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    The EU Clinical Trials Register currently displays   43925   clinical trials with a EudraCT protocol, of which   7306   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).

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    Summary
    EudraCT Number:2016-003352-67
    Sponsor's Protocol Code Number:E7389-G000-213
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-07-30
    Trial results View 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 number2016-003352-67
    A.3Full title of the trial
    A Phase 1/2 single-arm study evaluating the safety and efficacy of eribulin mesilate in combination with irinotecan in children with refractory or recurrent solid tumors
    Ensayo clínico fase 1/2 de un brazo para evaluar la seguridad y la eficacia del mesilato de eribulina en combinación con irinotecán en niños con tumores sólidos refractarios o recurrentes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1 and 2 trial studying how well a combination of eribulin mesilate and irinotecan works in children with different types of cancer that are not responding to treatment or have reappeared following an initial recovery. The aim of the study is to find out how safe and effective the drug combination is in this treating these types of cancer.
    Un ensayo de Fase 1 y 2 que estudia qué tal funciona la combinación de mesilato de eribulina e irinotecán en niña/os con diferentes tipos de cáncer que no responden al tratamiento o que han reaparecido después de una recuperación inicial. El objetivo del estudio es averiguar la seguridad y efectividad de la combinación de medicamentos en estos tipos de cáncer.
    A.4.1Sponsor's protocol code numberE7389-G000-213
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/330/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEisai Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Europe Ltd
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressMosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+440845676 1400
    B.5.5Fax number+440845676 1401
    B.5.6E-mailEUMedInfo@eisai.net
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Halaven
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe Ltd
    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 nameHalaven
    D.3.2Product code E7389
    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 INNERIBULIN MESILATE
    D.3.9.2Current sponsor codeE7389
    D.3.9.4EV Substance CodeSUB31134
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.44
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing 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.3.4Pharmaceutical 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
    D.3.9.3Other descriptive nameIninotecan hydrochloride
    D.3.9.4EV Substance CodeSUB02772MIG
    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.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
    Phase 1: paediatric subjects with relapsed/refractory solid tumors (excluding CNS)
    Phase 2: paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
    •Fase 1: en sujetos pediátricos con tumores sólidos recurrentes o refractarios (excepto del SNC).
    •Fase 2: en sujetos pediátricos con rabdomiosarcoma (RMS), sarcoma de partes blandas distinto del rabdomiosarcoma (SPBDR) o sarcoma de Ewing (SE) recurrente/refractario.
    E.1.1.1Medical condition in easily understood language
    Different types of cancer that are not responding to treatment or have
    reappeared following an initial recovery
    Diferentes tipos de cáncer que no responden al tratamiento o que tienen
    recaida después de una recuperación inicial
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with weekly and daily irinotecan hydrochloride in paediatric subjects with relapsed/refractory solid tumors (excluding CNS)
    • Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
    •Fase 1: Determinar la dosis máxima tolerada (DMT) y la dosis recomendada para la fase 2 (DRF2) del mesilato de eribulina en combinación con clorhidrato de irinotecán semanal y diario en sujetos pediátricos con tumores sólidos recurrentes o refractarios (excepto del SNC).
    •Fase 2: Evaluar la tasa de respuestas objetivas (TRO) y la duración de la respuesta (DR) con el mesilato de eribulina en combinación con clorhidrato de irinotecán en sujetos pediátricos con rabdomiosarcoma (RMS), sarcoma de partes blandas distinto del rabdomiosarcoma (SPBDR) o sarcoma de Ewing (SE) recurrente/refractario.
    E.2.2Secondary objectives of the trial
    Phase 1:
    • To assess the safety and tolerability of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects
    • To determine the optimal schedule of irinotecan hydrochloride when administered with standard schedule (Days 1 and 8) of eribulin mesilate in paediatric subjects
    Phase 2:
    • To assess Progression Free Survival (PFS) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects.
    • To assess the Clinical Benefit Rate (CBR) at 12 weeks of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects
    Phase 1&2:
    • To evaluate the pharmacokinetic (PK) profile of eribulin, irinotecan and its active metabolite and (both Phases) and potential for drug-drug interaction of eribulin mesilate and irinotecan hydrochloride and its active metabolite, when coadministered (Phase 1 only).
    Fase 1:
    •Evaluar la seguridad y la tolerabilidad del mesilato de eribulina en combinación con clorhidrato de irinotecán en sujetos pediátricos.
    •Determinar la pauta óptima de clorhidrato de irinotecán cuando se administra con la pauta habitual (días 1 y 8) de mesilato de eribulina a sujetos pediátricos.
    Fase 2:
    •Evaluar la supervivencia sin progresión (SSP) con el mesilato de eribulina en combinación con clorhidrato de irinotecán en sujetos pediátricos.
    •Evaluar la tasa de beneficio clínico (TBC) a las 12 semanas con el mesilato de eribulina en combinación con clorhidrato de irinotecán en sujetos pediátricos.
    Fases 1 y 2:
    •Evaluar los perfiles farmacocinéticos (FC) de eribulina, irinotecán y su metabolito activo y compararlos con datos históricos apropiados.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age: ≥12 months to <18 years old at the time of consent. >6 months and <12 months at the times of consent (Phase 1 and Schedule A only) subjects will be enrolled one dose level behind he dose level at which the ≥12 months to <18 years old group are enrolled.
    2. Diagnosis:
    Phase 1: Histologically confirmed solid tumor, excluding CNS tumor, which is relapsed or refractory, and for which there are no currently available therapies.
    Phase 2: Histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy), including primary treatment.
    3. Disease status:
    Phase 1: Subjects must have either measurable or evaluable disease as per RECIST 1.1.
    Phase 2: Subjects must have measurable disease as per RECIST 1.1.
    Measurable disease is defined as meeting the following criteria:
    a. At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 using computed tomography/magnetic resonance imaging (CT/MRI).
    b. Lesions that have had radiotherapy must show subsequent radiographic evidence of increase in size by at least 20% to be deemed a target lesion.
    4. Therapeutic options: Subject’s current disease state must be one for which there is no known curative therapy.
    5. Performance level: Performance score ≥50% Karnofsky (for subjects >16 years of age) or Lansky (for subjects ≤16 years of age).
    6. Subjects must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:
    • Myelosuppressive chemotherapy: Must not have received within 21 days to study drug administration (42 days if prior nitrosourea).
    • Hematopoietic growth factors: Must not have received a long-acting growth factor (eg, Neulasta) within 14 days or a short-acting factor within 7 days. For agents that have known AEs occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.
    • Targeted therapy (antineoplastic agent eg, tyrosine kinase inhibitor): Must not have received an antineoplastic targeted therapy within 14 days. For agents that have known AEs occurring beyond 14 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.
    • Immunotherapy: Must not have received immunotherapy, e.g. tumor vaccines, within 42 days.
    • Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
    • Radiotherapy (XRT): Must not have received within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if ≥50% radiation of pelvis.
    • Autologous Stem cell infusion: At least 84 days must have elapsed after stem cell infusion prior to study drug administration.
    • Allogeneic bone marrow transplant, including mini-transplant: No evidence of active Graft vs. Host disease and at least 100 days must have elapsed after transplant or stem cell infusion prior to study drug administration.
    7. Adequate bone marrow function, defined as:
    • Peripheral absolute neutrophil count (ANC) ≥1 × 109/L.
    • Platelet count ≥100 × 109/L.
    • Hemoglobin (Hb) at least 8.0 g/dL at baseline.
    As blood transfusions are permitted to meet the hemoglobin criteria, subjects must not be known to be refractory to red blood cell or platelet transfusions.
    8. Adequate renal function, defined as:
    • A serum creatinine based on age/gender.
    • Or serum creatinine clearance or radioisotope GFR ≥50ml/min/1.73m2, based on a 12 or 24h urine creatinine collection.
    9. Adequate liver function, defined as:
    • Bilirubin ≤1.5 times the ULN for age.
    • Alkaline phosphatase and aspartate aminotransferase ≤3 × ULN • Serum albumin ≥2 g/dL.
    10. Informed consent: must be signed for the applicable persons.
    1.Edad: ≥ 12 meses a < 18 años en el momento del consentimiento. > 6 meses y < 12 meses en el momento del consentimiento (fase 1, pauta A únicamente); se incluirá a los sujetos en un nivel de dosis por detrás del de los sujetos de 12 meses o más a fin de maximizar la seguridad de los lactantes.
    2.Diagnóstico: Fase 1: Tumor sólido confirmado histológicamente, excluidos los tumores del SNC, recurrente o refractario y para el que no existen tratamientos disponibles en la actualidad. Fase 2: RMS, SPBDR o SPE confirmado histológicamente, recurrente o refractario y que haya recibido al menos un tratamiento sistémico previo, incluido el tratamiento primario.
    3.Estado de la enfermedad:
    Fase 1: Los sujetos deberán presentar enfermedad mensurable o evaluable conforme a los criterios RECIST 1.1. Fase 2: Los sujetos deberán presentar enfermedad mensurable conforme a los criterios RECIST 1.1. La enfermedad mensurable se define como el cumplimiento de los criterios siguientes:
    a.Al menos una lesión igual o superior a 1 cm en su diámetro mayor si es extraganglionar o igual o superior a 1,5 cm en su diámetro menor si se trata de un ganglio linfático, sucesivamente mensurable mediante tomografía computarizada o resonancia magnética (TC/RM) conforme a los criterios RECIST, versión 1.1.
    b.Las lesiones que hayan recibido radioterapia deberán mostrar signos radiológicos posteriores de un aumento de tamaño de al menos un 20 % para considerarlas lesiones diana.
    4.Opciones terapéuticas: El estado actual de la enfermedad del sujeto debe ser uno para el que no exista tratamiento curativo conocido.
    5.Nivel funcional: Puntuación funcional ≥ 50 % en la escala de Karnofsky (sujetos mayores de 16 años) o Lansky (sujetos de 16 años o menos).
    6.Los sujetos deberán haberse recuperado totalmente de los efectos tóxicos agudos de todos los tratamientos antineoplásicos previos antes de la administración del fármaco del estudio:
    -Quimioterapia mielodepresora: No debe haberse recibido en los 21 días previos a la administración del fármaco del estudio (42 días en caso de nitrosourea previa).
    -Factores de crecimiento hematopoyéticos: No debe haberse recibido un factor de crecimiento de acción prolongada (p. ej., Neulasta) en los 14 días previos o un factor de crecimiento de acción corta en los 7 días previos. En el caso de fármacos con AA conocidos que aparezcan más de 7 días después de la administración, este período deberá prolongarse más allá del tiempo en que se sepa que pueden aparecer los AA. La duración de este intervalo deberá comentarse con el promotor.
    -Tratamiento dirigido (antineoplásico, por ejemplo, inhibidor de la tirosina cinasa): No debe haberse recibido un tratamiento antineoplásico dirigido en los 14 días previos. En el caso de fármacos con AA conocidos que aparezcan más de 14 días después de la administración, este período deberá prolongarse más allá del tiempo en que se sepa que pueden aparecer los AA. La duración de este intervalo deberá comentarse con el promotor.
    -Inmunoterapia: No debe haberse recibido inmunoterapia, por ejemplo, vacunas antitumorales, en los 42 días previos.
    -Anticuerpos monoclonales: No deben haberse recibido en el equivalente a, como mínimo, tres semividas del anticuerpo después de la última dosis de un anticuerpo monoclonal.
    -Radioterapia (RT): No debe haberse recibido en los 14 días previos a la administración del fármaco del estudio (campo pequeño) o en los 42 días previos con RT craneovertebral, o en caso de irradiación ≥ 50 % de la pelvis.
    -Autoinfusión de células madre: Debe haber transcurrido un mínimo de 84 días desde la infusión de células madre antes de la administración del fármaco del estudio.
    -Alotrasplante de médula ósea, incluido minitrasplante: No debe haber signos de enfermedad activa del injerto contra el huésped y debe haber transcurrido un mínimo de 100 días después del trasplante o la infusión de células madre antes de la administración del fármaco del estudio.
    7.Función adecuada de la médula ósea, definida como:
    -Recuento absoluto de neutrófilos (RAN) en sangre periférica ≥ 1,0 x 109/l
    -Recuento de plaquetas ≥ 100 × 109/l .
    -Hemoglobina (Hb) ≥ 8,0 g/dl en el momento basal.
    Dado que se permiten las transfusiones de sangre para cumplir los criterios de hemoglobina, los sujetos que precisen transfusiones no deben ser refractarios a las transfusiones de eritrocitos o plaquetas.
    8.Función renal adecuada, definida como:
    -Creatinina sérica según la edad y el sexo.
    -O aclaramiento de creatinina sérica o FG isotópica ≥ 50 ml/min/1,73 m2, basado en una muestra de orina de 12 o 24 horas para determinar la creatinina.
    9.Función hepática adecuada, definida como:
    -Bilirrubina ≤ 1,5 veces el LSN para la edad.
    -Fosfatasa alcalina y aspartato aminotransferasa ≤ 3 veces el LSN -Albúmina sérica ≥ 2 g/dl.
    10.Consentimiento informado: debe de ser firmado por las personas implicadas
    E.4Principal exclusion criteria
    1. Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at Screening A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    - Females of childbearing potential* who:
    ◦ Do not agree to use a highly effective method of contraception for the entire study
    period and for 6 months after study drug discontinuation, ie:
    ◦ Total abstinence (if it is their preferred and usual lifestyle)
    ◦ An intrauterine device (IUD) or intrauterine system (IUS)
    ◦ A contraceptive implant
    ◦ an oral contraceptive**
    OR
    ◦ Do not have a vasectomized partner with confirmed azoospermia.
    *All post pubertal females will be considered to be of childbearing potential unless they
    have early menopause or have been sterilized surgically.
    **Must be on a stable dose of the same oral hormonal contraceptive product for at least
    4 weeks before dosing with study drug and for the duration of the study and for 6 months after study drug discontinuation.
    2. Concomitant Medications:
    ◦ Corticosteroids: Subjects receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration.
    ◦ Anticancer agents: Subjects who are currently receiving other anticancer agents.
    ◦ Anti-GVHD agents post-transplant: Subjects who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant.
    ◦ Strong CYP3A4 inducers/inhibitors.
    3. Prior Therapies:
    ◦ Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug administration.
    ◦ Phase 2: Received prior therapies with eribulin mesilate or irinotecan hydrochloride.
    4. Any malignancy that required treatment (except for soft tissue sarcoma, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study drug administration.
    5. Has hypersensitivity to either study drug or any of the excipients.
    6. Has a known prior history* of viral hepatitis (B or C) as demonstrated by positive
    serology (presence of antigens) or have an uncontrolled infection requiring treatment (*
    Subjects with a known prior history of hepatitis B or C may be eligible pending
    agreement with the sponsor).
    7. Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded according to the Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies.
    8. Has cardiac pathology, defined as:
    ◦ Subjects with known congestive heart failure, symptomatic or LV ejection fraction
    <50% or shortening fraction <27% and subjects with congenital long QT syndrome,
    bradyarrhythmias, or QTc >480 msec on at least 2 separate ECGs.
    9. Has CNS disease: Subjects with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration.
    Subjects must be clinically stable. It is not the intention of this protocol to treat subjects with active brain metastases.
    10. Have had or are planning to have the following invasive procedures:
    ◦ Major surgical procedure or significant traumatic injury within 28 days prior to study
    drug administration.
    ◦ Laparoscopic procedure or open biopsy within 7 days prior to study drug
    administration.
    ◦ Central line placement or subcutaneous port placement is not considered major
    surgery but must be placed at least 2 days prior to study drug administration.
    ◦ Core biopsy, including bone marrow biopsy within 2 days prior to study drug
    administration.
    ◦ Fine needle aspirate within 3 days prior to study drug administration.
    11. Subjects with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV infected patients.
    12. Has any serious concomitant illness that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments.
    13. Has received a live-virus vaccination within 30 days of planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted.
    1.Mujeres en período de lactancia o embarazadas en las visitas de selección. Se hará otra evaluación basal en caso de que la prueba de embarazo negativa de selección se haya obtenido más de 72 horas antes de administrar la primera dosis del fármaco del estudio.
    -Mujeres en edad fértil* que:
    ◦No se comprometan a utilizar un método anticonceptivo muy eficaz durante todo el período del estudio y hasta 6 meses después de la suspensión del fármaco del estudio, es decir: Abstinencia total (si se trata de su estilo de vida preferido y habitual), Dispositivo intrauterino (DIU) o sistema intrauterino (SIU), Implante anticonceptivo, Anticonceptivo oral**. OCuya pareja no se haya sometido a una vasectomía con azoospermia confirmada.
    *Se considerará en edad fértil a todas las mujeres pospuberales, a menos que tengan una menopausia precoz o se hayan sometido a esterilización quirúrgica.
    **Debe recibir una dosis estable del mismo anticonceptivo hormonal oral durante al menos 4 semanas antes de la administración del fármaco del estudio, durante todo el estudio y hasta 6 meses después de la suspensión del fármaco del estudio.
    2.Medicamentos concomitantes:
    •Corticoides: Sujetos tratados con corticoides que no hayan recibido una dosis estable durante al menos 7 días antes de la administración del fármaco del estudio.
    •Antineoplásicos: Sujetos que estén recibiendo otros antineoplásicos.
    •Medicamentos anti-EICH después del trasplante: Sujetos que estén recibiendo ciclosporina, tacrolimus u otros medicamentos para prevenir la enfermedad del injerto contra el huésped después del trasplante de médula ósea.
    •Inductores/inhibidores potentes de la enzima CYP3A4.
    3.Tratamientos previos:
    •Fase 1: Recepción de tratamiento con mesilato de eribulina en los 6 meses previos a la administración del fármaco del estudio.
    •Fase 2: Recepción de tratamiento previo con mesilato de eribulina o clorhidrato de irinotecán.
    4.Cualquier neoplasia maligna que precise tratamiento (excepto cáncer de piel distinto del melanoma o escisión completa confirmada histológicamente de un carcinoma in situ) en los dos años previos a la administración del fármaco del estudio.
    5.Hipersensibilidad al fármaco del estudio o a alguno de los excipientes.
    6.Antecedentes* conocidos de hepatitis vírica (B o C) demostrados por una serología positiva (presencia de antígenos) o presencia de una infección no controlada con necesidad de tratamiento (*Los sujetos con antecedentes conocidos de hepatitis B o C podrán participar con la autorización del promotor).
    7.Presencia de neuropatía sensitiva periférica de grado > 1 o neuropatía motora periférica de grado > 1 según la Escala pediátrica de neuropatías periféricas (“Balis”) modificada.
    8.Presencia de una cardiopatía, definida como:
    •Sujetos con insuficiencia cardíaca congestiva conocida, fracción de eyección del ventrículo izquierdo sintomática < 50 % o fracción de acortamiento < 27 % y sujetos con síndrome de QT largo congénito, bradiarritmias o intervalo QTc > 480 ms en al menos dos ECG distintos.
    9.Presencia de afectación del SNC: Los sujetos con metástasis cerebrales o subdurales no podrán participar a menos que las metástasis estén asintomáticas y no precisen tratamiento o hayan recibido un tratamiento local adecuado (por ejemplo, cirugía o radioterapia) y se haya suspendido el uso de corticoides por esta indicación durante al menos 28 días antes de la administración del fármaco del estudio. Los sujetos deben encontrarse clínicamente estables. Este protocolo no tiene la intención de tratar a sujetos con metástasis cerebrales activas.
    10.Realización previa o previsión de someterse a los siguientes procedimientos invasivos:
    •Intervención de cirugía mayor o lesión traumática importante en los 28 días previos a la administración del fármaco del estudio.
    •Procedimiento laparoscópico o biopsia abierta en los 7 días previos a la administración del fármaco del estudio.
    •La colocación de una vía central o un puerto subcutáneo no se considera cirugía mayor, pero debe hacerse al menos dos días antes de la administración del fármaco del estudio.
    •Biopsia con aguja gruesa, incluida biopsia de médula ósea, en los dos días previos a la administración del fármaco del estudio.
    •Aspiración con aguja fina en los tres días previos a la administración del fármaco del estudio.
    11.Infección conocida por el virus de la inmunodeficiencia humana (VIH), debido a la falta de datos de seguridad disponibles sobre el tratamiento con eribulina en pacientes infectados por el VIH.
    12.Presencia de cualquier enfermedad concomitante grave que, en opinión del investigador, pueda afectar a la seguridad del sujeto o interferir en las evaluaciones del estudio.
    13.Recepción de una vacuna de virus vivos en los 30 días previos al comienzo previsto del tratamiento del estudio. Se permitirán las vacunas antigripales estacionales que no contengan virus vivos.
    E.5 End points
    E.5.1Primary end point(s)
    • Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory extra-cranial solid tumors, excluding CNS tumors. Note: Subjects <12 months will not contribute to the determination of MTD/RP2D and data is for descriptive purposes only.

    • Phase 2: Objective response rate (ORR): defined as the proportion of subjects achieving a best overall response of confirmed partial or complete response, as determined by investigator assessment.
    •Fase 1: DMT/DRF2 del mesilato de eribulina en combinación con clorhidrato de irinotecán en sujetos pediátricos con tumores sólidos recurrentes/refractarios, excepto tumores del SNC.
    Note: pacientes <12 meses no contribuirán a determinar DMT/DRF2 y los datos son solo con un próposito descriptivo.
    •Fase 2: Tasa de respuestas objetivas (TRO): proporción de sujetos que logren una mejor respuesta global de respuesta parcial o completa confirmada, según lo determinado por el investigador.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Phase 1: DLTs to establish the MTD are assessed during the first cycle for each subject on each dose level.

    • Phase 2: Tumour assessments are performed every 6 weeks until Week 24 and then and then the frequency of assessments may decrease to every 9 weeks (or sooner if clinically indicated).
    • Fase 1: los TLD para establecer el DMT se evalúan durante el primer ciclo para cada sujeto en cada nivel de dosis.

    • Fase 2: las evaluaciones del tumor se realizan cada 6 semanas hasta la semana 24 y, a continuación, la frecuencia de las evaluaciones puede disminuir a cada 9 semanas (o antes, si está clínicamente indicado).
    E.5.2Secondary end point(s)
    Phase 1 & 2 Endpoints:
    • Safety and tolerability: adverse events (AEs), serious adverse events, clinical laboratory values, ECG parameters, vital sign measurements and physical examinations

    Timepoint of evaluation:
    Following provision of informed consent/assent and through out the study until 28 days after the last dose of study drug.

    • The pharmacokinetic profile of eribulin, irinotecan and its active metabolite.

    Timepoint of evaluation:
    Phase 1 (Cycle 1): For subjects ≥12 months (Irinotecan, its metablite and eribulin will be assayed).
    Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first),
    and at the end of the eribulin infusion, then at 1, 2, 4, 6 and 24 hours post-eribulin
    infusion. Both irinotecan (and its metabolite, SN-38) and eribulin will be assayed. At 48, 72, 96 and 120 hours post eribulin infusion, eribulin only will be assayed.
    For subjects <12 months (Irinotecan, its metablite and eribulin will be assayed).
    Cycle 1, Day 1: Before the irinotecan and eribulin infusion and then immediately
    after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin
    infusion).
    Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.
    Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin infusion).

    Phase 2 Endpoints:
    • Progression-free survival (PFS): defined as the time from the first dose date to the date of disease progression as determined by investigator review, or death

    Timepoint of evaluation:
    Progression-free survival, defined as the time from the date of first dose to the date of first documentation of disease progression, or date of death (whichever occurs first).

    • The Clinical Benefit Rate (CBR) at 12 weeks: defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks)

    Timepoint of evaluation:
    Clinical Benefit Rate, defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks).
    Puntos finales de Fase 1 y 2:
    • Seguridad y tolerabilidad: eventos adversos (EA), eventos adversos graves, valores de laboratorio clínico, parámetros de ECG, mediciones de signos vitales y exámenes físicos
    Tiempo de evaluación: Después de la firma del consentimiento/asentimiento informado y durante todo el estudio hasta 28 días después de la última dosis del medicamento del estudio.
    Perfil farmacocinético de eribulina, irinotecán y su metabolito activo.
    Tiempo de evaluación:
    Fase 1 (Ciclo 1): Para sujetos ≥12 meses (se analizará Irinotecan su metabolito y eribulina).
    Ciclo 1, día 1: al final de la infusión de irinotecan (primero se administra irinotecan),
    y al final de la infusión de eribulina, luego a 1, 2, 4, 6 y 24 horas después de la infusión de eribulina. Se analizarán tanto el irinotecán (y su metabolito, SN-38) como la eribulina. A las 48, 72, 96 y 120 horas después de la infusión de eribulina, solo se analizará eribulina.
    Para sujetos <12 meses (Irinotecan, se analizará su metablite y eribulina).
    Ciclo 1, día 1: antes de la infusión de irinotecán y eribulina e inmediatamente
    después del final de la infusión de eribulina (es decir, 10 ± 5 minutos desde el comienzo de la infusión de eribulina).
    Ciclo 1, día 4 o 5: durante la recopilación de la primera muestra de CBC dos veces a la semana.
    Ciclo 1, día 8: antes de la infusión de eribulina e inmediatamente después del final de la infusión de eribulina (es decir, 10 ± 5 minutos desde el inicio de la infusión de eribulina).

    Puntos finales de la Fase 2:
    • Supervivencia libre de progresión: definida como el tiempo desde la primera fecha de la dosis hasta la fecha de progresión de la enfermedad según lo determinado por la revisión del investigador, o la muerte.

    Tiempo de evaluación
    Supervivencia libre de progresión, definida como el tiempo desde la fecha de la primera dosis hasta la fecha de la primera documentación de la progresión de la enfermedad o la fecha de la muerte (lo que ocurra primero).

    • La tasa de beneficio clínico (TBC) a las 12 semanas: se define como la proporción de sujetos con la mejor respuesta global (MRG) de RC, RP o EE duradera según los criterios RECIST 1.1 (EE duradera > 11 semanas).
    Tiempo de evaluación
    Tasa de beneficio clínico, definida como la proporción de sujetos con la mejor respuesta global (MRG) de RC, RP o EE duradera según RECIST 1.1 (EE duradera> 11 semanas).
    E.5.2.1Timepoint(s) of evaluation of this end point
    As detailed under Secondary endpoint (above). Not possible to detail in full in this field due to limit on number of characters.
    Se detalla en "seondary endpoint" (arriba). No es posible detallar completamente en este campo debido al límite en el número de caracteres.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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
    Paediatric study
    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 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 trial1
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA48
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    France
    Germany
    Greece
    Israel
    Italy
    Poland
    Spain
    Switzerland
    United Kingdom
    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
    Ultima visita el último paciente
    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 months8
    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 months3
    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: 111
    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: 7
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 74
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 111
    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)
    As long as the subject is still receiving clinical benefit and has not experienced intolerable toxicity, he or she can continue to receive study treatment for up to 1 year, after which any continued treatment would need to be discussed with the Sponsor.
    Mientras el paciente aún reciba un beneficio clínico y no haya experimentado una toxicidad intolerable, puede continuar recibiendo tratamiento de estudio por 1 año, después de lo cual cualquier tratamiento continuo deberá discutirse con el Patrocinador.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-05-17
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