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    Summary
    EudraCT Number:2018-001594-24
    Sponsor's Protocol Code Number:CABL001E2201
    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:2018-08-07
    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 number2018-001594-24
    A.3Full title of the trial
    A phase 2, multi-center, open-label, randomized study of oral asciminib added to imatinib versus continued imatinib versus switch to nilotinib in patients with CML-CP who have been previously treated with imatinib and have not achieved deep molecular response
    Estudio fase 2, multicéntrico, abierto, aleatorizado, de asciminib oral añadido a imatinib frente a la continuación del tratamiento con imatinib frente a cambiar el tratamiento a nilotinib, en pacientes con leucemia mieloide crónica en fase crónica (LMC-FC) que han sido tratados previamente con imatinib y no han alcanzado respuesta molecular profunda
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of efficacy and safety of asciminib in addition to imatinib in CML-CP patients without a deep level or response on imatinib
    Estudio de eficacia y de seguridad de asciminib en combinación con imatinib en pacientes con LMC-FC
    A.4.1Sponsor's protocol code numberCABL001E2201
    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 pointTrial Monitoring Organization (TMo)
    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+34 90 0353036
    B.5.5Fax number+34 93 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.3.9.4EV Substance CodeSUB188597
    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: 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 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.3.9.4EV Substance CodeSUB188597
    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: 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.3.1Product nameGlivec
    D.3.2Product code STI571
    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 INNimatinib
    D.3.9.1CAS number 152459-95-5
    D.3.9.2Current sponsor codeSTI571
    D.3.9.3Other descriptive nameIMATINIB
    D.3.9.4EV Substance CodeSUB25387
    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.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 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.3.1Product nameGlivec
    D.3.2Product code STI571
    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 INNimatinib
    D.3.9.1CAS number 152459-95-5
    D.3.9.2Current sponsor codeSTI571
    D.3.9.3Other descriptive nameIMATINIB
    D.3.9.4EV Substance CodeSUB25387
    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: 5
    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 Tasigna
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/375
    D.3 Description of the IMP
    D.3.1Product nameTasigna
    D.3.2Product code AMN107
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    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 Tasigna
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/375
    D.3 Description of the IMP
    D.3.1Product nameTasigna
    D.3.2Product code AMN107
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 imatinib and have not achieved deep molecular response
    Leucemia mieloide crónica en fase crónica (LMC-FC) que han sido tratados previamente con imatinib y no han alcanzado respuesta molecular profunda
    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
    E.1.1.1: La leucemia mieloide crónica es un cáncer de la sangre caracterizado por una mutación genética (cromosoma Filadelfia) que produce la proliferación de glóbulos blancos en la médula ósea
    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 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 assess whether asciminib 40 mg QD + imatinib or asciminib 60 mg QD + imatinib is more effective than continued imatinib
    Evaluar si asciminib 40 mg, administrado una vez al día (QD) + imatinib 400 mg QD o asciminib 60 mg QD + imatinib 400 mg QD resulta más eficaz que la continuación del tratamiento con imatinib
    E.2.2Secondary objectives of the trial
    • - To estimate efficacy of switch to nilotinib
    - To estimate difference in efficacy between asciminib 60 mg + imatinib and switch to nilotinib
    - To estimate difference in efficacy between asciminib 40 mg + imatinib and switch to nilotinib
    • To assess additional parameters of the efficacy of
    - asciminib 60 mg added to imatinib vs continued imatinib or switch to nilotinib
    - asciminib 40 mg added to imatinib vs continued imatinib or switch to nilotinib
    • To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib vs continued imatinib or switch to nilotinib
    • To assess the pharmacokinetic profile of asciminib 60 mg or 40 mg and imatinib when administered in combination
    -Calcular la eficacia del cambio a nilotinib
    -Calcular la diferencia en la eficacia entre asciminib 60 mg + imatinib y el cambio a nilotinib
    -Calcular la diferencia en la eficacia entre asciminib 40 mg + imatinib y el cambio a nilotinib
    -Evaluar parámetros adicionales de la eficacia de:
    a. asciminib 60 mg añadido a imatinib frente a continuar con imatinib o cambiar a nilotinib,
    b. asciminib 40 mg añadido a imatinib frente a continuar con imatinib o cambiar a nilotinib,
    -Caracterizar el perfil de seguridad y de tolerabilidad de asciminib 60 mg o 40 mg + imatinib frente a continuar con imatinib o cambiar a nilotinib
    -Evaluar el perfil farmacocinético de asciminib 60 mg o 40 mg e imatinib cuando se administran en combinación.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for inclusion in this study must meet all of the following criteria:
    1. Signed informed consent must be obtained prior to participation in the study.
    2. Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP defined as:
    • < 15% blasts in peripheral blood and bone marrow
    • < 30% blasts plus promyelocytes in peripheral blood and bone marrow
    • < 20% basophils in the peripheral blood
    • >= 100 x 109/L (≥ 100 000/mm3) platelets
    • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
    3. Minimum of two years (24 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months).
    4. BCR-ABL1 levels > 0.01% IS and <= 1% IS at the time of study entry as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) at any time during prior imatinib treatment.
    5. Patient must meet the following laboratory values before randomization:
    • Absolute Neutrophil Count >= 1.5 x 109/L
    • Platelets >= 75 x 109/L
    • Hemoglobin (Hgb) >= 9 g/dL
    • Serum creatinine < 1.5 mg/dL
    • Total bilirubin <= 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included with total bilirubin ≤ 3.0 x ULN
    • Aspartate transaminase (AST) <= 3.0 x ULN
    • Alanine transaminase (ALT) <= 3.0 x ULN
    • Alkaline phosphatase <= 2.5 x ULN
    6. Patients must have the following laboratory values (>= LLN) or corrected to within normal limits with supplements prior to randomization: potassium, magnesium, phosphorus, total calcium (corrected for serum albumin).
    Los pacientes elegibles para ser incluidos en este studio Deben cumplir los siguientes criterios:
    1. El consentimiento informado firmado deberá obtenerse antes de la participación en el estudio.
    2.Pacientes hombres o mujeres >= 18 años con un diagnóstico confirmado de LMC-FC definido como:
    •< 15% de blastos en sangre periférica y médula ósea
    •< 30% blastos más promielocitos en sangre periférica y médula ósea
    •< 20% de basófilos en sangre periférica
    •≥ 100x 109/L (>= 100,000/mm3) plaquetas
    •Sin evidencia de afectación leucémica extramedular, con la excepción de hepatoesplenomegalia
    3. Mínimo de dos años (24 meses de calendario) de tratamiento con imatinib en primera línea para la LMC-FC (los pacientes deberán recibir 400 mg de imatinib QD en la aleatorización y no haber cambiado la dosis en los últimos 3 meses).
    4. Niveles de BCR-ABL1 > 0.01% en la IS y <= 1% en la IS en el momento de entrar en el estudio, confirmado con evaluación central en la selección; los pacientes no deberán haber alcanzado respuesta molecular profunda (RM4 en la IS) en ningún momento durante el tratamiento previo con imatinib.
    5. Los pacientes deberán cumplir los siguientes valores de laboratorio antes de la aleatorización:
     -Recuento absoluto de neutrófilos >= 1.5 x 109 L
     -Plaquetas >= 75 x 109/L
     -Hemoglobina >= 9 g/dL
     -Creatinina sérica (Crs) < 1.5 mg/dL
     -Bilirrubina total (BLT) <= 1.5 x límite superior de normalidad (LSN), excepto para pacientes con síndrome de Gilbert, que solo pueden ser incluidos con bilirrubina total <= 3.0 x LSN
     -Aspartato aminotransferasa (AST) <= 3.0 x LSN
     -Alanina aminotransaminasa (ALT) <= 3.0 x LSN
     -Fosfatasa alcalina (FA) <= 2.5 x LSN
    6. Los pacientes deberán presentar los siguientes valores de laboratorio (≥ por debajo del límite de normalidad (LIN)) o corregidos para que se encuentren dentro de los límites de normalidad con suplementos antes de la aleatorización: potasio, magnesio, fósforo, calcio total (corregido para albúmina sérica).
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria are not eligible for inclusion in this study.
    1. Treatment failure according to European Leukemia Network criteria (Baccarani et al 2013) during imatinib treatment.
    • after 3 months of treatment no Complete Hematologic Response (CHR) and/or Ph+ > 95%
    • after 6 months of treatment BCR-ABL1 > 10% and/or Ph+ > 35%
    • after 12 months of treatment BCR-ABL1 > 1% and/or Ph+ > 0
    • at any time loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, clonal chromosomal abnormalities in Ph+ cells (CCA/Ph+)
    2. Known second chronic phase of CML after previous progression to AP/BC.
    3. Previous treatment with any TKIs other than imatinib.
    4. History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as:
    • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to randomization
    • Concomitant clinically significant arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
    • Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization
    • 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 including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
    • Concomitant medications with a "known" risk of Torsades de Pointes per qtdrugs.org that cannot be discontinued or replaced by safe alternative medication
    • inability to determine the QTcF interval
    5. 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, uncontrolled clinically significant hyperlipidemia and high serum amylase).
    6. History of acute pancreatitis within 1 year prior to randomization or past medical history of chronic pancreatitis.
    7. History of acute or chronic liver disease.
    8. History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively.
    9. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) will be performed at study entry.
    10. 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).
    11. Treatment with medications that meet one of the following criteria and that cannot be discontinued or switched to a different medication at least one week prior to the start of treatment and for the duration of the study:
    • Strong inducers or inhibitors of CYP3A
    • Substrates of CYP3A4/5 with narrow therapeutic index
    12. 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.
    13. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
    14. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
    15. Pregnant or nursing (lactating) women.
    Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 14 days of study treatment after stopping medication. Highly effective contraception methods include: - see more details in section 5.2 of the protocol.
    Los pacientes que cumplan alguno de los siguientes criterios no serán elegibles para su inclusion en el studio.
    1. El fallo durante el tratamiento con imatinib se define de acuerdo con los criterios de la European Leukemia Network (Baccarani et al 2013)
    •3 meses después del inicio de la terapia: Ninguna respuesta hematológica completa (RHC) y/ o > 95% Ph+
    •6 meses después del inicio de la terapia:niveles de BCR-ABL > 10% y/o > 35% Ph+
    •12 después del inicio de la terapia: proporción de BCR-ABL > 1% y/o > 0% Ph+
    •En cualquier momento después del inicio de la terapia, pérdida de RHC, pérdida de RCC, pérdida confirmada de la RMM , mutaciones, anomalías cromosómicas clonales en células Ph+ (CCA/Ph+ )
    2. Segunda fase crónica de LMC conocida después de la progresión previa a fase acelerada/crisis blástica (FA/CB).
    3. Tratamiento previo con cualquier otro ITK que no sea imatinib.
    4. Antecedentes o diagnóstico actual de anomalías en el ECG que indiquen un riesgo significativo o de seguridad para los pacientes que participen en el estudio como:
    -Antecedentes de infarto de miocardio (MI), angina de pecho, bypass coronario arterial por injerto (CABG) dentro de los 6 meses antes de la aleatorización
    -Arritmias concomitantes clínicamente significativas, por ejemplo, taquicardia ventricular sostenida y bloqueo auriculoventricular (AV) de segundo o de tercer grado clínicamente significativo sin un marcapasos.
    -QTcF en reposo ≥450 ms (varones o ≥460 ms (mujeres) antes de la aleatorización.
    -Síndrome de QT prolongado, antecedentes familiares de muerte súbita idiopática o de síndrome de QT prolongado congénito, o cualquiera de lo siguiente:
    a.Factores de riesgo de Torsades de Pointes incluyendo hipocalemia o hipomagnesemia no corregidas, antecedentes de insuficiencia cardíaca o antecedentes de bradicardia sintomática/clínicamente significativa.
    b.Medicación(es) concomitante(s) con un riesgo “conocido” de Torsades de Pointes según la qtdrugs.org que no puedan ser suspendidas o sustituidas por medicación alternativa segura.
    c.Incapacidad para determinar el intervalo QTcF
    5. 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 (por ejemplo, diabetes incontrolada, infección activa o incontrolada, hiperlipidemia incontrolada clínicamente significativa y niveles elevados de amilasa sérica).
    6. Antecedentes de pancreatitis aguda dentro del año previo a la aleatorización, antecedentes clínicos previos de pancreatitis crónica o antecedentes de enfermedad hepática crónica o aguda.
    7. Antecedentes de enfermedad hepática crónica o aguda.
    8. Antecedentes de otras neoplasias malignas activas dentro de los 3 años antes de la aleatorización con excepción de cáncer cutáneo de células basales, cáncer de próstata indolente y carcinoma in situ tratado curativamente.
    9.Antecedentes conocidos de virus de la inmunodeficiencia humana (VIH), infección por virus de la hepatitis B (VHB) o infección por virus de la hepatitis C (VHC). Se realizará la prueba del antígeno de superficie de la hepatitis B (HBsAg) y del anticuerpo contra el núcleo de la hepatitis B (HBcAb ) a la entrada en el estudio.
    10.Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de la medicación del estudio (por ejemplo, enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción, resección del intestino delgado o cirugía de bypass gástrico).
    11.Tratamiento con medicaciones que cumplan uno de los siguientes criterios y que no puedan ser suspendidas o cambiadas a una medicación diferente por lo menos una semana antes del inicio del tratamiento y durante el estudio:
    •Inductores potentes o inhibidores de CYP3A
    •Sustratos de CYP3A4/5, con estrecho índice terapéutico
    12.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
    13. Historia de hipersensibilidad a alguno de los tratamientos del estudio o sus excipientes o a fármacos de la misma clase.
    14.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
    15.Mujeres embarazadas o en periodo de lactancia.
    Mujeres en edad fértil, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, a no ser que utilicen métodos anticonceptivos altamente eficaces durante el tratamiento del estudio y durante 14 días después de finalizar la medicación del estudio. Los métodos anticonceptivos altamente eficaces incluyen:
    Ver seccion 5.2 del protocolo
    E.5 End points
    E.5.1Primary end point(s)
    • Molecular Response (MR)4.5 rate at 48 weeks
    Tasa de Respuesta molecular RM4.5 a las 48 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks
    48 semanas
    E.5.2Secondary end point(s)
    • - Molecular Response (MR)4.5 rate at 48 weeks
    - Difference in rate of MR4.5 at 48 weeks
    • - Rate of MR4.5 at 96 weeks
    - Rate of MR4.5 by 48 and 96 weeks
    - Sustained MR4.5 at 96 weeks
    - Time to MR4.5
    • Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs
    • Plasma concentrations of asciminib and imatinib when administered in combination. PK parameters include but are not limited to Cmax, Tmax, Cmin, AUClast and AUCtau
    Tasa de Respuesta molecular RM4.5 a las 48 semanas.
    Diferencia en la tasa de RM4.5 a las 48 semanas.
    Tasa de RM4.5 a las 96 semana.s
    Tasa de RM4.5 a las 48 y a las 96 semanas.
    RM4.5 prolongada a las 96 semanas.
    Tiempo hasta la RM4.5.
    Frecuencia y severidad de los acontecimientos adversos (AAs), cambios en los valores de laboratorio, anomalías en los ECGs y en las constantes vitales clínicamente notables
    Concentraciones en plasma de asciminib e imatinib cuando se administran en combinación. Los parámetros de PK incluyen pero no están limitados a Cmax, Tmax, Cmin, AUClast y AUCtau
    E.5.2.1Timepoint(s) of evaluation of this end point
    The assessments are done for each parameter according to visits indicated in the Visit Schedule. For more details please refer to Visit Evaluation Schedule table 8-1 and 8-2 of the protocol
    Las evaluaciones se realizan para cada parámetro según las visitas indicadas en el esquema de visitas. Para obtener más información, consulte la tabla visitas de evaluación 8-1 y 8-2 del protocolo
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.6Cross over Yes
    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 trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Canada
    Chile
    Hong Kong
    Japan
    Korea, Republic of
    Russian Federation
    Taiwan
    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
    Study completion is defined as 96 weeks after the last randomized subject received the first dose of treatment + 30 days for the safety Follow up, or ... for further details see section 9.2 of the protocol.
    La finalización del estudio se define como 96 semanas después de que el último sujeto aleatorizado recibió la primera dosis de tratamiento + 30 días para el seguimiento de seguridad, o ... para más detalles, consulte la sección 9.2 del protocolo
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 108
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 120
    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)
    At the time of the study completion, subjects eligible for TFR may enter a separate TFR study. For subjects who do not enter a separate TFR study and in the opinion of the investigator are continuing to benefit from the study drug(s), efforts will be made to continue providing the study treatment outside the study. Options include, but are not limited to, a post-trial access program or access to commercial supplies in applicable countries.
    A la finalización del estudio, los sujetos elegibles a RLT pueden entrar a un estudio de RLT aparte. Para los pacientes que no entren en un estudio de RLT aparte y en opinión del investigador continúan beneficiándose de la medicación del estudio, se harán todos los esfuerzos por continuar suministrando el tratamiento del estudio fuera del estudio. Algunas opciones incluyen, pero no están limitadas a un programa de acceso post estudio o acceso a tratamientos comerciales en los países 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 Decision2018-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-16
    P. End of Trial
    P.End of Trial StatusOngoing
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