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    Summary
    EudraCT Number:2016-002461-66
    Sponsor's Protocol Code Number:CABL001A2301
    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:2017-07-12
    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 number2016-002461-66
    A.3Full title of the trial
    A phase 3, multi-center, open-label, randomized study of oral ABL001 versus bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with 2 or more tyrosine kinase inhibitors
    Estudio fase 3, multicéntrico, abierto, aleatorizado, de ABL001 oral frente
    a bosutinib, en pacientes con leucemia mieloide crónica en fase crónica
    (LMC-FC) previamente tratados con 2 o más inhibidores de la tirosina
    quinasa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study comparing treatment of patients with Chronic Myelogenous Leukemia with ABL001 versus Bosutinib
    Estudio de fase 3 que compara el tratamiento de ABL001 frente a Bosutinib en pacientes con leucemia mieloide crónica
    A.4.1Sponsor's protocol code numberCABL001A2301
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+3490 0353036
    B.5.5Fax number+3493 2479903
    B.5.6E-maileecc.novartis@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ABL001
    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 INNasciminib
    D.3.9.2Current sponsor codeABL001
    D.3.9.3Other descriptive nameABL001
    D.3.9.4EV Substance CodeSUB129559
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP 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 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 nameBosutinib
    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.3.9.4EV Substance CodeSUB29176
    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 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.3.2Product code ABL001
    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 INNasciminib
    D.3.9.2Current sponsor codeABL001
    D.3.9.3Other descriptive nameABL001
    D.3.9.4EV Substance CodeSUB129559
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 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 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 nameBosutinib
    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.3.9.4EV Substance CodeSUB29176
    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.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 Myelogenous Leukemia in chronic phase (CML-CP), previously treated with 2 or more tyrosine kinase inhibitors
    Leucemia mieloide crónica en fase crónica (LMC-FC) previamente tratados con 2 o más inhibidores de la tirosina quinasa
    E.1.1.1Medical condition in easily understood language
    Chronic Myelogenous Leukemia is a cancer of the blood characterized by a gene mutation (Philadelphia chromosome) which causes proliferation of white blood cells in the bone marrow.
    La leucemia mieloide crónica es un cancer de la sangre que se caracteriza por la mutación de un gen (cromosoma Filadelfia), el cual, causa la proliferación de globulos blancos en la medula osea.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009012
    E.1.2Term Chronic myelogenous leukemia
    E.1.2System Organ Class 100000013009
    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 MMR rate at 24 weeks of ABL001 versus bosutinib
    Comparar la tasa de respuesta molecular mayor (RMM) a las 24 semanas de ABL001 frente a bosutinib
    E.2.2Secondary objectives of the trial
    To compare additional parameters of the efficacy of ABL001 versus bosutinib
    Comparar parámetros de eficacia adicionales de ABL001 frente a
    bosutinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients with a diagnosis of CML-CP >= 18 years of age
    2. Patients must meet all of the following laboratory values at the screening visit:
    - < 15% blasts in peripheral blood and bone marrow
    - < 30% blasts plus promyelocytes in peripheral blood and bone marrow
    - < 20% basophils in the peripheral blood
    - ≥ 50 x 109/L (≥ 50,000/mm3) platelets
    - Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable
    - No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
    3. BCR-ABL ratio ≥ 1% IS according to central laboratory at the screening examination
    4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, dasatinib, radotinib or ponatinib)
    5. Failure or intolerance to the last previous TKI therapy at the time of screening (adapted from the 2013 ELN Guidelines Bacarrani 2013)
    - Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows. Patients must meet at least 1 of the following criteria.
    Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases
    Six months after the initiation of therapy: BCR-ABL ratio > 10% IS and/or > 65% Ph+ metaphases
    Twelve months after initiation of therapy: BCR-ABL ratio > 10% IS and/or > 35% Ph+ metaphases
    At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
    At any time after the initiation of therapy, the development of new BCR-ABL mutations
    At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL ratio ≥ 1% IS
    At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+
    - Intolerance is defined as:
    Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal)
    Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer
    6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
    7. Adequate end organ function as defined by (as per central laboratory tests):
    - Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
    - Aspartate transaminase (AST) ≤ 3.0 x ULN
    - Alanine transaminase (ALT) ≤ 3.0 x ULN
    - Serum amylase ≤ ULN
    - Serum lipase ≤ ULN
    - Alkaline phosphatase ≤ 2.5 x ULN
    - Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
    8. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange
    juice is allowed.
    9. Written informed consent obtained prior to any screening procedures.
    10. Patients must have the following electrolyte values within normal limits (as per central laboratory tests) or corrected to be within normal limits with supplements prior to first dose of study medication:
    - Potassium
    - Magnesium
    - Total calcium (corrected for serum albumin)
    1. Pacientes hombres y mujeres con un diagnóstico de LMC-FC >= 18
    años
    2. Los pacientes deberán cumplir los siguientes valores de laboratorio en la visita de selección:
    - < 15% de blastos en sangre periférica y médula ósea
    - < 30% blastos más promielocitos en sangre periférica y medula ósea
    - < 20% de basófilos en sangre periférica
    - >= 50 x 109/L (>= 50,000/mm3) de plaquetas
    - Se acepta trombocitopenia transitoria relacionada con terapia
    previa (< 50,000/mm3 durante <=30 días antes de la selección)
    - Sin evidencia de afectación leucémica extramedular, con la
    excepción de hepatoesplenomegalia.
    3. Proporción de BCR-ABL >= 1% IS según el laboratorio central, en el
    análisis de selección
    4. Tratamiento previo con un mínimo de 2 ITKs de unión al bolsillo ATP
    (es decir, imatinib, nilotinib, dasatinib, radotinib o ponatinib)
    5. Fallo o intolerancia a la última terapia previa con ITK en el momento
    de la selección (adaptado de las directrices de la ELN 2013, Bacarrani
    2013).
    - El fallo se define del siguiente modo para los pacientes con LMCFC
    (FC en el momento del inicio de la última terapia). Los pacientes deberán cumplir por lo menos 1 de los siguientes criterios:
    - Tres meses después del inicio de la terapia: Ninguna respuesta
    hematológica completa (RHC) o > 95% de metafases Ph+
    - Seis meses después del inicio de la terapia: Proporción de BCR-ABL > 10% IS y/o > 65% de metafases Ph+
    - Doce meses después del inicio de la terapia: proporción de BCR-ABL> 10% IS y/o > 35% metafases Ph+
    - En cualquier momento después del inicio de la terapia, pérdida de RHC, RCC o de respuesta citogenética parcial (RCP)
    En cualquier momento después del inicio de la terapia, desarrollo de nuevas mutaciones en BCR-ABL
    En cualquier momento después del inicio de la terapia, pérdida confirmada de RMM en dos análisis consecutivos, uno de los cuales deberá presentar una proporción de BCRABL ≥ 1% IS
    En cualquier momento después del inicio de la terapia, nuevas anomalías cromosómicas clonales en células Ph+: CCA/Ph+
    La intolerancia se define como:
    - Intolerancia no hematológica: Pacientes con toxicidad de grado 3 ó 4 durante la terapia o con toxicidad de grado 2 persistente que no responde al manejo óptimo, incluyendo ajustes de la dosis (a menos que la reducción de la dosis no se considere lo mejor para el paciente si la respuesta ya es subóptima)
    - Intolerancia hematológica: Pacientes con toxicidad de grado 3 ó 4 (recuento absoluto de neutrófilos [RAN] o plaquetas) durante la terapia, que recurre después de la reducción de la dosis a la dosis más baja recomendada por el fabricante.
    6. Estado funcional (EF) del Grupo de Oncología Cooperativo del Este
    (ECOG) de 0, 1 ó 2.
    7. Función orgánica final adecuada definida por (según análisis del
    laboratorio central)
    - Bilirrubina total <= 1.5 x límite superior de normalidad (LSN), excepto para pacientes con síndrome de Gilbert que sólo pueden
    ser incluidos si la bilirrubina total <= 3.0 x LSN o la bilirrubina directa ≤ 1.5 x LSN
    - Aspartato aminotransferasa (AST) <= 3.0 x LSN
    - Alanina transaminasa (ALT) <= 3.0 x LSN
    - Amilasa sérica <= LSN
    - Lipasa sérica <= LSN
    - Fosfatasa alcalina <= 2.5 x LSN
    - Aclaramiento de creatinina >= 50ml/min, calculado utilizando la
    fórmula de Cockcroft-Gault
    8. Los pacientes deberán evitar el consumo de pomelo, naranjas de
    Sevilla o productos que contengan el zumo de estas frutas durante todo el estudio y preferiblemente 7 días antes de la primera dosis de las medicaciones del estudio, debido al potencial de interacción de
    CYP3A4 con las medicaciones del estudio. Se permite el zumo de
    naranja normal
    9. Consentimiento informado por escrito antes de cualquier
    procedimiento de selección.
    10. Los pacientes deberán tener los siguientes valores de electrolitos
    (según los análisis del laboratorio central) dentro de los límites de
    normalidad o corregidos para que se encuentren dentro de los límites
    de normalidad con suplementos, antes de la primera dosis de la medicación del estudio:
    - Potasio
    - Magnesio
    - Calcio total (corregido para albúmina sérica)
    E.4Principal exclusion criteria
    1. Known presence of the T315I or V299L mutation at any time prior to study entry
    2. Known second chronic phase of CML after previous progression to AP/BC
    3. Previous treatment with a hematopoietic stem-cell transplantation
    4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
    5. Cardiac or cardiac repolarization abnormality, including any of the following:
    - History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
    - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    - QTcF at screening ≥450 ms (male patients), ≥460 ms (female patients)
    - Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
    Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
    Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointes that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
    Inability to determine the QTcF interval
    6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary
    hypertension)
    7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
    8. History of elevation in amylase or lipase (> ULN) within 1 year other than that which may have occurred with gallstones, trauma, or medical procedures
    9. History of acute or chronic liver disease
    10. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
    11. History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
    12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
    13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
    14. Treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with study treatment
    - Moderate or strong inducers of CYP3A
    - Moderate or strong inhibitors of CYP3A and/or P-gp
    - Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic index
    15. Previous treatment with or known/ suspected hypersensitivity to ABL001 or any of its excipients
    16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its excipients
    17. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer
    18. Pregnant or nursing (lactating) women
    19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of ABL001. Highly effective contraception
    methods include - see details in protocol
    20. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
    (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of
    the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
    21. Sexually active males unless they use a condom during intercourse while taking the drug during treatment and for 3 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.
    1 Presencia conocida de la mutación T315I o V299L en cualquier
    momento antes del inicio del estudio
    2. 2ª Fase crónica de LMC conocida después de la progression previa a fase acelerada (FA)/crisis blástica (CB)
    3 Tto previo con un trasplante de células madre hematopoyéticas
    4 Ptes a los que se les tenga previsto realizar un trasplante
    alogénico de células madre hematopoyéticas
    5 Anomalía cardíaca o de repolarización cardíaca que incluya alguna de las siguientes alteraciones:
    -Antecedentes dentro de los 6 meses antes de iniciar el tto
    del estudio de IM, angina de pecho, bypass coronario arterial por injerto (CABG)
    -Arritmias cardíacas significativas (ej. taquicardia ventricular), bloqueo completo de rama izda, bloqueo AV de grado alto (ej, bloqueo bifascicular, tipo II de Mobitz y bloqueo AV de 3 grado).
    -QTcF en la selección >=450 ms (varones), >=460 ms (mujeres)
    -Síndrome de QT prolongado, antecedentes familiares de muerte
    súbita idiopática o de síndrome de QT prolongado congénito, o
    cualquiera de lo siguiente:
    Factores de riesgo de Torsades de Pointes (TdP) incluyendo hipocalemia o hipomagnesemia no corregidas, antecedents de insuficiencia cardíaca o antecedentes de bradicardia sintomática/ clínicamente significativa.
    Medicación(es) concomitante(s) con un riesgo conocido de prolongar el intervalo QT y/o que se conozca que causan Torsades de Pointes que no puedan ser suspendidas o sustituidas 7 días antes del inicio de la medicación del estudio por 1 medicación alternativa segura.
    Incapacidad para determinar el intervalo QTcF
    6. Enfermedad clínica concurrente incontrolada y/o severa que, a juicio del investigador, pudiese causar riesgos de seguridad inaceptables o comprometer el cumplimiento con el protocolo (ej, diabetes incontrolada, infección activa o incontrolada, hipertensión pulmonary)
    7. Antecedentes de pancreatitis aguda dentro del año previo al inicio del estudio o antecedentes clínicos previos de pancreatitis crónica.
    8.Antecedentes de elevación de la amilasa o de la lipasa (> LSN) dentro de 1 año, aparte de la que pueda haber ocurrido debido a calculus biliares, traumatismo o procedimientos médicos.
    9.Antecedentes de enfermedad hepática crónica o aguda.
    10.Presencia conocida de alteración hemorrágica congénita o adquirida significativa no relacionada con el cáncer.
    11.Antecedentes de otras enf. malignas dentro de los 3 años antes del inicio del estudio, con la excepción de cánceres cutaneos basales concomitantes o previos y de carcinoma in situ previo tto curativamente.
    12.Antecedentes de VIH, hepatitis B o hepatitis C. Se realizará la prueba del HBsAg y del HBcAb/anti-HBc en la selección.
    13. Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de la medicación del estudio (ej. enf. ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción, resección del intestino delgado o cirugía de bypass gástrico).
    14.Tto con medicaciones que cumplan 1 de los siguientes criterios y que no puedan ser suspendidas por lo menos 1 semana antes del inicio del tto del estudio:
    -Inductores potentes o moderados de CYP3A
    -Inhibidores potentes o moderados de CYP3A y/o de la gp-P
    -Sustratos de CYP3A4/5, CYP2C8 o CYP2C9 con estrecho índice
    terapéutico
    15.Tto previo con o hipersensibilidad sospechada/conocida a ABL001 o a alguno de sus excipientes.
    16.Tto previo con o hipersensibilidad sospechada/ conocida a bosutinib o a algun excipiente
    17.Participación en un estudio de investigación previo dentro de los 30 días antes de la aleatorización o dentro de 5 semividas del producto en investigación, lo que sea más largo.
    18.Mujeres embarazadas o en periodo de lactancia
    19.Mujeres en edad fértil, definidas como mujeres
    fisiológicamente capaces de quedarse embarazadas, a no ser que
    utilicen métodos anticonceptivos altamente eficaces durante la dosis y 3 días después de la última dosis de ABL001. Los métodos anticonceptivos altamente eficaces incluyen (ver protocolo)
    20. Las mujeres se considerarán postmenopáusicas y físicamente no fértiles si presentan amenorrea natural durante 12 meses con un perfil clínico apropiado (ej., edad apropiada, historial de síntomas vasomotores) o han sido sometidas a ooforectomía bilateral quirúrgica (con o sin histerectomía), histerectomía total o a ligadura de trompas por lo menos 6 semanas antes. En el caso de sólo ooforectomía , sólo cuando el estado reproductor de la mujer haya sido confirmado con evaluación de seguimiento del nivel hormonal será considerada físicamente no fértil.
    21.Varones sexualmente activos, a menos que utilicen un preservativo durante el coito mientras reciban la medicación durante el tto y durante 3 días después de suspender el tto y no deberían engendrar hijos durante este periodo. Los varones vasectomizados también deberán utilizar preservativo, así como durante el coito con 1 pareja masculina, para evitar la liberación del fármaco vía fluido seminal
    E.5 End points
    E.5.1Primary end point(s)
    Major Molecular Response (MMR) rate at 24 weeks
    Tasa de Respuesta Molecular Mayor (RMM) en la semana 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 semanas
    E.5.2Secondary end point(s)
    MMR rate at 96 weeks
    Tasa de RMM en la semana 96
    E.5.2.1Timepoint(s) of evaluation of this end point
    96 weeks
    96 semanas
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    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
    Argentina
    Australia
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Lebanon
    Mexico
    Netherlands
    Norway
    Romania
    Russian Federation
    Saudi Arabia
    Spain
    Switzerland
    Turkey
    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
    The end of the study will occur 5 years from the date when the last patient enrolled into the study received the first dose of the randomized treatment.
    El final del estudio tendra lugar 5 años despues de la fecha en que el ultimo paciente incluido en el estudio recibió la primera dosis de tratamiento aleatorizado.
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    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: 222
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 88
    F.4.2.2In the whole clinical trial 222
    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 treatment period the assigned study treatment will be made available to patients who in the opinion of the Investigator are still deriving clinical benefit. This may be outside of this study through alternative options including, but not limited to, an expanded access/compassionate use /managed access program or access to commercial supplies in applicable countries.
    Despúes del final del periodo del tratamiento del estudio, para los pacientes que en opinion del investigador aún obtengan beneficio clinico, estará disponible la asignación del tratamiento del estudio. Esto podrá ser fuera del estudio a traves de varias alternativas que incluyen, pero no se limitan, a un acceso expandido/ uso compasivo/ programas de acceso gestionado o acceso a suministro commercial, en los paises que aplique.
    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 Decision2017-09-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-27
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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