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    Summary
    EudraCT Number:2015-005437-53
    Sponsor's Protocol Code Number:ITCC053
    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:2019-04-04
    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 number2015-005437-53
    A.3Full title of the trial
    A phase 1B of crizotinib either in combination or as single agent in pediatric patients with ALK, ROS1 or MET positive malignancies
    Study ITCC 053
    Fase 1B de crizotinib en combinación o como agente único en pacientes pediátricos con tumores malignos positivos para ALK, ROS1 o MET
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study evaluating the safety and activity of the drug Crizotinib for children with malignant tumors
    Estudio de evaluación de la seguridad y la actividad del fármaco Crizotinib para niños con tumores malignos
    A.3.2Name or abbreviated title of the trial where available
    CRISP
    CRISP
    A.4.1Sponsor's protocol code numberITCC053
    A.5.4Other Identifiers
    Name:NTRNumber:5584
    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 SponsorErasmus Medical Center
    B.1.3.4CountryNetherlands
    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 supportPfizer BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus Medical Center
    B.5.2Functional name of contact pointTrialmanager DCOG-ECTC
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 2400, internal postal address NA-1603
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post codeNL 3000CA
    B.5.3.4CountryNetherlands
    B.5.6E-mailtrialmanagement@prinsesmaximacentrum.nl
    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 Xalkori
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameCrizotinib
    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 INNCrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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.2.1.1.1Trade name Xalkori
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameCrizotinib
    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 INNCrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 280
    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 Xalkori
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameCrizotinib
    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 INNCrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number280
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Children with malignancies carrying a genetic alteration of ALK, MET or ROS1 with no better treatment options according to the current (inter)national guidelines
    Niños con malignidades que presentan una alteración genética de ALK, MET o ROS1 sin mejores opciones de tratamiento de acuerdo a las actuales pautas internacionales
    E.1.1.1Medical condition in easily understood language
    Children with cancer who are carrying a special genetic alteration in their tumor tissue and who do not have any reasonable treatment options left
    Niños con cáncer que presentan una alteración genética especial en su tejido tumoral y que no tienen ninguna opción razonable de tratamiento.
    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
    * Stratum 1: to determine the RP2D of vinblastine in combination with crizotinib in relapsed/refractory ALCL with ALK aberrations
    * Stratum 2: to determine the RP2D of crizotinib in combination with temsirolimus in patients with relapsed/refractory RMS or NBL with ALK or MET aberrations
    * Stratum 3: to determine the safety and preliminary activity of single‐agent crizotinib forALK/ROS1/MET aberrant malignancies
    • Estrato 1: determinar la dosis de fase 2 recomendada (RP2D) de vinblastina en combinación con crizotinib en ALCL refractario/con recaída con aberraciones de ALK.
    • Estrato 2: determinar la RP2D de crizotinib en combinación con temsirolimus en pacientes con rabdomiosarcoma (RMS) refractario/con recaída o neuroblastoma (NBL) con aberraciones en ALK o MET.
    • Estrato 3: determinar la seguridad y actividad preliminar del agente único crizotinib para malignidades aberrantes en ALK/ROS1/MET.
    E.2.2Secondary objectives of the trial
    * To study the preliminary activity of crizotinib in combination with standard relapse
    chemotherapy for ALCL, or crizotinib in combination with temsirolimus for NBL and RMS.
    * To study pharmacokinetics of single‐agent crizotinib, and crizotinib in combination with
    vinblastine or temsirolimus to study potential drug‐drug interactions
    * To assess the duration of response, time to progression, progression free survival and overall
    survival
    • Estudiar la actividad preliminar de crizotinib en combinación con la quimioterapia estándar de recaída para ALCL, o crizotinib en combinación con temsirolimus para NBL o RMS.
    • Estudiar la farmacocinética del agente único crizotinib, y crizotinib en combinación con vinblastina o temsirolimus para estudiar las interacciones potenciales fármaco-fármaco.
    • Evaluar la duración de la respuesta, tiempo de progresión, supervivencia libre de progresión y supervivencia media.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Stratum 1:
    •Histologically or cytologically confirmed diagnosis of ALCL
    •• Target gene aberration as defined as:
    o The t(2;5) translocation or other translocation encoding for ALK aberrations (e.g. (1;2), t(2;3), inv(2), t(2;22)) This should be apparent in all tumor cells
     This can be proven by either ALK- immunohistochemistry, FISH or PCR
    •Disease involvement:
    o For dose escalation measurable and non measurable disease is allowed
    o For does expansion measurable disease is mandated
    o Measurable disease is defined as at least one nodule with a longest diameter
    greater than 1.5 cm

    Stratum 2:
    •Histologically or cytologically confirmed diagnosis NBL or RMS
    •Target gene aberration as defined as:
    o A point mutation in the kinase domain of ALK that results in an amino‐acid
    change, and is not a known polymorphism
    o An amplification of the ALK gene, defined as ≥9 copies per cell, or 4 copies
    per haploid genome. When assessed by FISH, ALK amplification must be
    observed in focal clusters of tumor cells (not only single cells) or in more than
    one‐third of the tumor cells
    o A translocation in >15% of the tumor cells (by break apart FISH‐assay)
    OR
    o An amplification of the MET‐gene, defined as of ≥5 MET signals per tumor
    cell (by break apart FISH)
    o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional
    sequencing of exon 16‐19 of MET)
    o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
    break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
    •Disease involvement:
    o For dose escalation measurable and non‐measurable disease is allowed
    o For does expansion measurable disease is mandated, except for
    neuroblastomas where MIBG disease is sufficient
    o For RMS: Measurable disease defined as per RECIST 1.1 with a target lesion
    of at least 10 mm
    o For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease
    (I123 MIBG uptake with or without bone marrow metastases)

    Stratum 3:
    •Histologically or cytologically confirmed diagnosis of other solid tumor or lymphomas
    other than ALCL (at initial diagnosis) that is relapsed or refractory to standard therapy. Or
    patients with newly diagnosed IMT in whom radical surgery is deemed infeasible or will
    result in significant morbidity/mutilation
    •Target gene aberration as defined as:
    For ALK:
    o A point mutation in the kinase domain of ALK that results in an amino‐acid
    change, and is not a known polymorphism
    o An amplification of the ALK gene, defined as ≥9 copies per cell, or 4 copies
    per haploid genome. When assessed by FISH, ALK amplification must be
    observed in focal clusters of tumor cells (not only single cells) or in more than
    one‐third of the tumor cells
    o A translocation in >15% of the tumor cells (by break apart FISH‐assay)
    For ROS1
    o A ROS1 rearrangement in >15% of the tumor cells (by break apart FISHassay)
    For MET
    o An amplification of the MET‐gene, defined as of ≥5 MET signals per tumor
    cell (by break apart FISH)
    o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional
    sequencing of exon 16‐19 of MET )
    o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
    break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
    •Disease involvement:
    o Measurable disease according to RECIST 1.1 with a target lesion of at least
    10 mm
    o Or, measurable disease as defined as at least one nodule with a longest
    diameter greater than 1.5 cm (pediatric NHL response criteria)
    •No prior therapy directly targeting ALK or ROS1or MET
    Estrato 1:
    - Diagnóstico confirmado de ALCL mediante histología o citología
    - Aberración del gen diana definida como: la translocación t(2;5) u otra translocación codificante para aberraciones de ALK (ej: (1;2), t(2;3), inv(2), t(2;22)). Esto debería ser evidente en todas las células tumorales
    Esto puede demostrarse mediante inmunohistoquímica de ALK, FISH o PCR

    Implicación de la enfermedad:
    - Para escalada de dosis, la enfermedad medible y no medible está permitida
    - Para expansión de dosis, la enfermedad medible es obligatoria
    - La enfermedad medible es definida como al menos un nódulo con un diámetro mayor que 1.5cm

    Estrato 2:
    Diagnóstico confirmado de NBL o RMS mediante histología o citología
    Aberración del gen diana definida como:
    - Mutación puntual del dominio quinasa de ALK que resulta en un cambio de aminoácido, y no es conocido como polimorfismo.
    - Amplificación del gen ALK, definida como 9 o más copias por célula, o 4 copias por genoma haploide. Cuando se evalúa por FISH, la amplificación de ALK debe ser observada en grupos focales de células tumorales (no solo células únicas) o en más de un tercio de las células tumorales.
    - Translocación en >15% de las células tumorales (por FISH)
    - Amplificación del gen MET, definida como 5 o más señales de MET por célula tumoral (por FISH)
    - Mutación de MET, definida como la presencia de una mutación somática (secuenciación directa o bidireccional del exón 16-19 de MET)
    - Reordenamiento de TFE3, definido como al menos un 15% de las células reordenadas (mediante FISH de conjunto de sondas de TFE3: RP11-344N17 y RP11-552J9)

    Implicación de la enfermedad:
    - Para escalada de dosis, la enfermedad medible y no medible está permitida
    - Para expansión de dosis, la enfermedad medible es obligatoria, excepto para neuroblastomas donde la enfermedad por MIBG es suficiente
    - Para RMS: la enfermedad medible se define según RECIST 1.1 con una lesión diana de al menos 10 mm
    - Para NBL: la enfermedad medible se define por RECIST 1.1 o enfermedad evaluable (administración de I123 con o sin metástasis de médula ósea)

    Estrato 3:
    Mediante histología o citología, diagnóstico confirmado de de otro tumor sólido o linfomas diferentes a ACLC (en el diagnóstico inicial) que recaen o refractan en la terapia estándar. O pacientes con nuevo diagnóstico IMT en el que la cirugía radical se considera inviable o resultará en una morbilidad/mutilación significativa

    Aberración del gen diana definida como:
    - Mutación puntual del dominio quinasa de ALK que resulta en un cambio de aminoácido, y no es conocido como polimorfismo.
    - Amplificación del gen ALK, definida como 9 o más copias por célula, o 4 copias por genoma haploide. Cuando se evalúa por FISH, la amplificación de ALK debe ser observada en grupos focales de células tumorales (no solo células únicas) o en más de un tercio de las células tumorales.
    - Translocación en >15% de las células tumorales (por FISH)

    Para ROS1
    - Reordenamiento de ROS1 en >15% de las células tumorales (mediante FISH)

    Para MET
    - Amplificación del gen MET, definida como 5 o más señales de MET por célula tumoral (por FISH)
    - Mutación de MET, definida como la presencia de una mutación somática (secuenciación directa o bidireccional del exón 16-19 de MET)
    - Reordenamiento de TFE3, definido como al menos un 15% de las células reordenadas (mediante FISH de conjunto de sondas de TFE3: RP11-344N17 y RP11-552J9)

    Implicación de la enfermedad:
    - Enfermedad medible según RECIST 1.1 con una lesión diana de al menos 10 mm
    - Enfermedad medible definida como al menos un nódulo con un diámetro mayor de 1.5 cm (criterios de respuesta de NHL pediátrico)
    - No terapia previa dirigida directamente a ALK o ROS1 o MET.
    E.4Principal exclusion criteria
    • Other serious illnesses or medical conditions
    • Current uncontrolled infection
    • History of allergic reactions to the compounds or their solvents
    • Patients with known CNS metastases and/or primary CNS tumors and/or meningeal
    lymphoma involvement, defined as CNS3 status (patients with CNS2 are eligible)
    • Concurrent use of drugs or foods that are known potent CYP3A4 inducers or inhibitors as
    well as medication with known QT‐prolongation
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
    absorption of crizotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
    or malabsorption syndrome)
    • Not able to comply with scheduled follow‐up and with management of toxicity.
    • A cardiac shortening fraction < 29%
    • Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any
    grade, or QTcF interval >470 msec.
    • History of extensive disseminated/bilateral or known presence of grade 3 or 4 interstitial
    fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity
    pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and
    pulmonary fibrosis, but not history of prior radiation pneumonitis.
    • No evidence of active graft‐vs‐host disease (GVHD) and at least 3 months post‐allogeneic
    HSCT. Must not receive GVHD prophylaxis.
    • For patients with childbearing potential, a negative test for pregnancy and agreement to use
    effective contraceptive measures is required before entry on study.

    Plus for stratum 1:
    • Patients with ALCL and skin lesions only, are excluded

    Plus for stratum 2:
    • Patients with neuroblastoma and bone marrow disease only, are excluded.
    - Otras enfermedades o condiciones médicas serias
    - Infección actual descontrolada
    - Historial de reacciones alérgicas a compuestos u otros solventes
    - Pacientes con metástasis conocidas del SNC y/o tumores primarios del SNC y/o implicación de linfoma meníngeo, definido como el estado de SNC3 (pacientes con SNC2 son elegibles)
    - Uso concurrente de fármacos o alimentos conocidos como potentes inductores o inhibidores de CYP3A4 así como medicación con prolongación QT conocida
    - Discapacidad de la función gastrointestinal (GI) o enfermedad GI que puede alterar de manera significativa la absorción de crizotinib (ej: enfermedades de úlcera, náusea descontrolada, vómitos, diarrea o síndrome de mala absorción)
    - Incapaz de cumplir con el seguimiento programado y con la gestión de la toxicidad
    - Fracción del acortamiento cardíaco <29%
    - Disritmias cardíacas de NCI CTCAE Grado igual o mayor de 2, fibrilación atrial descontrolada de cualquier grado, o intervalo QTcF >470 mseg
    - Historial de fibrosis intersticial o enfermedad pulmonar intersticial diseminada/bilateral o con presencia conocida de grado 3 o 4, incluyendo historial de pneumonitis, pneumonitis hipersensible, pneumonia intersticial, enfermedad pulmonar intersticial, bronquiolitis obliterativa, y fibrosis pulmonar, pero no historial de pneumonitis por radiación previa
    - No evidencias de enfermedad de injerto contra huésped (GVHD) activa y al menos 3 meses de HSCT post-alogénico. Muchos no reciben profilaxis para GVHD
    Para pacientes con potencial de maternidad, un test negativo de embarazo y acuerdo para el uso de medidas contraceptivas efectivas son requeridos antes de entrar en el estudio

    Plus para el estrato 1:
    - Pacientes con ALCL y solo lesiones de piel, son excluidos

    Plus para el estrato 2:
    - Pacientes con neuroblastoma y solo enfermedad de médula ósea, son excluidos
    E.5 End points
    E.5.1Primary end point(s)
    • Stratum 1 and 2 Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment
    • Stratum 3: overall response rate (descriptive)
    - Las Dosis Límite de Toxicidad del estrato 1 y 2 se evalúan durante los primeros 28 días de tratamiento
    - Estrato 3: ratio de respuesta media (descriptivo)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessed during the first 28 days of treatment
    Evaluado durante los primeros 28 días de tratamiento
    E.5.2Secondary end point(s)
    • Pharmacokinetic parameters, parameters, including but not limited to AUClast, AUCtau, Cmin, Cmax, Tmax, and T1/2, of crizotnib, temsirolimus and vinblastine
    • Safety: AEs, as characterized by type, frequency, severity (as graded using CTCAE version 4.03), timing, seriousness, and relation to study therapy
    • Response rate defined as the number of patients achieving complete and partial responses by disease after 2 courses (8 weeks).
    • Response rate defined as the number of patient achieving complete and partial response during the total study period.
    • Clinical benefit ratio defined as the number of patients achieving CR/PR/SD during the total study period
    • Duration of response, Progression free, event free and overall survival
    - Parámetros farmacocinéticos, incluyendo pero no limitado a AUClast, AUCtau, Cmin, Cmax, Tmax, Racc, y T1/2, de crizotinib, temsirolimus y vinblastina
    - Seguridad: AAs, caracterizados por tipo, frecuencia, severidad (graduada según la versión 4.03 CTCAE), tiempos, seriedad, y relación con la terapia de estudio
    - Ratio de respuesta definido como el número que logran presentar respuestas completas o parciales a la enfermedad después de 2 cursos (8 semanas).
    - Ratio de respuesta definido como el número que logran presentar respuestas completas o parciales durante el periodo total de estudio.
    - Ratio de beneficio clínico definido como el número de pacientes que logran RC (respuesta completa), RP (respuesta parcial), SE (supervivencia de la enfermedad) durante el periodo total del estudio
    - Duración de la respuesta y de la supervivencia libre de progresión, libre de eventos y supervivencia media
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Stratum 1: at the end of cycle 2, then every 4 months, and after a year every 6 months.
    • Solid tumors (stratum 2 and 3): at the end of cycle 2 and then every other cycle for stratum 2 and every 3 cycles for stratum 3.
    • Blood samples for PK analysis: at the start of the 2nd cycle at the day that vinblastine (stratum 1) or temsirolimus (stratum 2) are also administered.
    • PFS: the time interval between the date of enrolment and the date of confirmed disease progression or death (events) whatever the cause, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow-up examination.
    - Estrato 1: al final del ciclo 2, luego cada 4 meses, y después de un año, cada 6 meses.
    - Tumores sólidos (estratos 2 y 3): al final del ciclo 2 y luego cada otro ciclo para el estrato 2 y cada 3 ciclos para el estrato 3.
    - Muestras de sangre para análisis farmacocinéticos: al comienzo del segundo ciclo en el día que la vinblastina (estrato 1) o temsirolimus (estrato 2) son también administrados.
    - Supervivencia libre de progresión: el intervalo de tiempo entre la fecha de reclutamiento y la fecha de confirmación de progresión de la enfermedad o muerte (eventos) por cualquier causa y la que sea que se produzca primero. Si no se ha observado ningún evento, entonces el paciente es censurado en la fecha del examen del 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 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
    Phase 1b intervention trial
    Ensayo de intervención de fase 1b
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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
    All patients will have a safety evaluation visit at 1 month after the last dose of crizotinib. Here AEs and SAEs will be assessed and concomitant medication recorded, this will be repeated at 3 months. Moreover, there will be a 2 year follow up, 3 monthly, by telephone. The trial is ended when this follow up is completed for all patients.
    Todos los pacientes tendrán una visita de evaluación de seguridad al mes después de la última dosis de crizotinib. Los AAs y AAGs serán evaluados y la medicación concomitante registrada, y esto será repetido cada 3 meses. Además, habrá 2 años de seguimiento, 3 mensuales, por teléfono. El ensayo se dará por terminado cuando este seguimiento se complete para todos los pacientes.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 82
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 33
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 33
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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
    This study will be conducted in patients ≥1 year of age and ≤ 21 years. For minors the informed consent of the parents or legal guardians will be mandatory.
    El estudio contará con pacientes de 1 año de edad o más y 21 años o menos. Para los menores, el consentimiento informado de los padres o tutores legales será obligatorio.
    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 82
    F.4.2.2In the whole clinical trial 82
    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)
    If patients benefit from the trial medication we will provide them medication (off label) if possible
    Si los pacientes se benefician de la mediación del ensayo, les proporcionaremos (fuera de etiqueta) si es posible
    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 Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-26
    P. End of Trial
    P.End of Trial StatusOngoing
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