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    Summary
    EudraCT Number:2013-002766-39
    Sponsor's Protocol Code Number:ET13-002
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2014-01-21
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-002766-39
    A.3Full title of the trial
    SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma
    A.3.2Name or abbreviated title of the trial where available
    SIOP Ependymoma II
    A.4.1Sponsor's protocol code numberET13-002
    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 SponsorCENTRE LEON BERARD
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPHRC 2012
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportSFCE
    B.4.2CountryFrance
    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 organisationCENTRE LEON BERARD
    B.5.2Functional name of contact pointDRCI- Pôle opérations cliniques
    B.5.3 Address:
    B.5.3.1Street Address28 rue Laennec
    B.5.3.2Town/ cityLyon Cedex 08
    B.5.3.3Post code69008
    B.5.3.4CountryFrance
    B.5.4Telephone number33426556829
    B.5.5Fax number33478782715
    B.5.6E-mailjulien.gautier@lyon.unicancer.fr
    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 nameVincristine
    D.3.2Product code VCR
    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 INNVINCRISTINE
    D.3.9.1CAS number 57-22-7
    D.3.9.2Current sponsor codeVCR
    D.3.9.4EV Substance CodeSUB00059MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEtoposide
    D.3.2Product code VP16
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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.2.5The 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.3.2Product code CPM
    D.3.4Pharmaceutical form Powder 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 50-18-0
    D.3.9.2Current sponsor codeCPM
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number500 to 1000
    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.2.5The 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.3.2Product code CDDP
    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.3.9.2Current sponsor codeCDDP
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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.2.5The 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.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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: 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 nameSodium Valproat
    D.3.2Product code VPA
    D.3.4Pharmaceutical form
    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 INNSODIUM VALPROATE
    D.3.9.1CAS number 1069-66-5
    D.3.9.2Current sponsor codeVPA
    D.3.9.4EV Substance CodeSUB12318MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeup to
    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: 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 nameMethotrexate
    D.3.2Product code MTX
    D.3.4Pharmaceutical form Concentrate 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 INNMETHOTREXATE
    D.3.9.1CAS number 59052
    D.3.9.2Current sponsor codeMTX
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Newly diagnosed with an intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary, myxopapillary, clear-cell and tanycytic) or anaplastic ependymoma.
    E.1.1.1Medical condition in easily understood language
    ependymoma brain tumour
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014967
    E.1.2Term Ependymoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •Overall program
    To determine whether the assessment of residual disease can be improved by a centralized review of post-operative MRI and whether such review increases the rate of complete resection compared to historical controls. Does central neurosurgical and radiological review increase resection rates?

    •Stratum 1
    To compare PFS in patients who receive 16 weeks chemotherapy with VEC+CDDP following complete surgical resection, with no residual disease, and radiotherapy when compared to those that undergo complete surgical resection, with no residual disease, and radiotherapy alone.

    •Stratum 2
    To compare the activity of 2 post-operative chemotherapy schedules with VEC or VEC+HD-MTX in patients who have incompletely resected tumour.

    •Stratum3
    To evaluate the PFS in children unable to receive radiation therapy and who receive valproate, as a HDCAI in addition to the primary chemotherapy strategy when compared to those that undergo chemotherapy without valproate.
    E.2.2Secondary objectives of the trial
    •Overall program
    To evaluate second look surgery rates as compared to historical controls

    •Stratum 1
    To describe in both study arms, the efficacy in each molecular sub-group (stratum 2 and 3)
    To evaluate whether OS is improved
    To compare the neuroendocrine morbidity
    To evaluate the QoS
    To evaluate the neuropsychological morbidity
    To determine the safety and the tolerance

    •Stratum 2
    To determine the safety and tolerability
    To evaluate whether OS is improved
    To evaluate whether PFS is improved
    To compare neuroendocrine morbidity
    To evaluate the QoS
    To evaluate the neuropsychological morbidity
    To determine Safety of 8 Gy Boost radiotherapy

    •Stratum 3
    To evaluate whether OS is improved
    To evaluate whether radiotherapy free survival is improved
    To compare the neuroendocrine morbidity
    To evaluate the Quality of Survival
    To evaluate the neuropsychological morbidity
    To determine the safety and tolerability of valproate
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Integrated Biological Study:
    This part of the program will be organised by the European Ependymoma biology consortium called “Biomarkers of Ependymomas in Children and Adolescents (BIOMECA)” throughout a cooperation agreement with the aim to identify informative prognostic biomarkers for assessment of disease status and predictive response to therapy. The SIOP Ependymoma Program II supports the identification of informative prognostic biomarkers within the collaborative BIOMECA study. This high priority initiative is an essential element of the overall program to improve future treatment of ependymoma.

    Exploratory objectives:
    •To test the hypothesis that key molecular events are predictive of clinical behaviour of ependymoma.
    •To identify new biomarkers for Ependymoma clinical and biological behaviour (location, recurrence, chemo resistance, invasion, metastasis).
    •To validate known biomarkers in the context of the new international prospective study for newly diagnosed Ependymoma
    •To provide a new comprehensive grading scheme based on the histological, and immunohistochemical and/or biological criteria that could be used for newly diagnosed Ependymoma.
    •To validate and compare the techniques to assess biomarkers for further use in the stratification of patients
    •To select the best biomarker(s) and establish a prognostic signature for ependymoma.
    •To prospectively evaluate 1q and 6q copy-number status, Tenascin C, RELA-fusion, YAP fusion, H3.3K27me3 and molecular subgroup (by methylation array) as prognostic and predictive biomarkers in ependymoma within clinical trial setting in addition to a number of exploratory markers.
    E.3Principal inclusion criteria
    Overall program
    •Main residence in one of the participating countries
    •Age < 22 years old at the diagnosis
    •Newly diagnosed intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary myxopapillary, clearcell and tanicytic) or anaplastic ependymoma
    •Delivery of FFPE tumour tissue blocks (or charged slides with sufficient interpretable material and curls in an Eppendorf tube) to national referral pathology center
    •Written informed consent for data and study biological samples collection
    •All patients and/or their parents or legal guardians willing and able to comply with protocol schedule and agree to sign a written informed consent
    •Patients must be affiliated to a Social Security System in countries where this is mandatory

    After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy.

    Patients with centrally and histologically confirmed intracranial ependymoma (histology confirmed by National Reference centre for Biology and Pathology review) meeting the following criteria will be enrolled into one of interventional strata:

    •Main residence in one of the participating countries,
    •Age below 22 years old at the diagnosis,
    •Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: cellular, papillary, clear-cell and tanycytic or anaplastic ependymoma.
    •Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial,
    •Males and females of reproductive age and childbearing potential with effective contraception (see section 4.1.2.4 Definition of highly effective methods of contraception) for the duration of their treatment and 6 month after the completion of their treatment,
    •Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure

    Specific inclusion criteria have been defined for each stratum of the program.

    Stratum 1:
    •Age ≥ 12 months and < 22 years at time of study entry
    •No residual measurable ependymoma based on the central neuroradiological review (detailed in protocol)
    •Histologically confirmed WHO Grade II-III ependymoma by central pathological review
    •No metastasis on spinal MRI and on CSF cytology assessments
    •No previous radiotherapy
    •No previous chemotherapy
    •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
    •No medical contraindication to radiotherapy and chemotherapy,
    •No signs of infection
    •Adequate bone marrow function(detailed in protocol)
    •Adequate liver function (detailed in protocol)
    •Adequate renal function (detailed in protocol)

    Stratum 2:
    •Age ≥ 1 year and <22 years at time of entry to study
    •Residual non reoperable measurable ependymoma based on central neuro-radiological review (detailed in protocol)
    •Histologically confirmed WHO Grade II-III ependymoma by central pathological review
    •No metastasis on spinal MRI and on CSF cytology assessments
    •No previous radiotherapy
    •No previous chemotherapy
    •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
    •No medical contraindication to radiotherapy and chemotherapy,
    •No signs of infection
    Adequate bone marrow function( detailed in protocol)
    •Adequate liver function (detailed in protocol)
    •Adequate renal function (detailed in protocol)


    Stratum 3
    •Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician/parent decision and according to national criteria
    •Histologically confirmed WHO Grade II-III ependymoma by central pathological review
    •Adequate bone marrow function(detailed in protocol)
    •Adequate liver function (detailed in protocol)
    •Adequate renal function (detailed in protocol)
    •No previous chemotherapy
    •No previous radiotherapy
    •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
    •No contraindication to chemotherapy

    Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed
    E.4Principal exclusion criteria
    All interventional stata
    •Tumour entity other than primary intracranial ependymoma
    •Primary diagnosis predating the opening of SIOP Ependymoma II
    •Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas
    •Patients with spinal cord location of the primary tumour
    •Participation within a different trial for treatment of ependymoma
    •Age ≥ 22 years
    •Contraindication to one of the IMP used in this stratum according to the SmPCs in appendix 4 of the study protocol (SmPCs in appendices are those from UK which were chosen for the assessment of the safety as aspects of the study)
    •Concurrent treatment with any anti-tumour agents
    •Inability to tolerate chemotherapy
    •Unable to tolerate intravenous hydration
    •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the Investigator
    •Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion
    •Pregnancy and breast feeding

    Stratum 1 and 2:
    •Ineligible to receive radiotherapy
    •Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion
    •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator

    Stratum 3:
    •Pre-existing severe hepatic (liver) and/or renal (kidney) damage
    Family history of severe epilepsy
    •Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial
    •Elevated blood ammonium level ≥ 1.5 x upper limit of the normal
    •Elevated Blood lactate level ≥ 1.5 x upper limit of the normal
    •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator
    E.5 End points
    E.5.1Primary end point(s)
    Overall program: Gross Total Resection (GTR) rate (Only descriptive statistics will be produced)

    Stratum 1 Progression free survival from the date of randomisation to the date of event defined as progression or death due to any cause.

    Stratum 2: Number of chemotherapy responders. Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.

    Stratum 3: Progression free survival from the date of randomisation to the date of event defined as progression or death due to any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Stratum 1:The final analysis of trial data will be performed after 3 years follow-up of the last included patient.

    Stratum 2:The first main analysis of trial data will take place 6 months after the final patient has been entered into the study, when response data from all patients will be available.

    Stratum 3:
    The first main analysis of trial data for primary outcome will take place 2.5 years after the final patient has been entered into the study.
    E.5.2Secondary end point(s)
    Overall program:
    Second look surgery rate (Only descriptive statistics will be produced)

    •Startum 1:
    Overall survival measured from the date of randomisation to the date of death due to any cause.
    Quality of survival (QoS)
    Neuropsychological outcomes
    Neuroendocrine outcomes (Neuroendocrine late effects)
    Short and long term Safety: Adverse Events (CTCAE v4.03)

    •Stratum 2:
    Overall survival measured from the date of randomisation to the date of death due to any cause.
    Progression Free Survival from the date of randomisation to the date of event defined as progression or death due to any cause.
    Quality of survival (QoS)
    Neuropsychological outcomes
    Neuroendocrine outcomes (Neuroendocrine late effects)
    Short and long term safety of frontline chemotherapy: Adverse Events (CTCAE v4.03)

    Exploratory endpoint measure:
    Toxicity will be monitored in the subgroup receiving radiotherapy boost.
    Event Free survival for patients with boost of radiotherapy.


    •Stratum 3:
    Overall survival measured from the date of randomisation to the date of death due to any cause.
    Radiotherapy free survival rate
    Quality of survival (QoS)
    Neuropsychological outcomes
    Neuroendocrine outcomes (Neuroendocrine late effects)
    Short and long term Safety and Toxicity of frontline chemotherapy based on proportion of patients experiencing Toxicity grade 3 to 4 (Adverse Events (CTCAE v4.03)).

    Exploratory Endpoint measures (optional):
    Pharmacokinetic modelling will be carried out using Valproate pharmacokinetic parameters in conjunction with patient characteristics and clinical parameters in order to investigate the key factors involved in determining individual valproate drug exposures within the patient population.
    •Valproate pharmacodynamics will be followed throughout changes in histone H3 and H4 acetylation. Changes between baseline and time of steady state valproate will be correlated with valproate trough levels and clinical response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Stratum 1:
    5 years after the last patient recruited has completed his treatment

    Stratum 2:
    5 years after the last patient recruited has completed his treatment

    Stratum 3:
    5 years after the last patient recruited has completed his treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life, quality of survival, neuropsychological and neuroendocrine morbidity.
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Stratum1:Observation/Stratum2:VEC alone/Stratum3:Standard alterned ± myelosuppressive chemotherapy
    E.8.2.4Number of treatment arms in the trial6
    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 concerned59
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months2
    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: 536
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 100
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 311
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 100
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children under age of giving consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 536
    F.4.2.2In the whole clinical trial 536
    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)
    After the end of the trial, best treatment plan will be decided by each investigator according to the state of health of the patient concerned.
    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 SFCE: Société française de lutte contre les cancers et les leucemies de l'Enfant et de l'adolescent
    G.4.3.4Network Country France
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation SIOP: Société Internationale d'oncologie Pediatrique
    G.4.3.4Network Country Switzerland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-13
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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