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    Summary
    EudraCT Number:2013-005101-31
    Sponsor's Protocol Code Number:AV001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-06-09
    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 number2013-005101-31
    A.3Full title of the trial
    A Multicenter Phase 3 Randomized, Open-Label Study of Bosutinib versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
    Estudio comparativo abierto, multicéntrico, aleatorizado y de fase 3 entre bosutinib e imatinib en pacientes adultos diagnosticados recientemente con leucemia mielógena crónica en fase crónica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multicenter Phase 3 Randomized, Open-Label Study of Bosutinib versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
    Estudio comparativo abierto, multicéntrico, aleatorizado y de fase 3 entre bosutinib e imatinib en pacientes adultos diagnosticados recientemente con leucemia mielógena crónica en fase crónica
    A.4.1Sponsor's protocol code numberAV001
    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 SponsorAvillion Development 1 Limited
    B.1.3.4CountryGuernsey
    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 supportAvillion Development 1 Limited
    B.4.2CountryGuernsey
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChiltern
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street Address171 Bath Road
    B.5.3.2Town/ citySlough, Berkshire
    B.5.3.3Post codeSL1 4AA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+34911872700
    B.5.5Fax number+34911872849
    B.5.6E-mailregulatory.spain@chiltern.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Bosulif comprimidos recubierto con película 100mg
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/762
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.1CAS number 380843-75-4
    D.3.9.2Current sponsor codePF-05208763; SKI-606
    D.3.9.3Other descriptive nameSKI-606 monohydrate
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Glivec
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGlivec
    D.3.9.1CAS number 152459-95-5
    D.3.9.3Other descriptive nameImatinib
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Glivec
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGlivec
    D.3.9.1CAS number 152459-95-5
    D.3.9.3Other descriptive nameImatinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 (CML)
    Leucemia Mieloide Crónica (LMC)
    E.1.1.1Medical condition in easily understood language
    CML is a type of leukemia resulting due to changes in chromosones. It is characterised by the uncontrolled growth of white blood cells.
    CML es un tipo de leucemia resultante debido a cambios en chromosones. Es caracterizado por el crecimiento descontrolado de células blancas de la sangre.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10054352
    E.1.2Term Chronic phase chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the proportion of patients demonstrating Major Molecular Response (MMR) at 12 months (48 weeks) in the bosutinib arm with that of the imatinib arm in newly diagnosed Philadelphia chromosome positive (Ph+) chronic phase (CP) chronic myelogenous leukemia (CML) patients.
    Comparar la proporción de pacientes que presenten una RMM a los 12 meses (48 semanas)
    en el grupo de bosunitib con los del grupo de imatinib en pacientes diagnosticados
    recientemente con LMC con Ph+ en FC.
    E.2.2Secondary objectives of the trial
    Secondary:
    ?To evaluate MMR by 18 months in the bosutinib treatment group compared with the imatinib treatment group.
    ?To evaluate the duration of MMR in the bosutinib treatment group compared with the imatinib treatment group.
    ?To estimate the proportion of patients demonstrating a cytogenic response (CCyR) by 12 months in both treatment groups.
    ?To evaluate the duration of CCyR in both treatment groups.
    ?To evaluate event free survival (EFS) in both treatment groups.
    ?To evaluate overall survival (OS) in both treatment groups.
    ?To assess the population pharmacokinetics (PK) of bosutinib administered once daily.
    ?To assess correlations between trough concentrations of bosutinib and key efficacy and safety parameters.
    ?To evaluate the safety profile of bosutinib and imatinib treatments.

    Please see protocol for exploratory endpoints
    ? Evaluar la RMM a los 18 meses en el grupo tratado con bosutinib en comparación con el
    grupo tratado con imatinib.
    ? Evaluar la duración de la RMM en el grupo tratado con bosutinib en comparación con el
    grupo tratado con imatinib.
    ? Calcular la proporción de pacientes que presenten una RCgC a los 12 meses en ambos
    grupos de tratamiento.
    ? Evaluar la duración de la RCgC en ambos grupos de tratamiento.
    ? Evaluar la SSE en ambos grupos de tratamiento.
    ? Evaluar la supervivencia global (SVG) en ambos grupos de tratamiento.
    ? Evaluar la farmacocinética (FC) poblacional del bosutinib administrado una vez al día.
    ? Evaluar las correlaciones entre las concentraciones mínimas de bosutinib y los
    parámetros de seguridad y eficacia clave.
    ? Evaluar el perfil de seguridad de los tratamientos con bosutinib e imatinib.

    Véase el Protocolo para ver los objetivos de exploración
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Main Inclusion Criteria:
    1. Molecular diagnosis of CP CML of ? 6 months (from initial diagnosis).
    ? Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL rearrangement at screening (cytogenetic assessment for Philadelphia chromosome is not required for enrollment); diagnosis of CP CML will be defined as all of the following:
    (a) <15% blasts in peripheral blood and bone marrow;
    (b) <30% blasts plus promyelocytes in peripheral blood and bone marrow;
    (c) <20% basophils in peripheral blood;
    (d) ?100 x 109/L platelets (?100,000/mm3);
    (e) No evidence of extramedullary disease except hepatosplenomegaly; AND
    (f) No prior diagnosis of AP or BP CML.
    ? Philadelphia chromosome status will be identified at screening. Both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) patients may be included.
    2. Adequate hepatic, renal and pancreatic function defined as:
    ? Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ?2.5 x upper limit of normal (ULN) or ?5 x ULN if attributable to liver involvement of leukemia.
    ? Total bilirubin ?2.0 x ULN (unless associated with Gilbert?s syndrome).
    ? Creatinine ?1.5 x ULN.
    3. Ability to take oral tablets.
    4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
    5. Age ? 18 years.
    6. Negative serum pregnancy test within 2 weeks of the first dose of study drug if the patient is a woman of childbearing potential. A woman of childbearing potential is defined as a woman who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Patients and patient's partners of childbearing potential (physcially able to have children) and who are sexually active must agree to use birth control consitently and correctly during the study and for at least 28 days after they have stopped taking the study drug.
    7. Ability to provide written informed consent prior to any study related screening procedures being performed.
    Principales criterios de inclusión:
    1. Diagnóstico molecular de LMC en FC de ? 6 meses (desde el diagnóstico inicial).
    ? Diagnóstico de LMC en FC con confirmación molecular mediante la detección de
    reordenamiento BCR-ABL en la fase de cribado (para la inscripción no se exige la
    evaluación citogenética relativa al cromosoma Filadelfia). El diagnóstico de LMC en FC
    se definirá de una de las siguientes maneras:
    a) <15 % de blastocitos en la sangre periférica y la médula ósea;
    b) <30 % de blastocitos y promielocitos en la sangre periférica y la médula ósea;
    c) <20 % de basófilos en la sangre periférica;
    d) ?100 x 109 /l plaquetas (?100.000/mm3 );
    e) Ningún indicio de enfermedad extramedular excepto hepatoesplenomegalia; Y
    f) Ausencia de diagnóstico anterior de LMC en FA o CB.
    ? El estado del cromosoma Filadelfia se identificará en la fase de cribado. Se incluirá a
    pacientes que tengan tanto Ph+ como Ph-.
    2. Una función hepática y renal satisfactoria se define de la siguiente manera:
    ? Niveles de AST/ALT de ? 2,5 veces el límite superior de normalidad (LSN) o de ? 5
    veces el LSN si se puede atribuir a la afectación hepática de la leucemia.
    ? Niveles de bilirrubina total de ? 2,0 veces el LSN (a menos que esté relacionada con el
    síndrome de Gilbert).
    ? Niveles de creatinina de ? 1,5 veces el LSN.
    3. Capacidad para tomar comprimidos orales.
    4. Escala de estado funcional ECOG de 0 o 1.
    5. Edad ? 18 años.
    6. Prueba de embarazo en suero negativa transcurridas 2 semanas desde la primera dosis del
    fármaco en estudio si el paciente es una mujer en edad fértil. Una mujer en edad fértil se
    define como una mujer que biológicamente tiene la capacidad de quedarse embarazada.
    Esto incluye a mujeres que están utilizando métodos anticonceptivos o cuyas parejas
    sexuales son estériles o utilizan métodos anticonceptivos. Los pacientes y las parejas de
    los pacientes que estén en edad fértil (que físicamente puedan concebir niños) y que sean
    sexualmente activos deben acceder a usar métodos anticonceptivos de forma continuada
    y correctamente durante el estudio y durante al menos 28 días después de haber dejado de
    tomar el fármaco en estudio.
    7. Capacidad de facilitar un consentimiento informado por escrito antes de que se lleven a
    cabo los procedimientos de cribado relacionados con el estudio
    E.4Principal exclusion criteria
    Main Exclusion Criteria:
    1. Any prior medical treatment for CML including tyrosine kinase inhibitors (TKIs) with the exception of hydroxyurea and/or anagrelide treatment.
    2. Any past or current CNS involvement, including leptomeningeal leukemia.
    3. Hypersensitivity to the active substance or to any of the following excipients: Microcrystalline cellulose (E460), croscarmellose sodium (E468), poloxamer 188, povidone (E1201), magnesium stearate (E470b), polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, Talc (E553b), iron oxide red (E172).
    4. Extramedullary disease only.
    5. Major surgery or radiotherapy within 14 days of randomization.
    6. Concomitant use of or need for medications known to prolong the QT interval.
    7. History of clinically significant or uncontrolled cardiac disease, including:
    ? History of, or active, congestive heart failure.
    ? Uncontrolled angina or hypertension within 3 months.
    ? Myocardial infarction (within 12 months).
    ? Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
    ? Diagnosed or suspected congenital or acquired prolonged QT history or prolonged QTc. (QTcF should not exceed 500 msec).
    ? Unexplained syncope.
    8. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease.
    9. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's Disease, Ulcerative Colitis or prior total or partial gastrectomy.
    10. History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least 12 months.
    11. Uncontrolled hypomagnesemia or uncorrected hypokalemia, due to potential effects on the QT interval.
    12. Current, or recent (within 6 months), participation in other clinical trials.
    13. Women who are pregnant, planning to become pregnant during the study or are breastfeeding a child, or men who are planning to father a child during their participation in this study.
    Principales criterios de exclusión:
    1. Cualquier tratamiento médico anterior para LMC, incluidos ITC, a excepción del
    tratamiento con hidroxiurea o anagrelida.
    2. Cualquier afectación anterior o actual del SNC, incluida la leucemia leptomeníngea.
    3. Hipersensibilidad al principio activo o a cualquiera de los siguientes excipientes: celulosa
    microcristalina (E460), croscarmelosa de sodio (E468), poloxámero 188, povidona
    (E1201), estearato de magnesio (E470b), alcohol polivinílico, dióxido de titanio (E171),
    macrogol 3350, talco (E553b), óxido de hierro rojo (E172).
    4. Solo enfermedad extramedular.
    5. Cirugía mayor o radioterapia en los 14 días siguientes a la aleatorización.
    6. Uso simultáneo o necesidad de medicamentos que prolonguen el intervalo QT.
    7. Antecedentes de enfermedad cardíaca clínicamente relevante o no controlada, incluido lo
    siguiente:
    ? Antecedentes o presencia actual de insuficiencia cardíaca congestiva.
    ? Angina de pecho o hipertensión no controladas en el plazo de 3 meses.
    ? Infarto de miocardio (en el plazo de 12 meses).
    ? Arritmia ventricular clínicamente relevante (como taquicardia ventricular, fibrilación
    ventricular o torsades de pointes).
    ? Diagnóstico o sospecha de antecedentes de intervalo QT prolongado congénito o
    adquirido o QTc prolongado (el QTcF no debería ser superior a 500 ms).
    ? Síncope idiopático.
    8. Seropositividad conocida al virus de la inmunodeficiencia humana (VIH), presencia
    actual de hepatitis B aguda o crónica (antígeno de superficie de la hepatitis B positivo),
    hepatitis C o indicios de enfermedad hepática descompensada.
    9. Trastorno GI clínicamente relevante reciente o activo, por ejemplo, enfermedad de
    Crohn, colitis ulcerosa o gastrectomía total o parcial previa.
    10. Historia de otro tumor maligno en los 5 últimos años, exceptuando el carcinoma de
    células basales o el carcinoma cervical in situ o cáncer en estadio 1 o 2 que se considere
    adecuadamente tratado y que actualmente esté en total remisión durante al menos 12
    meses.
    11. Hipomagnesemia no controlada o hipopotasemia no corregida debida a posibles efectos
    en el intervalo QT.
    12. Participación reciente (en los 6 últimos meses) o actual en otros ensayos clínicos.
    13. Mujeres que estén embarazadas, que tengan pensado quedarse embarazadas durante el
    estudio o que estén amamantando a un niño, u hombres que estén pensando concebir un
    hijo durante el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    Primary Efficacy Endpoint:
    The primary efficacy endpoint is MMR at 12 months (48 weeks). All Ph+ patients harboring either the b2a2 or b3a2 p210 transcript will be assessed and followed-up for MMR as the primary endpoint.
    * MMR is defined as BCR-ABL1 ?0.1% on the international scale (IS) by
    real-time quantitative polymerase chain reaction (RQ-PCR).

    Safety:
    Safety will be assessed on an ongoing basis by physical examination including measurement of vital signs, laboratory assessments, standard safety evaluations (electrocardiograms [ECGs] for monitoring of QTc interval changes and echocardiograms/MUGA scans for monitoring
    ventricular function) and recording of adverse events (AEs) and serious adverse events (SAEs). Adverse events will be graded according to the NCI CTC version 4. Discontinuations due to AEs will be considered the main comparative safety endpoint for AEs. In addition standard
    laboratory assessments will be performed.
    Eficacia:
    Criterio principal de valoración de la eficacia:
    El criterio principal de valoración de la eficacia es la RMM a los 12 meses (48 semanas) en pacientes con LMC con Ph+.
    ? La RMM se define como ? 0,1 % de BCR-ABL1 en la escala internacional (EI) a través de la reacción en cadena de la polimerasa cuantitativa en tiempo real (RQ-PCR).
    Seguridad: La seguridad se evaluará de forma continua mediante exámenes físicos, entre ellos la medición de las constantes vitales, pruebas clínicas, evaluaciones de seguridad estándar (electrocardiogramas [ECG] para supervisar los cambios en el intervalo QTc y ecocardiogramas/MUGA para supervisar la función ventricular) y registro de acontecimientos adversos (AA) y acontecimientos adversos graves (AAG). Los acontecimientos adversos se clasificarán de acuerdo con la versión 4 de los CTC del NCI. Las interrupciones del tratamiento debidas a AA se considerarán el principal criterio de valoración de la seguridad comparativo para AA, además de los análisis clínicos estándar. Se realizarán también evaluaciones clínicas estándar.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ? Hematology including CBC with differential will be conducted weekly for first 4wks, every 2wks during Months 2 and 3, then monthly until 12 Month visit (Wk48). In the follow up phase the Investigator should continue to perform chemistry and hematology testing per standard of care for CML patients and as clinically indicated in line with local guidelines, and at a minimum to reflect the schedule of assessments.
    ?Bone marrow aspirate and differential will be performed every 3 months (12 weeks) for the first year until MMR is achieved; MMR is
    defined as BCR-ABL1 ?0.1% BCR-ABL transcript on the international scale (IS) by real-time quantitative polymerase chain reaction (RQ PCR). Once MMR has been achieved, bone marrow aspirates will be performed only if clinically indicated.
    -Pruebas hematológicas con hemograma completo (HgC) en las primeras 4 sem, cada 2 sem durante meses 2 y 3, y mensualmente hasta visita mes 12 (sem 48). En fase seguimiento se realizarán pruebas químicas y hematológicas como práctica habitual para pacientes con LMC y como está clínicamente indicado en línea con directrices locales y como mínimo a reflejar el calendario de evaluaciones.-El aspirado de médula ósea y diferencial se llevará a cabo cada 3 meses (12 sem) en el primer año hasta que se alcanza la RMM; La RMM se define como BCR-ABL1 ?0,1 % de transcrito BCR-ABL en la escala internacional (EI) a través de la reacción en cadena de la polimerasa cuantitativa en tiempo real (RQ-PCR).Alcanzado la RMM, el aspirado de médula ósea se realizará únicamente si está clínicamente indicado
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    ? MMR by 18 months.
    ? Duration of MMR.
    ? CCyR by 12 months .
    ? Duration of CCyR.
    ? EFS
    ? OS

    Pharmacokinetic Endpoints
    ? Population PK of bosutinib.
    ? Correlations between trough concentrations of bosutinib and key
    efficacy and safety parameters.
    Estos criterios de valoración incluyen lo siguiente:
    ? RMM a los 18 meses.
    ? Duración de la RMM.
    ? RCgC a los 12 meses.
    ? Duración de la RCgC.
    ? Supervivencia sin episodios (SSE) definida como el tiempo transcurrido
    ? Supervivencia global (SVG)

    Los criterios farmacocinéticos de valoración (clasificados como criterios de valoración
    secundarios) incluyen:
    ? FC poblacional de bosutinib.
    ? Correlaciones entre concentraciones mínimas de bosutinib y parámetros clave de
    eficacia y seguridad.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy data:
    ?MMR by 3, 6 and 9 months, MMR at 18 months and beyond 12 months.
    ?Both ? 4 and ? 4.5 log reduction in BCR-ABL transcripts in bosutinib
    treatment group with imatinib at 3, 6, 9, 12 months and beyond 12
    months.

    Pharmacokinetic Data (bosutinib treatment group only):
    A total of 4 PK samples per patient will be drawn. All patients will provide pre-dose blood samples on Day 1, Day 28, Day 56, and Day 84.
    Datos eficaces:
    -RMM en los meses 3, 6 y 9, RMM a los 18 meses y posterior a los 12 meses
    -reducción ? 4 y ? 4,5 en escala logarítmica en los
    transcritos BCR-ABL en el grupo tratamiento de bosutinib con imatinib al mes3, 6, 9, 12 y después del mes 12.
    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 No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA81
    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
    Australia
    Belgium
    Canada
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Mexico
    Netherlands
    New Zealand
    Norway
    Poland
    Russian Federation
    Singapore
    Slovakia
    Spain
    Sweden
    Taiwan
    Ukraine
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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 No
    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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 446
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 79
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 265
    F.4.2.2In the whole clinical trial 525
    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)
    After the end of the study, patients will be treated according to local standard practice.
    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 Decision2014-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-15
    P. End of Trial
    P.End of Trial StatusOngoing
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