Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41231   clinical trials with a EudraCT protocol, of which   6758   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2012-000072-42
    Sponsor's Protocol Code Number:RG_11-087
    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:2014-04-01
    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 number2012-000072-42
    A.3Full title of the trial
    A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma ? BEACON-Neuroblastoma Trial
    Estudio aleatorizado de fase IIb con bevacizumab asociado a temozolomida ± irinotecán en niños y jóvenes con neuroblastoma resistente o recidivante ? Ensayo BEACON-Neuroblastoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomised trial of bevacizumab added to temozolomide with our without irinotecan for children with neuroblastoma that has relapsed, or is resistant to current treatment
    Estudio aleatorizado de bevacizumab añadido a la temozolamida con o sin irinotecan para niños con neuroblastoma en recaída o resistente al tratamiento actual.
    A.3.2Name or abbreviated title of the trial where available
    BEACON-Neuroblastoma Trial: Bevacizumab, Temozolomide ± Irinotecan
    A.4.1Sponsor's protocol code numberRG_11-087
    A.5.4Other Identifiers
    Name:ITCC-Innovative therapies for children with cancerNumber:032
    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 SponsorThe University of Birmingham
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCancer Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportF. Hoffman-La Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINSTITUTO DE INVESTIGACION SANITARIA LA FE
    B.5.2Functional name of contact pointUREC
    B.5.3 Address:
    B.5.3.1Street AddressAV. BULEVAR SUR S/N
    B.5.3.2Town/ cityValencia
    B.5.3.3Post code46026
    B.5.3.4CountrySpain
    B.5.4Telephone number34961246611
    B.5.5Fax number34961246620
    B.5.6E-mailinvestigacion_clinica@iislafe.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTemozolomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTemozolomide
    D.3.9.1CAS number 85622-93-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number250
    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 RoleComparator
    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 AuthorisationEuropean Union
    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 nameIrinotecan hydrochloride trihydrate
    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 INNIrinotecan hydrochloride trihydrate
    D.3.9.1CAS number 100286-90-6
    D.3.9.4EV Substance CodeAS2
    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.2.1.1.1Trade name Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameBevacizumab
    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 INNBevacizumab
    D.3.9.1CAS number 216974-75-3
    D.3.9.3Other descriptive namerhuMAb VEGF, antiVEGF
    D.3.9.4EV Substance CodeAS3
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Neuroblastoma
    Neuroblastoma
    E.1.1.1Medical condition in easily understood language
    Neuroblastoma is a cancer of specialised nerve cells called neural crest cells. These cells are involved in the development of the nervous system and other tissues.
    El neuroblastoma es un tumor de las células de la cresta neural.
    Estas células están implicadas en el desarrollo del sistema nervioso y otros
    tejidos.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10029261
    E.1.2Term Neuroblastoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide or irinotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma

    - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma
    - Comprobar si la adición del bevacizumab a una pauta quimioterápica básica (temozolomida o irinotecán+temozolomida) demuestra actividad en los niños con neuroblastoma resistente o recidivante.
    - Comprobar si la adición del irinotecán a la temozolomida aumenta la actividad de la quimioterapia en niños con neuroblastoma resistente o recidivante.
    E.2.2Secondary objectives of the trial
    To evaluate the safety of the above therapy regimens and to compare how the combinations influence the frequency of relapsing and prolong the survival of treated patients.
    - Evaluar la seguridad (toxicidad) de las pautas empleadas y comparar la forma en que las diferentes combinaciones influyen en la frecuencia de las recaídas y prolongan la supervivencia de los pacientes tratados.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Disease specific

    ? Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
    ? Relapsed or refractory neuroblastoma
    o Relapsed: any relapsed or progressed high-risk neuroblastoma
    o Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g myeloablative chemotherapy)
    ? Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study

    General

    ? Age ?1 to ?21 years
    ? Informed consent from patient, parent or guardian

    Performance and organ function

    ? Performance Status:
    o Lansky ? 50%, Karnofsky ? 50% or ECOG ?3
    (Patients who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score)
    ? Life expectancy of ?12 weeks
    ? Bone marrow function (within 72 hours of eligibility assessment):
    o No bone marrow disease:
    ? Platelets ? 75 x 10e9/L (unsupported for 72 hours)
    ? ANC ? 0.75 x 10e9/L (no G-CSF support for 72 hours)
    ? Haemoglobin > 7.5 g/dL (transfusions allowed)
    o Bone marrow disease:
    ? Platelets ? 50 x109/L (unsupported for 72 hours)
    ? ANC ?0.5 x 10e9/L (no G-CSF for 72 hours)
    ? Haemaglobin > 7.5 g/dL (transfusions allowed)
    ? Renal function (within 72 hours of eligibility assessment):
    o Absence of clinically significant proteinuria (early morning urine dipstick ?2+). When the dipstick urinalysis shows a proteinuria > 2+, a protein:creatinine (Pr/Cr) ration must be < 0.5 or a 24 hour protein excretion must be < 0.5g
    o Serum creatinine ?1.5 ULN for age, if higher, a calculated GFR (radioisotope) must be ? 60 ml/min/1.73 m2
    ? Liver function (within 72 hours of eligibility assessment): AST and ALT ?2.5 ULN and total bilirubin ?1.5 ULN. In case of liver metastases, AST and ALT ?5 ULN and total bilirubin ?2.5 ULN
    ? Cardiac function, shortening fraction ?29% on echocardiogram
    ? Coagulation, patients not on anticoagulation must have an INR ?1.5 and APTT ?1.5 ULN for age. Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment. Blood pressure below 95th centile for age and sex. Use of antihypertensive medication is permitted
    ? Males or females of reproductive potential may not participate unless they agree to use an effective contraceptive method, for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche
    Específicos de la enfermedad
    ? Neuroblastoma con confirmación histológica según definición INSS (Sistema Internacional de Estadificación del Neuroblastoma).
    ? Neuroblastoma resistente o recidivante.
    o Tumor recidivante: cualquier neuroblastoma de alto riesgo con recidiva o progresión.
    o Tumor resistente de alto riesgo: ausencia de respuesta suficiente al tratamiento de primera línea que impide al paciente pasar a los tratamientos de consolidación (p. ej., quimioterapia mieloablativa).
    ? Tumor mensurable mediante imagen transversal (RECIST) o evaluable (captación en gammagrafía con MIBG, con o sin histología de médula ósea). Los pacientes con tumor detectable exclusivamente en la médula ósea (biopsia por trépano o aspiración de médula ósea) NO se consideran aptos para el estudio.
    Generales
    ? Edad: de ? 1 a ? 21 años.
    ? Consentimiento informado firmado por el paciente, progenitor o tutor.
    Estado funcional y funciones orgánicas
    ? Estado funcional:
    o Lansky ? 50%, Karnofsky ? 50% o ECOG ? 3.
    (Los pacientes incapaces de caminar por parálisis, pero con capacidad de sedestación sin ayuda en una silla de ruedas, se consideran deambulantes para la valoración del estado funcional).
    ? Esperanza de vida ? 12 semanas.
    ? Función de la médula ósea (en las 72 horas previas a la evaluación de idoneidad).
    o Médula ósea sana:
    ? Plaquetas ? 75 × 109/l (sin apoyo durante 72 horas).
    ? Neutrófilos ? 0,75 × 109/l (sin apoyo con G-CSF durante 72 horas).
    ? Hemoglobina ? 7,5 g/dl (se permiten transfusiones).
    o Médula ósea afectada:
    ? Plaquetas ? 50 × 109/l (sin apoyo durante 72 horas).
    ? Neutrófilos ? 0,5 × 109/l (sin apoyo con G-CSF durante 72 horas).
    ? Hemoglobina ? 7,5 g/dl (se permiten transfusiones).
    ? Función renal (en las 72 horas previas a la evaluación de idoneidad):
    o Ausencia de proteinuria de trascendencia clínica (tira reactiva en primera orina de la mañana < ++). Si en la tira se aprecia proteinuria ? ++, debe demostrarse un cociente proteínas/creatinina (Pr/Cr) < 0,5 o proteinuria total < 0,5 g en orina de 24 horas.
    o Creatinina sérica ? 1,5 LSN (límite superior de la normalidad, ajustado para la edad); si fuera superior, el FG calculado por gammagrafía debe ser ? 60 ml/min/1,73 m2.
    ? Función hepática (en las 72 horas previas a la evaluación de idoneidad): ASAT o ALAT ? 2,5 LSN y bilirrubina total ? 1,5 LSN. En caso de metástasis hepáticas, ASAT o ALAT ? 5 LSN y bilirrubina total ? 2,5 LSN.
    ? Función cardíaca: fracción de acortamiento ? 29% por ecocardiografía.
    ? Pruebas de coagulación: pacientes no anticoagulados con IIN ? 1,5 y TTPa ? 1,5 LSN ajustado para la edad; se permite la anticoagulación si el IIN o la TTPa están dentro de los límites terapéuticos (según criterios habituales del centro) y el paciente lleva recibiendo una dosis estable de anticoagulantes durante al menos las dos semanas previas a su incorporación al estudio.
    ? Tensión arterial < centil 95 por edad y sexo; se permite el tratamiento antihipertensor.
    Los pacientes de ambos sexos en edad de procrear no pueden participar en el estudio a menos que se comprometan a utilizar un método anticonceptivo eficaz mientras dure el tratamiento en estudio y hasta 6 meses después de la última dosis de los fármacos en estudio. En las chicas que hayan pasado la menarquia, debe obtenerse una prueba negativa de embarazo en orina en las 72 horas previas a la primera dosis.
    E.4Principal exclusion criteria
    ? Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
    ? Known hypersensitivity to:
    o Any study drug or component of the formulation
    o Chinese hamster ovary products or other recombinant human or humanised antibodies
    ? Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis)
    ? Any ongoing arterial thrombo-embolic events
    ? Patient less than (at point of eligibility assessment):
    o 48 hours post bone marrow aspirate/trephine
    o 48 hours post central line insertion
    o Four weeks post major surgery
    o One week post core biopsy
    o Two weeks from prior chemotherapy
    o Six weeks from prior craniospinal or MIBG therapy and two weeks from radiotherapy to the tumour bed
    o Eight weeks from prior myeloablative therapy with haempoietic stem cell rescue (autologous stem cell transplant)
    o Three months from prior allogeneic stem cell transplant
    o Two weeks from last administration of an IMP in an IMP-trial
    ? Bleeding metastases (Patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
    ? Invasion of major blood vessels
    ? Use of enzyme inducing anticonvulsants within 72 hours of eligibility assessment
    ? History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)
    ? History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment
    ? Pregnant or lactating patient
    ? Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
    ? Low probability of treatment compliance
    ? Tratamiento previo con bevacizumab, temozolomida, irinotecán o cualquier combinación de estos fármacos
    ? Antecedentes de hipersensibilidad a:
    o Cualquiera de los fármacos en estudio o ingredientes de la formulación.
    o Productos derivados de células CHO (ovario de hámster chino) u otros anticuerpos recombinantes humanos o humanizados.
    ? Antecedentes de episodios tromboembólicos arteriales graves (p. ej.: isquemia cardíaca, accidente cerebrovascular, trombosis arterial periférica).
    ? Episodios tromboembólicos arteriales en curso.
    ? Intervalo transcurrido (en el momento de evaluar la idoneidad) inferior a:
    o 48 horas tras biopsia por trépano o aspiración de médula ósea.
    o 48 horas tras colocación de una vía central.
    o Cuatro semanas tras operación de cirugía mayor.
    o Una semana tras biopsia con aguja gruesa.
    o Dos semanas tras quimioterapia previa.
    o Seis semanas tras radioterapia craneoespinal o tratamiento con MIBG y dos semanas tras radioterapia del lecho tumoral.
    o Ocho semanas tras tratamiento mieloablativo con rescate de células progenitoras hematopoyéticas (autotrasplante de células progenitoras).
    o Tres meses tras alotrasplante de células progenitoras.
    o Dos semanas tras la última administración de un medicamento en investigación en un ensayo clínico.
    ? Metástasis hemorrágicas (se permite la participación de pacientes con metástasis en el SNC siempre que las metástasis no estén sangrando).
    ? Invasión de grandes vasos sanguíneos.
    ? Uso de anticonvulsivos inductores enzimáticos en las 72 horas previas a la evaluación de idoneidad.
    ? Antecedentes o indicios de diátesis hemorrágica hereditaria o coagulopatía importante con riesgo de hemorragia (esto es, sin anticoagulación terapéutica).
    ? Antecedentes de fístula abdominal, perforación gastrointestinal, absceso intrabdominal o hemorragia digestiva activa en los 6 meses previos a la incorporación al estudio.
    ? Embarazo o lactancia.
    ? Cualquier enfermedad no controlada que suponga algún riesgo añadido para el paciente (p. ej., hemoptisis, alteraciones de la cicatrización, fracturas óseas, úlceras y heridas).
    ? Expectativas de escaso cumplimiento terapéutico.
    Vacunación programada con vacunas elaboradas con microbios vivos.
    E.5 End points
    E.5.1Primary end point(s)
    Best response (Complete Response [CR], or Partial Response [PR]) at any time during the 6 cycles of trial treatment.
    Mejor respuesta (respuesta completa [RC] o respuesta parcial [PR]) en cualquier momento durante los 6 primeros ciclos del tratamiento en estudio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response will be assessed after 2, 4 and 6 cycles of trial treatment.
    La respuesta se evaluará después de los ciclos 2, 4 y 6 de tratamiento.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    - Safety of the combinations: Incidence and severity of Adverse Events (AE)s
    - Progression-free survival (PFS)
    - Overall survival (OS)

    Exploratory/Tertiary Endpoints:
    - Changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: ? Primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2*.
    - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples
    - Pharmacokinetics of bevacizumab
    - Pilot descriptive study of angiogenesis markers that may include:
    o O6-methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling
    o Optional somatic DNA analysis of polymorphisms in genes implicated in angiogenesis and tumorigenesis (such as VEGFR1, VEGFA SNPs)
    o Levels and dynamics of circulating angiogenic cytokines throughout the treatment
    Criterios de valoración Secundarios:
    -Seguridad de las pautas empleadas: incidencia e intensidad de acontecimientos adversos (AA).
    - Supervivencia sin progresión (SVSP).
    - Supervivencia global (SVG).

    Criterios de valoración Terciarios:
    - Cambios en los biomarcadores de la angiogénesis mediante análisis funcional por RM, determinados por RM cuantitativa de contraste dinámico: como biomarcadores primarios se utilizarán la constante de transferencia Ktrans [min?1] y el área inicial bajo la curva de captación del gadolinio de 0 a 60 segundos (AIBCG60, mM Gd min); como biomarcadores secundarios, el coeficiente aparente de difusión tumoral (CAD, 10?6 cm2 s?1), los tiempos naturales de relajación T1 y T2 (ms) y la tasa de relajación transversal R2*.
    - Cambios en los valores circulantes de ARNm para TH, PHOX2B y DCX en muestras de sangre y médula ósea.
    - Farmacocinética del bevacizumab.
    - Estudio piloto descriptivo de marcadores de angiogénesis:
    o O6-metilguanina-metiltransferasa (MGMT), inmunohistoquímica y marcadores de inmunofluorescencia en muestras tumorales (como densidad de microvasos (DMV), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), extracción de ADN/ARN a partir de cortes tisulares para cribado de mutaciones tumorales y perfilado de la expresión tumoral.
    o Análisis optativo de ADN somático para polimorfismos en los genes implicados en la angiogénesis y la oncogénesis (como SNP de VEGFA, VEGFR1).
    Concentración y dinámica de citocinas angiógenas circulantes durante el tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up until the last follow up
    Hasta el último seguimiento.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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
    For the purposes of the Competent Authorities, the end of trial will be 6 months after the last patient has completed treatment. This will allow sufficient time for the completion of protocol procedures, data collection and data input. For the purposes of the main REC approval, the trial end date is deemed to be 12 months after the last data capture following 5 years of long-term follow-up.
    A los efectos de las autoridades competentes, al final del ensayo será de 6 meses después del último paciente haya completado el tratamiento. Esto le dará tiempo suficiente para completar los procedimientos del protocolo, la recopilación de datos y la entrada de datos. A los efectos de la aprobación principal REC, la fecha de finalización del ensayo se considera que 12 meses después de la última captura de datos tras 5 años de seguimiento a largo plazo de seguimiento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years6
    E.8.9.2In all countries concerned by the trial months9
    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: 116
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 71
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children under 12 years.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-05
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA