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    Summary
    EudraCT Number:2015-002916-34
    Sponsor's Protocol Code Number:ITCC-054/AAML1621
    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:2017-03-31
    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 number2015-002916-34
    A.3Full title of the trial
    A phase I/II study of Bosutinib in pediatric patients with Chronic Myeloid Leukemia who are resistant or intolerant to at least one prior Tyrosine Kinase Inhibitor therapy, ITCC-054/AAML1621
    Ensayo de fase I/II de bosutinib en niños con leucemia mieloide crónica resistentes o intolerantes al menos a un tratamiento previo con un inhibidor de la tirosina quinasa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Bositinib in pediatric CML patients
    A.3.2Name or abbreviated title of the trial where available
    Bosutinib in pediatric CML
    A.4.1Sponsor's protocol code numberITCC-054/AAML1621
    A.5.4Other Identifiers
    Name:NTRNumber:NTR5501
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/016/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorErasmus MC
    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
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital Universitario Infantil Niño Jesús
    B.5.2Functional name of contact pointDr. Lucas Moreno
    B.5.3 Address:
    B.5.3.1Street AddressAvenida Menéndez Pelayo, 65
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28009
    B.5.3.4CountrySpain
    B.5.4Telephone number0034915035900
    B.5.5Fax number0034915035902
    B.5.6E-mailensayosclinicos.hnjs@salud.madrid.org
    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 bosulif
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer 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 nameBosulif
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codeBosutinib
    D.3.9.3Other descriptive nameBOSUTINIB MONOHYDRATE
    D.3.9.4EV Substance CodeSUB120769
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 bosulif
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer 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 nameBosulif
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codeBosutinib
    D.3.9.3Other descriptive nameBOSUTINIB MONOHYDRATE
    D.3.9.4EV Substance CodeSUB120769
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 nameBosulif
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codeBosutinib
    D.3.9.3Other descriptive nameBOSUTINIB MONOHYDRATE
    D.3.9.4EV Substance CodeSUB120769
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 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 nameBosulif
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codebosutinib
    D.3.9.3Other descriptive nameBOSUTINIB MONOHYDRATE
    D.3.9.4EV Substance CodeSUB120769
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Chronic Myeloid Leukemia
    Leucemia Mieloide Crónica
    E.1.1.1Medical condition in easily understood language
    leukemia
    Leucemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10009700
    E.1.2Term CML
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective
    To determine a Recommended Phase 2 Dose (RP2D) of bosutinib in pediatric patients with CML,who are resistant or intolerant to at least one prior TKI therapy, based on the pharmacokinetic, safety and tolerability profile.
    Objetivo Principal
    Determinar una dosis recomendada de fase II de bosutinib en pacientes pediátricos con LMC resistentes o intolerantes a al menos un tratamiento ITC previo en base a la farmacocinética y al perfil de seguridad y tolerabilidad.
    E.2.2Secondary objectives of the trial
    Secondary Objectives
    -To evaluate the overall safety profile during the first cycle of therapy;
    -To evaluate the safety and tolerability profile during the prolonged exposure (max. 2 years) to bosutinib
    -To characterize the pharmacokinetics of bosutinib in pediatric CML patients;
    -To preliminary evaluate the anti-leukemic activity in pediatric patients with Philadelphia chromosome positive CML following resistance or intolerance to one or more TKIs.
    Objetivos Secundarios
    - Evaluar el perfil de seguridad global durante el primer ciclo de tratamiento.
    - Evaluar el perfil de seguridad y tolerabilidad durante la exposición prolongada (máximo de 2 años) a bosutinib.
    - Caracterizar la farmacocinética de bosutinib en pacientes pediátricos con LMC.
    - Evaluar de forma preliminar la actividad antileucémica en pacientes pediátricos con LMC cromosoma Filadelfia positivo (Ph+) resistentes o intolerantes a al menos un tratamiento ITC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML38 at either time of initial CML diagnosis or at time of study screening:
    -Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases.
    -Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted.
    -Qualitative RT-PCR should be performed on RNA extracted from freshly collected bone marrow or peripheral blood cells. It identifies the transcript type, either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCR-ABL protein weight (P210, rarely P230 or P190).
    2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines24) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI).
    • The 2013 European LeukemiaNet guidelines24 will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 and 4.
    -Intolerance to prior TKI therapy will be determined by the treating investigator, but generally applies to patients who are unable to receive standard or reduced doses of a TKI due to significant drug-related toxicity and/or when the drug-related toxicity is not responding to appropriate medical management. Patients who enroll as a result of intolerance to prior TKI therapy may have any level of response to their prior therapy and still be eligible.
    3. Age ≥1 and <18 years at day of attaining the informed consent.
    4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 5).
    5. Adequate bone marrow function:
    -For second-line and third-line CP CML patients:
    -Absolute neutrophil count >1000/mm3 (>1.0 x109/L);
    -Platelets ≥75,000/mm3 (≥75 x109/L) without any platelet transfusions during the preceding 7 days.
    -For fourth-line CP and all for all AP/BP CML patients:
    -Absolute neutrophil count >500/mm3 (>0.5 x109/L);
    -Platelets ≥50,000/mm3 (≥50 x109/L) without any platelet transfusions during the preceding 7 days.
    6. Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR (see appendix 11).
    7. Adequate liver function, including:
    • AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver;
    • Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.
    8. Recovered to Grade 0-1, or to baseline, from any acute toxicities of prior chemotherapy, immunotherapy, radiotherapy, differentiation therapy, or biologic therapy, with the exception of alopecia
    Able to reliably swallow whole capsules, whole tablets, or drug substance (from capsule contents) added to a suitable foodstuff.
    10. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.
    11. Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
    12. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
    13. Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
    1. Diagnóstico citogenético y molecular de LMC con cromosoma Filadelfia positivo38 bien en el momento del diagnóstico inicial de LMC o en la fase de selección del estudio:
    - La citogenética se debe realizar mediante el análisis del bandeo cromosómico de las metafases de las células de la médula ósea y requiere al menos 20 metafases.
    - Solo en el caso de que no se puedan dividir las células de la médula o de que exista un número insuficiente de metafases, el análisis de bandeo cromosómico se puede sustituir por hibridación in situ con fluorescencia de interfase (I-FISH) de células de médula ósea o sanguíneas periféricas mediante sondas de fusión dobles bicolor que permiten la detección de núcleos de BCR-ABL. Se deben contar al menos 200 núcleos.
    - Se debe realizar la prueba de reacción en cadena de la polimerasa con transcriptasa inversa (RCP-TI) cualitativa en el ARN de muestras de células sanguíneas periféricas o de médula ósea recién obtenidas. De esta forma se identificará el tipo de transcrito, e14a2 o 13a2 (también denominado b3a2 y b2a2) o el mucho más raro e19a2 o e1a2, que indica el peso de la proteína BCR-ABL (P210, rara vez P230 o P190).
    2. Resistencia (con respuesta insuficiente o fracaso, según la definición de las directrices de 2013 de la red europea LeukemiaNet24) o intolerancia (con o sin respuesta insuficiente o fracaso) a al menos un tratamiento inhibidor de la tirosina cinasa (ITC) previo.
    - Las directrices de 2013 de la red europea LeukemiaNet24 se utilizarán para definir la respuesta insuficiente y el fracaso de cualquier tratamiento ITC previo. En los apéndices 3 y 4 se incluye información detallada al respecto.
    - El investigador encargado del tratamiento determinará la intolerancia a cualquier tratamiento ITC previo. No obstante, en general se aplica a los pacientes que no pueden recibir dosis estándar o reducidas de un ITC debido a un acontecimiento adverso grave relacionado con el fármaco en cuestión o en los casos en los que el acontecimiento adverso relacionado con el fármaco no responde a un tratamiento médico adecuado. Los pacientes que participen en el estudio como resultado de su intolerancia a cualquier tratamiento ITC previo pueden tener cualquier nivel de respuesta al tratamiento previo y seguir siendo aptos.
    Entre ≥ 1 y < 18 años de edad en el momento de obtención del consentimiento informado.
    4. Puntuación funcional según la escala de Lansky ≥ 50 % para pacientes ≤ 16 años o la escala de Karnofsky de ≥ 50 % para pacientes > 16 años (apéndice 5).
    5. Función adecuada de la médula ósea:
    - En el caso de pacientes con LMC en fase crónica que se van a someter a un tratamiento de segunda y tercera línea:
    * Recuento absoluto de neutrófilos > 1000/mm3 (> 1,0 x 109/l);
    * Plaquetas ≥ 75.000/mm3 (≥ 75 x 109/l) sin ninguna transfusión de plaquetas durante los 7 días anteriores.
    - En el caso de pacientes con LMC en fase crónica que se van a someter a un tratamiento de cuarta línea y de todos los pacientes en fase acelerada o blástica:
    * Recuento absoluto de neutrófilos > 500/mm3 (> 0,5 x 109/l);
    * Plaquetas ≥ 50.000/mm3 (≥ 50 x 109/l) sin ninguna transfusión de plaquetas durante los 7 días anteriores.
    6. Función renal adecuada: los sujetos deben tener una depuración de creatinina (CrCl) de ≥ 60 ml/min/1,73 m2, calculada mediante la fórmula de Schwartz para determinar la tasa de filtración glomerular (TFG) (consulte el apéndice 11).
    7. Función hepática adecuada, incluido:
    - Alanina aminotransferasa/aspartato aminotransferasa (AST/ALT) ≤ 2,5 x límite superior de la normalidad (LSN) o ≤ 5 x LSN si se puede atribuir a la afectación hepática.
    - Bilirrubina total ≤ 1,5 x LSN, a menos que se compruebe que el paciente padece síndrome de Gilbert.
    8. Recuperación hasta el grado 0 o 1 o el valor inicial de cualquier acontecimiento adverso agudo de una quimioterapia, inmunoterapia, radioterapia, terapia de diferenciación o terapia biológica previa, con excepción de la alopecia.
    9. Capacidad de tragar cápsulas enteras, comprimidos enteros o el fármaco (contenido de la cápsula) añadido a alimentos adecuados.
    10. Prueba de embarazo de orina/suero (todas las niñas con como mínimo la edad menárquica) negativa en el momento de la selección.
    11. Los niños y niñas en edad fértil y con riesgo de embarazo deben aceptar el uso de un método anticonceptivo altamente eficaz durante todo el estudio y al menos los 30 días posteriores a la última dosis del tratamiento asignado. Se considerará que un paciente es fértil si, en opinión del investigador, es biológicamente capaz de tener descendencia y es sexualmente activo.
    12. Consentimiento informado por escrito de los padres, tutores legales o los pacientes (en función de la edad y la normativa y legislación local).
    13. Voluntad y capacidad de los pacientes (incluidos los representantes legales de los menores cuando corresponda) para cumplir con las visitas programadas, el plan de tratamiento, las pruebas de laboratorio y otros procedimientos del estudio.
    E.4Principal exclusion criteria
    1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
    2. In patients with AP/BC CML: leptomeningeal leukemia, defined as positive cytology on lumbar puncture (including both CNS2 and CNS3 status), or clinical symptoms or signs present. This assessment is not required for inclusion of CP CML patients.
    3. Extramedullary disease only.
    4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. This exclusion criterion is based on whether there is a known history of these mutations at the time of study entry. If these mutations become evident during the study the patient will go off study).
    5. Any prior treatment with a TKI within 7 days prior to study entry, or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to study entry.
    6. Prior growth factors or biologic agents within 7 days prior to study entry.
    7. Concomittant use of moderate or strong CYP3A inducers/inhibitors (see appendix 8).
    8. Concomittant use of proton pump inhibitors.
    9. Prior radiotherapy within 3 months prior to study entry.
    10. Allogeneic stem cell transplantation within 3 months prior to study entry.
    11. Donor lymphocyte infusion (DLI) within 1 month prior to study entry.
    12. Hereditary bone marrow failure disorder.
    13. Graft-versus-host disease (GVHD) within 60 days prior to study entry.
    14. Major surgery within 14 days prior to study entry (recovery from any previous surgery should be complete before day 1).
    15. History of clinically significant or uncontrolled cardiac disease, including:
    • History of or active congestive heart failure;
    • Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
    • Diagnosed or suspected congenital or acquired prolonged QT syndrome;
    • History of prolonged QTc.
    16. Prolonged QTc (>450 msec, average of triplicate ECGs).
    17. Need for medications known to prolong the QT interval.
    18. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
    19. Left ventricular ejection fraction <50% or shortening fraction <28%.
    20. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
    21. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
    22. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
    23. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study
    1. Diagnóstico de leucemia linfoblástica aguda Ph+.
    2. En pacientes con LMC en fase acelerada o crisis blástica: leucemia leptomeníngea, que se define como una citología positiva en la punción lumbar (incluidos los estados CNS2 y CNS3) o presencia de los signos o síntomas correspondientes. Esta evaluación no es necesaria para la inclusión de pacientes con LMC en fase crónica.
    3. Solo enfermedad extramedular.
    4. Antecedentes previos comprobados de mutaciones de T315I o V299L BCR-ABL1 (nota: la prueba de la mutación de BCR-ABL1 se realizará durante la selección para obtener una evaluación inicial, pero los resultados no se utilizarán para determinar la idoneidad. Este criterio de exclusión se basa en la existencia de antecedentes conocidos de estas mutaciones en el momento del inicio del estudio. Si las mutaciones se descubren durante el estudio, la participación del paciente en este finalizará).
    5. Cualquier tratamiento previo con un ITC en el plazo de los 7 días anteriores al inicio del estudio u otros tratamientos antitumorales o antileucémicos (con la excepción de hidroxiurea y anagrelida) en el plazo de los 14 días anteriores al inicio del estudio.
    6. Administración previa de factores de crecimiento o agentes biológicos en el plazo de los 7 días anteriores al inicio del estudio.
    7. Uso simultáneo de inhibidores/inductores de la CYP3A (consulte el apéndice 8).
    8. Uso simultáneo de inhibidores de la bomba de protones.
    9. Radioterapia en el plazo de los 3 meses anteriores inicio del estudio.
    10. Alotrasplante de células madre en el plazo de los 3 meses anteriores al inicio del estudio.
    11. Infusión de linfocitos del donante (ILD) en el plazo del mes anterior al inicio del estudio.
    12. Insuficiencia medular hereditaria.
    13. Enfermedad injerto contra huésped (EICH) en el plazo de los 60 días anteriores al inicio del estudio.
    14. Cirugía mayor en el plazo de los 14 días anteriores al inicio del estudio (la recuperación de cualquier cirugía previa debe completarse antes del día 1).
    15. Antecedentes de cardiopatías no controladas o clínicamente significativas, incluidos:
    - Antecedentes de insuficiencia cardíaca congestiva o activa.
    - Arritmia ventricular clínicamente significativa (como taquicardia ventricular, fibrilación ventricular o taquicardia ventricular en entorchado).
    - Síndrome de QT largo adquirido o congénito, presunto o diagnosticado.
    - Antecedentes de QTc largo.
    16. QTc largo (> 450 ms, media de ECG por triplicado).
    17. Necesidad de medicamentos que prolongan el intervalo QT.
    18. Hipopotasiemia o hipomagnesiemia no corregidas debido a los posibles efectos sobre el intervalo QT.
    19. Fracción de acortamiento < 28 % o fracción expulsada del ventrículo izquierdo < 50 %
    20. Trastorno digestivo clínicamente significativo en curso o reciente que pueda interferir con la ingesta o la absorción del fármaco.
    21. Indicios de infección vírica, fúngica o bacteriana grave activa.
    22. Historial conocido de infección por el virus de la hepatitis B (VHB), virus de la hepatitis C (VHC), virus de la inmunodeficiencia humana (VIH) o de afecciones relacionadas con el síndrome de inmunodeficiencia adquirida (SIDA).
    23. Otros trastornos médicos o psiquiátricos graves agudos o crónicos o anomalías de laboratorio que puedan aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en fase investigación o que puedan interferir con la interpretación de los resultados del estudio y, que a criterio del investigador, harían que el paciente no fuese adecuado para participar en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment. Pharmacokinetic parameters of bosutinib: Cmax, AUC.
    Acontecimientos adversos limitantes de la dosis (TLD) evaluados durante los primeros 28 días del tratamiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after first cycle regarding DLTs and PK; response is assessed every 3 cycles for 24 months;
    después del primer ciclo en relación a TLD y FC; la respuesta es evaluada cada 3 ciclos durante 24 meses;
    E.5.2Secondary end point(s)
    AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;
    -Laboratory abnormalities as characterized by type, frequency, severity and timing;
    -PK parameters of bosutinib: t1/2, tmax, CL/F, Vss/F will be assessed if possible;
    -Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR, defined as CCyR plus PCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecularly undetectable disease (definitions in appendix 2).
    Acontecimientos adversos (AA) caracterizados por tipo, frecuencia, gravedad (según la versión 4.03 de los criterios comunes de terminología para acontecimientos adversos [CTCAE]), desarrollo cronológico y relación con el tratamiento del estudio.
    - Anomalías de laboratorio caracterizadas por tipo, frecuencia, gravedad y desarrollo cronológico.
    - Parámetros farmacocinéticos de bosutinib: si es posible, se evaluarán t1/2, tmáx, depuración total aparente (CL/F), volumen de distribución en estado estable (Vss/F).
    - Respuesta acumulada global a la enfermedad: respuesta hematológica completa (RHC), respuesta citogenética mayor (RCgM, que se define como RCgC más RCgP), respuesta citogenética completa (RCgC), respuesta molecular mayor (RMM) y enfermedad indetectable a nivel molecular (definiciones en el apéndice 2).
    E.5.2.1Timepoint(s) of evaluation of this end point
    3-4 years
    3-4 años
    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 Yes
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Israel
    Switzerland
    United States
    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
    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: 45
    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: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) 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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 45
    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)
    stem cell transplantation (not part of this study)
    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 COG
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation ITCC
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-27
    P. End of Trial
    P.End of Trial StatusOngoing
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