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    Summary
    EudraCT Number:2013-003579-36
    Sponsor's Protocol Code Number:BAY73-4506/15906
    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:2017-09-18
    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 number2013-003579-36
    A.3Full title of the trial
    A multi-center, open-label, non-randomized, phase I dose escalation study of regorafenib (BAY 73-4506) in pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy.
    Ensayo fase I de escalado de dosis, multicéntrico, abierto, no aleatorizado, de Regorafenib (BAY 73-4506) en pacientes pediátricos con tumores sólidos malignos recurrentes o refractarios al tratamiento estándar.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, tolerability and pharmacokinetics of regorafenib in pediatric subjects.
    Seguridad, tolerabilidad y farmacocinética del regorafenib en pacientes pediátricos
    A.4.1Sponsor's protocol code numberBAY73-4506/15906
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/091/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBayer AG
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post codeD-13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034.900102372
    B.5.6E-mailclinical-trials-contact@bayer.com
    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 No
    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 nameRegorafenib 20 mg coated tablet
    D.3.2Product code BAY 73-4506 TABL 20MG 122 COAT
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNRegorafenib
    D.3.9.1CAS number 755037-03-7
    D.3.9.2Current sponsor codeBAY 73-4506
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 No
    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 nameRegorafenib 5 mg granules
    D.3.4Pharmaceutical form Granules
    D.3.4.1Specific paediatric formulation Yes
    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 INNRegorafenib
    D.3.9.1CAS number 755037-03-7
    D.3.9.2Current sponsor codeBAY 73-4506
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 No
    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 nameRegorafenib 20 mg granules
    D.3.4Pharmaceutical form Granules
    D.3.4.1Specific paediatric formulation Yes
    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 INNRegorafenib
    D.3.9.1CAS number 755037-03-7
    D.3.9.2Current sponsor codeBAY 73-4506
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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.2.1.1.1Trade name Irinotecan cell pharm 20mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holdercell pharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIrinotecan cell pharm 20mg/ml concentrate for solution for infusion
    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
    D.3.9.1CAS number 97682-44-5
    D.3.9.4EV Substance CodeSUB08295MIG
    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: 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.2.1.1.1Trade name cellcristin 1mg/ml solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holdercell pharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 INNvincristine sulphate
    D.3.9.1CAS number 57-22-7
    D.3.9.3Other descriptive nameVINCRISTINE SULFATE
    D.3.9.4EV Substance CodeSUB05101MIG
    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 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 Yes
    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
    RMS and other solid malignant tumors (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor) in which treatment with vincristine/irinotecan is considered backbone chemotherapy at relapse and a scientific rationale to combine irinotecan with regorafenib exists.
    El RMS y otros tumores malignos sólidos (sarcoma de Ewing, hepatoblastoma, neuroblastoma y tumor de Wilms) en los cuales el tratamiento con vincristina e irinotecán se considere quimioterapia de base en recidivas y exista una justificación científica para combinar irinotecán con regorafenib.
    E.1.1.1Medical condition in easily understood language
    Pediatric patients with cancer
    Pacientes pediátricos con cáncer
    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 LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000020935
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally in combination with backbone chemotherapy (vincristine and irinotecan) at relapse in pediatric subjects with rhabdomyosarcoma (RMS) and other solid malignant tumors recurrent or refractory to standard therapy
    •Definir el perfil de seguridad, la DMT y la RP2D de regorafenib administrado por vía oral en combinación con quimioterapia de base (vincristina e irinotecán) en recidivas en pacientes pediátricos con rabdomiosarcoma (RMS) y otros tumores malignos sólidos recurrentes o refractario al tratamiento de estándar
    E.2.2Secondary objectives of the trial
    - To characterize the pharmacokinetics (PK) of regorafenib in combination with vincristine and irinotecan
    - To evaluate the anti-tumor activity of regorafenib in combination with vincristine and irinotecan
    - To characterize the pharmacokinetics (PK) of irinotecan
    - To evaluate pharmacodynamic parameters of regorafenib in combination with vincristine and irinotecan
    - Acceptability and palatability of the regorafenib formulations - tablets and granulates
    •Caracterizar la farmacocinética (FC) de regorafenib en combinación con vincristina e irinotecán.
    •Evaluar la actividad antitumoral de regorafenib en combinación con vincristina e irinotecán
    •Caracterizar la farmacocinética (FC) del irinotecán.
    •Evaluar los parámetros farmacodinámicos de regorafenib en combinación con vincristina e irinotecán
    •Aceptabilidad y palatabilidad de las formulaciones de regorafenib: comprimidos y granulado
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Dose Expansion Phase:
    - Signed Informed Consent Form by subjects and/or subjects’ parents/legal guardians and age appropriate Assent Form by the subjects obtained before any study specific procedure
    - Age: from 6 months to less than 18 years old
    - Diagnosis: subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor) in which treatment with vincristine/irinotecan is considered backbone chemotherapy at relapse and a scientific rationale to combine vincristine/irinotecan with regorafenib exists.
    - Sexually active females of childbearing potential and sexually active males must agree to use adequate contraception before entering the program until at least 3 months after the last study drug administration. Abstinence is considered an adequate contraception method. For sexually active females, 2 forms of highly effective contraception are mandatory. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. Male patients after puberty onset are advised not to father a child during and up to 6 months after vincristine treatment; for all male patients after puberty onset, prior to study treatment, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of vincristine treatment.
    - Female subjects of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.
    - Subjects must have at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For neuroblastoma subjects with osteomedullary disease, the SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma Group) score will be used.
    - Bone scans (if clinically indicated) should be obtained ≤ 12 weeks prior to the start of treatment.
    - Life expectancy of at least 12 weeks from the time of signing informed consent/assent
    - Performance level: Karnofsky ≥ 70% for subjects > 12 years of age and Lansky ≥ 70% for subjects ≤ 12 years of age. Note the performance level should not be considered
    reduced by limitations to movement or play caused by motor paresis or paralysis due to
    disease. Any neurological deficits must have been stable for a minimum of 1 week prior to first dose of study treatment.
    - Adequate hematological function assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
    o Peripheral absolute neutrophil count (ANC): ≥ 1.0 x 10 9/L
    o Platelet count : ≥ 100 x 109/L (transfusion independent)
    o Hemoglobin : ≥ 8.0 g/ dL
    - Adequate renal function defined as creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2
    - International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
    - Lipase ≤ 1.5 x ULN
    - Adequate hepatic function defined as:
    o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3.0 x ULN
    o Total bilirubin (sum of conjugated and unconjugated) ≤ 1.5 ULN
    - Alkaline phosphatase limit ≤ 2.5 x ULN for age (≤ 5 x ULN for subjects with bone tumors)
    FASE DE EXPANSIÓN:
    •Formulario de consentimiento informado firmado por el paciente y/o los padres/tutores legales del paciente y formulario de asentimiento adecuado a la edad firmado por el paciente obtenido antes de cualquier procedimiento específico del estudio
    •Edad: pacientes de 6 meses a menos de 18 meses
    •Los pacientes deben presentar RMS o un tumor maligno sólido (sarcoma de Ewing, hepatoblastoma, neuroblastoma y tumor de Wilms) recidivante o refractario al tratamiento en el cual el tratamiento con vincristina e irinotecán se considere quimioterapia de base en recidivas y exista una justificación científica para combinar vincristina/irinotecán con regorafenib.
    •Las pacientes sexualmente activas en edad fértil y los pacientes sexualmente activos deberán aceptar el uso de métodos anticonceptivos adecuados desde antes de participar en el programa hasta como mínimo 3 meses después de la administración de la última dosis del fármaco del estudio. Se recomienda a los pacientes de sexo masculino que ya hayan iniciado la pubertad que no dejen embarazada a su pareja durante y hasta transcurridos 6 meses después de finalizar el tratamiento con vincristina; antes del tratamiento del estudio, todos los pacientes de sexo masculino que ya hayan iniciado la pubertad deberían informarse sobre la conservación de esperma debido a la posibilidad de que se produzca una esterilidad irreversible como consecuencia del tratamiento con vincristina.
    La abstinencia sexual se considera una medida anticonceptiva adecuada. En las pacientes sexualmente activas es obligatorio el uso de dos métodos anticonceptivos altamente eficaces. El investigador o el personal designado deberá aconsejar al paciente para garantizar un control de la natalidad adecuado. En el estudio, los métodos anticonceptivos aceptables se definen como cualquier método (o combinación de métodos) recomendado desde el punto de vista médico, según la práctica clínica habitual .
    •Las pacientes en edad fértil deberán someterse a una prueba de embarazo un máximo de 7 días antes del inicio del tratamiento del estudio, y se deberá documentar un resultado negativo antes del inicio del tratamiento del estudio.
    •Los pacientes deben disponer de al menos una lesión mensurable o evaluable conforme a la versión 1.1. de los Criterios de evaluación de la respuesta en tumores sólidos (RECIST). En los pacientes con neuroblastoma con enfermedad osteomedular, se empleará la puntuación del SIOPEN (Grupo de Neuroblastoma de la Sociedad Internacional de Oncología Pediátrica Europea). Se deben obtener gammagrafías óseas (si están clínicamente indicadas) ≤ 12 semanas antes del inicio del tratamiento.
    •Los pacientes deben disponer de al menos una lesión mensurable o evaluable conforme a la versión 1.1. de los Criterios de evaluación de la respuesta en tumores sólidos (RECIST). En los pacientes con neuroblastoma con enfermedad osteomedular, se empleará la puntuación del SIOPEN (Grupo de Neuroblastoma de la Sociedad Internacional de Oncología Pediátrica Europea). Se deben obtener gammagrafías óseas (si están clínicamente indicadas) ≤ 12 semanas antes del inicio del tratamiento.
    •Esperanza de vida de al menos 12 semanas a partir del momento en el que se firma el formulario de consentimiento informado/asentimiento.
    •Nivel funcional: Karnofsky ≥ 70 % en pacientes > 12 años de edad o Lansky ≥ 70 % en pacientes ≤ 12 años de edad. Téngase en cuenta que el nivel de rendimiento no debe considerarse reducido por limitaciones en el movimiento o el juego causadas por paresia o parálisis motora debida a la enfermedad. Cualquier deficiencia neurológica debe haber permanecido estable durante un mínimo de 1 semana antes de la primera dosis del tratamiento del estudio.
    Los pacientes con tumores cerebrales o metástasis cerebrales deben haber mantenido una dosis estable de corticosteroides durante al menos 1 semana antes de la primera dosis del tratamiento del estudio.
    •La función hematológica adecuada debe evaluarse durante los 7 días previos al inicio del tratamiento del estudio y se deben presentar resultados aceptables según los siguientes criterios analíticos:
    *Recuento absoluto de neutrófilos periféricos (ANC) ≥ 1,0 × 109/l
    *Recuento de plaquetas ≥ 100 x 109/l (independiente de la transfusión)
    *Hemoglobina ≥ 8,0 g/dl
    •Función renal adecuada definida como aclaramiento de creatinina basado en la estimación de Schwartz ≥ 70 ml/min/1,73 m2 (1).
    •Cociente internacional normalizado (INR) ≤ 1,5 y tiempo de tromboplastina parcial (TTP) o tiempo de tromboplastina parcial activada (TTPa) ≤ 1,5 veces el límite superior de la normalidad (LSN).
    •Lipasa ≤ 1,5 veces el LSN
    •Función hepática adecuada definida como:
    *Aspartato-aminotransferasa/alanina-aminotransferasa (AST/ALT) ≤ 3,0 veces el LSN
    *Bilirrubina (suma de la conjugada y la no conjugada) ≤ 1,5 veces el LSN
    *Límite de fosfatasa alcalina ≤ 2,5 veces el LSN según la edad (≤ 5 veces el LSN para pacientes con tumores óseos).
    E.4Principal exclusion criteria
    Dose Expansion Phase
    - Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
    - Subjects with brain tumors or subjects with known CNS metastases
    - Active or uncontrolled infection (> National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Grade 2 at screening).
    - Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
    - Known history of human immunodeficiency virus (HIV) infection
    - Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Bone marrow biopsy and central lines will not be considered as a major surgical procedure.
    - Non-healing wound, ulcer, or bone fracture
    - Seizure disorder requiring medication with: carbamazepine, phenobarbital, phenytoin, ethosuximide, valproic acid, tiagabine, felbamate, tiagabine, zomisamide and lamotrigine. Subjects with history of seizures controlled with levetiracetam or gabapentin are allowed to enter the study.
    - Subjects with uncontrolled baseline hypertension higher than Grade 1 NCICTCAE v.4.0 (recurrent or persistent [≥24 hours] blood pressure [BP] >ULN: BP > the 95th percentile for age, height, and gender measured as described in Appendix 14.5). Additional information about hypertension is provided in Appendix 14.6.
    - Clinically significant bleeding (NCI-CTCAE v. 4.0 Grade 3 or higher) within 30 days before start of study medication
    - Arterial or venous thrombotic or embolic events such as deep vein thrombosis or pulmonary embolism within 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study treatment)
    - Subjects with evidence or history of disorders of coagulation or thrombosis
    - Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure Classification for Children ≥ class 2) and cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
    - History of organ allograft (including allogeneic bone marrow transplant)
    - Unresolved toxicity higher than NCI-CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia, chemotherapy-induced ototoxicity, and, as per above eligibility criteria, anemia with hemoglobin ≥ 8 mg/dL and ANC ≥ 1.0 x 10 9/L )
    - Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE v. 4.0 Grade 2 dyspnea)
    - Any other malignant disease treated prior to study entry
    - Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
    - Pregnancy or breast feeding
    - Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn’s disease or any malabsorption condition
    - Interstitial lung disease with ongoing signs and symptoms at the time of screening
    - Any other serious or unstable illness, or medical, psychological or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject’s participation in the study or evaluation of the study results
    - Close affiliation with the investigational site, e.g. a close relative of the investigator or a dependent person (e.g. employee or student of the investigation site).

    Prohibited prior therapy
    - Other anticancer treatment is prohibited, including any investigational new drugs within 28 days or 5
    drug half-lives (if drug half-life in subjects is known), whichever is shorter (or within 6 weeks for mitomycin C), before start of study treatment. In the dose expansion phase, prior treatment with vincristine and/or irinotecan is permitted but subject must undergo proper washout (5 drug half-lives)
    - Hematopoietic growth factors: within the past 21 days before start of study treatment
    -Radiation therapy: ≤ 4 weeks prior to start of study treatment (≤ 2 weeks if limited field
    radiation therapy); ≥ 6 months must have elapsed if ≥ 50% radiation of pelvis; 3 months
    must have elapsed for cranial-spinal irradiation.
    - Autologous stem cell transplant (without total body irradiation) or stem cell rescue
    within 3 months prior to start of treatment
    - Therapeutic anticoagulation within 3 weeks prior to start of study treatment. Prophylactic anticoagulation of venous or arterial access devices is allowed provided that the requirements for prothrombin time (PT), INR and PTT are met.
    - Strong CYP3A4 inhibitors or CYP3A4 within 2 weeks or 5 drug half-lives whichever is longer, before start of study treatment
    •Tratamiento previo con regorafenib. Pacientes retirados permanentemente de la participación en el estudio no podrán ser readmitidos.
    •Pacientes con tumores cerebrales o los pacientes con metástasis del SNC conocida.
    •Infección no controlada o activa ( [CTCAE del NCI] v. 4.0, G2 en la selección).
    •Hepatitis B o C activa, hepatitis crónica B o C que requiere tto antiviral.
    •Antecedentes conocidos de infección por el virus VIH.
    •Procedimiento quirúrgico mayor o lesión traumática significativa en los 28 días previos al inicio del tto del estudio. La biopsia de médula ósea y las vías centrales no se consideran intervenciones quirúrgicas mayores.
    •Herida tórpida, úlcera sin cicatrizar o fractura ósea no consolidada.
    •Trastornos convulsivos que requieran medicación con:carbamazepina, fenobarbital, fenitoína, etosuximida, ácido valproico, tiagabina, felbamato, tiagabina, zonisamida y lamotrigina. Los pacientes con antecedentes de convulsiones controladas con levetiracetam o gabapentina y los pacientes con tumores cerebrales que reciban tratamiento profiláctico con levetiracetam o gabapentina pueden participar en el estudio.
    •Pacientes con hipertensión inicial no controlada de grado >1 según CTCAE del NCI, v. 4.0 (PA recurrente o persistente [>=24 horas] > LSN: PA mayor al percentil 95 de edad, estatura y sexo
    •Hemorragia clínicamente significativa (>=G3 según los criterios CTCAE del NCI, v. 4.0) en los 30 días previos al inicio del tratamiento del estudio.
    •Acontecimientos embólicos o trombóticos venosos o arteriales como trombosis venosa profunda o embolia pulmonar en los 6 meses anteriores al inicio del tto del estudio (excepto trombosis venosa por catéter tratada adecuadamente que se produzca más de 1 mes antes del inicio del tto del estudio).
    •Pacientes con indicios o antecedentes de trastornos de la coagulación o trombosis.
    •Anomalías cardíacas como insuficiencia cardíaca congestiva (>=clase 2 en la Clasificación de Ross modificada de insuficiencia cardíaca en niños) y arritmias cardíacas que requieran tto antiarrítmico (los betabloqueantes o la digoxina están permitidos).
    •Antecedentes de aloinjerto de órganos (incluido el alotrasplante de médula ósea).
    •Toxicidad no resuelta de grado >1 según CTCAE del NCI, v. 4.0, atribuida a cualquier tratamiento/procedimiento anterior (excepto alopecia, ototoxicidad inducida por quimioterapia, neuropatía inducida por quimioterapia de G2 y, según los criterios de inclusión anteriores, anemia con hemoglobina ≥ 8 mg/dl y ANC ≥ 1,0 x 10 9/l).
    •Derrame pleural o ascitis que provoca una afectación respiratoria (disnea de G 2 según CTCAE del NCI, v. 4.0).
    •Cualquier otra enfermedad maligna tratada antes del inicio del estudio.
    •Hipersensibilidad conocida a cualquiera de los ttos del estudio, clases de los tratamientos del estudio o excipientes de la formulación.
    •Embarazo o lactancia.
    •Trastornos gastrointestinales significativos con diarrea como principal síntoma; por ejemplo, enfermedad de Crohn o cualquier trastorno de malabsorción.
    •Neumopatía intersticial con signos y síntomas en curso en el momento de la selección.
    •Cualquier otra enfermedad o trastorno médico, psicológico o social inestable o grave que pueda poner en peligro la seguridad del paciente y/o su cumplimiento con los procedimientos del estudio, o que pueda interferir en la participación del paciente en el estudio o en la evaluación de los resultados del estudio.
    •Relación estrecha con el centro en que se realiza la investigación
    •Se prohíbe cualquier otro tratamiento antineoplásico, incluido cualquier nuevo fármaco en investigación, en un plazo de 28 días o 5 semividas del fármaco (si se conoce la vida media del fármaco en el paciente), lo que sea más corto (o en un plazo de 6 semanas en el caso de la mitomicina C), antes del inicio del tto del estudio. Se permite el tratamiento previo con vincristina o irinotecán, pero el paciente debe someterse al periodo de reposo farmacológico adecuado (5 semividas).
    •Factores de crecimiento hematopoyéticos: en los 21 días anteriores al inicio del tto del estudio.
    •Radioterapia: <=4 semanas antes del inicio del tratamiento del estudio (<= 2 semanas en el caso de radioterapia de campo limitado); deben haber transcurrido >=6 meses si se da >=50 % de radiación en la pelvis; deben haber transcurrido 3 meses en el caso de irradiación craneoespinal .
    •Trasplante autólogo de células madre (sin irradiación corporal total) o rescate con células madre en los 3 meses previos al inicio del tto del estudio.
    •Anticoagulación terapéutica en las 3 semanas previas al inicio del tto del estudio). Se permite la anticoagulación profiláctica de dispositivos de acceso venoso o arterial siempre y cuando se cumplan los requisitos relativos al tiempo de protrombina (TP), INR y TTP.
    •Inductores o inhibidores potentes de la isoenzima CYP3A4 en un plazo de 2 semanas o 5 semividas, lo que sea más largo, antes del inicio del tto del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    - To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally in combination with backbone chemotherapy (vincristine and irinotecan) at relapse in pediatric subjects with rhabdomyosarcoma (RMS) and other solid malignant tumors recurrent or refractory to standard therapy
    •Definir el perfil de seguridad, la dosis máxima tolerada (DMT) y la dosis recomendada para la fase II (RP2D) de regorafenib administrado por vía oral en combinación con la quimioterapia estándar (vincristina e irinotecán) en pacientes pediátricos con rabdomiosarcoma y otro tumores malignos sólidos recurrentes o refractarios al tratamiento estándar
    E.5.1.1Timepoint(s) of evaluation of this end point
    During cycle 1
    Durante el primer ciclo
    E.5.2Secondary end point(s)
    - To characterize the pharmacokinetics (PK) of regorafenib in combination with vincristine and irinotecan
    - To evaluate the anti-tumor activity of regorafenib in combination with vincristine and irinotecan
    - To characterize the pharmacokinetics (PK) of irinotecan
    - To evaluate pharmacodynamic parameters of regorafenib in combination with vincristine and irinotecan
    - Acceptability and palatability of the regorafenib formulations - tablets and granulates
    •Caracterizar la farmacocinética (FC) de regorafenib en combinación con vincristina e irinotecán.
    •Evaluar la actividad antitumoral de regorafenib en combinación con vincristina e irinotecán
    •Caracterizar la farmacocinética (FC) del irinotecán
    •Evaluar los parámetros farmacodinámicos de regorafenib en combinación con vincristina e irinotecán
    •Aceptabilidad y palatabilidad de las formulaciones de regorafenib: comprimidos y granulado
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Tumor evaluation is conducted every 8 weeks.
    -Pharamcodynamic parameters evaluated during screening phase and end of treatment
    - Taste and texture questionnaire is collected during cycle 1.
    -La evaluación tumoral se realiza cada 8 semanas.
    -Los parámetros farmacodinámicos se evalúan durante la fase de selección y al final del tratamiento.
    -El cuestionario de sabor y textura se recoge durante el Ciclo 1.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I dose escalation in pediatric subjects
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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 No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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 No
    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
    Última visita del último sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years3
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days14
    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: 77
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 52
    F.1.2Adults (18-64 years) No
    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
    Consent obtained from subject's parents/legal guardians, if the subject is unable to give consent personally. Age appropriate assent form obtained from the subjects.
    Los padres /tutores del paciente otorgarán el consentimiento, siempre que el paciente no pueda hacerlo personalmente. Cuando aplique, se obtendrá el asentimiento del paciente.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 77
    F.4.2.2In the whole clinical trial 77
    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)
    During active follow up, after the treatment period, subjects will not be restricted with regard to pursuing available treatments for their disease. All subjects enrolled should be followed for overall survival and to obtain information on long term effects of regorafenib and all new anti-cancer regimens for a last two years after the last dose of study treatment.
    Durante el periodo de seguimiento activo, tras el final del tratamiento, se permite el uso de otros tratamientos antineoplásicos . Todos los pacientes incluidos deberán ser contactados para determinar el estado general de supervivencia, para obtener información sobre los efectos del regorafenib a largo plazo y para obtener información sobre todas las pautas posológicas de tratamientos antineoplásicos recibidos durante al menos los 2 años posteriores a la última dosis del fármaco del estudio
    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 ITCC
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-17
    P. End of Trial
    P.End of Trial StatusOngoing
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