologických studiích (nádorových a zárodečných), a musí být získán písemný informovaný souhlas se svolením k účastí.
    o)Souhlas národní a místní etické komise v souladu s právními předpisy každé ze zúčastněných zemí (zahrnující schválení biologických studií).

    Léčebné rameno - SR, stejně jako výše s výjimkou a,f:
    a)věk v době stanovení diagnózy, nejméně 3 – 5 let (závisí od jednotlivé země) a méně než 22 let. Datum stanovení diagnózy je datum operace.
    f)Biologický profil středního rizika je definován jako podskupina s negativitou WNT. WNT negativní tumory jsou definovány (i) β-kateninovou jadernou imunonegativitou za použití IHC (povinné testování), absencí mutace β-kateninu (povinné testování) a monosomií 6 (dobrovolné testování), nebo (ii) jadernou imunopozitivitou β-kateninu vyšetřenou IHC metodou (povinné testování) za absence mutace β-kateninu a monosomie 6, nebo (iii) monosomií 6 za absence β-kateninové jaderné imunopozitivity za pouzití IHC nebo mutace β-kateninu.
    Podskupina WNT pozitivních nádorů vzniká u pacientů diagnostikovaných ve věku ≥16 let. WNT podskupina je definována přítomností (i) mutace β-kateninu (povinné testování), nebo (ii) β-kateninovou jadernou imunopozitivitou za použití IHC (povinné testování) a β -kateninovou mutací, nebo (iii) β - catenin jadernou imuno-pozitivitou za použití IHC a monosomií 6 (dobrovolné testování).
    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)Jedno z vstupních kritérií chybí
    b)Primitivní neuro-ektodermální nádor supratentoriální nebo mozkového kmene
    c)Atypický teratoidní/rabdoidní nádor;
    d)Meduloepiteliom; Ependymoblastom
    e)Velkobuněčný meduloblastom, anaplastický meduloblastom, nebo meduloblastom s extenzívní nodularitou (MBEN), potvrzený a centrálně zhodnocený patologem
    f)Nepříznivý nebo neurčitelný biologický profil, definovaný jako amplifikace MYC nebo MYCN, nebo neurčitelná WNT podskupina
    g)Metastazující meduloblastom (dle CNS MRI a / nebo pozitivní cytospin z mozkomíšního moku po operaci;
    h)Pacient dříve léčený pro mozkový nádor nebo pro jiné zhoubné onemocnění;
    i) Syndromy s poškozenou DNA (např. Fanconiho anémie, Nijmegenův syndrom lomivosti) nebo jiné syndromy, nebo Gorlinův, Turcotův, či Li
    Fraumeni syndrom
    j) Pacientky, které jsou těhotné;
    k)Pacientky, které jsou sexuálně aktivní a neberou spolehlivou antikoncepci;
    l) Pacienti, kteří nemohou být pravidelně sledováni z důvodů psychologických, sociálních, rodinných nebo geografických;
    m)Pacienti, u kterých se předpokládá, že nebudou dodržovat pokyny vázané na toxicitu
    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
    Primárním hodnotícím kritériem v rameni SR je přežití bez příhody (EFS).
    Primárním hodnotícím kritériem je EFS parametr 3- letého přežití bez příhody v rameni 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
    Léčebné rameno - LR: 3 roky po vstupu posledního pacienta
    Léčebné rameno - SR: po 105 příhodách (relapsech) nebo po očekávaném follow upu 4 roky po vstupu posledního pacienta
    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) EFS - přežití bez příhody
    2) OS - celkové přežití
    3) OSend - celkové přežití
    4) PFS - přežití bez progrese
    5) Proveditelnost léčby karboplatinou
    6) Reziduální nádor (< 1.5 cm2) pooperačně, odečtěný prostřednictvím MRI na základě posudku z centrály
    7) Zhodnocení relapsu bude provedeno na konci léčby
    8) Nepřímá měření kvality přežití
    9) Ototoxicita
    10) Endokrinní funkce
    11) Neurologické funkce
    12) Biologické markery nádoru
    13) Leukoencephalopatie (LEP)
    14) Audit na dodržování protokolem definované terapie

    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)
    Po očekávaném follow upu 4 roky po vstupu posledního pacienta (obě ramena)
    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
    SR rameno: skupina s karboplatinou během radioTP oproti skupině s radio TP bez karboplatiny
    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 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 concerned2
    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
    Poslední pacient, poslední návštěva
    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 2016-10-21. 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.
    U dětí a adolescentů, kteří jsou ještě mladí pro podpis informovaného souhlasu, bude dle národních pravidel informovaný souhlas získán od rodičů. Informované svolení pacienta bude obdrženo dle národních požadavků.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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.
    Vzhledem k závažnosti, chronické povaze onemocnění a dlouhodobým následkům, které onemocnění s sebou nese, podstoupí pacienti další navazující návštěvy jako součást standardní péče. Budou hlášeny příhody i potíže.
    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 Onology
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-08
    P. End of Trial
    P.End of Trial StatusOngoing
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