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    Summary
    EudraCT Number:2018-001594-24
    Sponsor's Protocol Code Number:CABL001E2201
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-09-10
    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 ConcernedFrance - ANSM
    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
    Etude de phase II, randomisée, en ouvert, multicentrique, évaluant l’asciminib associé à l’imatinib administrés par voie orale versus la poursuite de l’imatinib seul versus le passage au traitement par nilotinib chez des patients atteints de leucémie myéloïde chronique en phase chronique, ayant été traités par imatinib et n’ayant pas atteint une réponse moléculaire profonde
    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
    Etude d'efficacité et de tolérance de l'asciminib associé à l'imatinib chez des patients atteints de LMC en phase chronique sans niveau profond ou réponse sous imatinib
    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 Pharma AG
    B.1.3.4CountrySwitzerland
    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 Pharma S.A.S
    B.5.2Functional name of contact pointInformation&Communication Médicales
    B.5.3 Address:
    B.5.3.1Street Address2 et 4 rue Lionel Terray
    B.5.3.2Town/ cityRueil-Malmaison
    B.5.3.3Post code92500
    B.5.3.4CountryFrance
    B.5.4Telephone number+33 1 5547 6600
    B.5.5Fax number+33 1 5547 6100
    B.5.6E-mailicm.phfr@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
    Leucémie myéloïde chronique en phase chronique, précédemment traités par l’imatinib et avec une réponse moléculaire profonde non atteinte
    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
    Leucémie myéloïde chronique est un cancer du sang caractérisé par une mutation génétique (chromosome Philadelphie) qui entraine la prolifération de globules blancs dans la moelle osseuse
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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
    Déterminer si l’association asciminib 40 mg 1 fois/jour + imatinib ou l’association asciminib 60 mg 1 fois/jour + imatinib est plus efficace que l’imatinib seul
    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
    •- Estimer l’efficacité du passage au nilotinib
    - Estimer la différence d’efficacité entre l’association asciminib 60 mg + imatinib et le passage au nilotinib
    - Estimer la différence d’efficacité entre l’association asciminib 40 mg + imatinib et le passage au nilotinib
    •-Evaluer d’autres paramètres de l’efficacité de :
    - L’association asciminib 60 mg + imatinib versus la poursuite de l’imatinib seul ou le passage au nilotinib
    - L’association asciminib 40 mg + imatinib versus la poursuite de l’imatinib seul ou le passage au nilotinib
    •Caractériser le profil d’innocuité et de tolérance de l’association asciminib 60 ou 40 mg + imatinib versus la poursuite de l’imatinib seul ou le passage au nilotinib
    •Evaluer le profil pharmacocinétique (PK) de l’association asciminib 60 ou 40 mg + imatinib
    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).
    Les patients eligible à l'inclusion dans cette étude doivent satisfaire les critères suivants:
    1. Le consentement éclairé signé doit être obtenu avant de pouvoir participer à l’étude.
    2. Homme ou une femme, âgé de 18 ans ou plus avec un diagnostic confirmé de LMC en phase chronique défini comme suit :
    •Taux de blastes < 15 % dans le sang périphérique et la moelle osseuse
    •Taux de blastes + Promyélocytes < 30 dans le sang périphérique et la moelle osseuse
    •Taux de basopiles < 20 % dans le sang périphérique
    •Plaquettes ≥ 100 x 109/L (≥ 100 000/mm3)
    •Pas de signe d’atteinte extramédullaire de la leucémie, à l’exception d’une hépatosplénomégalie
    3. Avoir reçu au minimum 2 ans (24 mois calendaires) d’imatinib comme première ligne dans le traitement de la LMC en phase chronique (les patients doivent être sous imatinib 400 mg 1 fois/jour lors de la randomisation et ne pas avoir eu de changement de dose dans les 3 mois précédents).
    4. Rapport BCR-ABL1 > 0,01 % et ≤ 1 % selon l’échelle internationale (EI) lors de l’entrée dans l’étude, confirmé par une évaluation centralisée à la sélection ; les patients ne doivent pas avoir atteint une réponse moléculaire profonde (RM4 EI) au cours de leur précédent traitement par l’imatinib.
    5. Les patients doivent présenter les paramètres biologiques suivants avant randomisation :
    •Nombre absolu de neutrophiles ≥ 1,5 x 109/l
    •Plaquettes ≥ 75 x 109/l
    •Hémoglobine ≥ 9 g/dl
    •Créatinine sérique < 1,5 mg/dl
    •Bilirubine totale ≤ 1,5 x la limite supérieure de la normale (LSN), à l’exception des patients atteints de syndrome de Gilbert qui ne peuvent être inclus que si la bilirubine totale est ≤ 3,0 x LSN
    •ASAT ≤ 3,0 x LSN
    •ALAT ≤ 3,0 x LSN
    •Phosphatase alcaline ≤ 2,5 x LSN
    6. Les patients doivent présenter les paramètres biologiques suivants dans les limites de la normale (≥ la limite inférieure de la normale), avec ou sans supplémentation, avant la randomisation : potassium, magnésium, phosphore, calcium total (corrigé pour l’albumine sérique).
    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.
    Les patients satisfaisant l'un des critères suivants ne sont pas éligible à l'inclusion dans cette étude:
    1. Echec du traitement par l’imatinib selon les critères du « European Leukemia Network » :
    • Après 3 mois de traitement : pas de réponse hématologique complète (RHC) et/ou Ph+ > 95 %
    •Après 6 mois de traitement : BCR-ABL1 > 10 % et/ou Ph+ > 35 %
    • Après 12 mois de traitement : BCR-ABL1 > 1 % et/ou Ph+ > 0
    • A tout moment : perte de RHC, perte de réponse cytogénétique complète, perte confirmée de réponse moléculaire majeure, mutations, anomalies chromosomiques clonales au sein des cellules Ph+
    2. Deuxième phase chronique connue de la LMC après une progression antérieure en phase accélérée ou en crise blastique.
    3. Traitement antérieur par des ITK autres que l’imatinib.
    4. Antécédents ou présence d’anomalies des ECG indiquant un risque significatif pour la sécurité des patients participant à l’étude tels que :
    •Antécédents d’infarctus du myocarde, d’angine de poitrine ou de pontage aorto-coronarien dans les 6 mois précédant la randomisation
    •Arythmies cardiaques concomitantes cliniquement significatives (par ex. tachycardie ventriculaire soutenue et bloc atrio-ventriculaire de deuxième ou troisième degré cliniquement significatif sans pacemaker)
    • Intervalle QT corrigé d’après la formule de Fridericia (QTcF) au repos ≥ 450 msec (pour les hommes) ou ≥ 460 msec (pour les femmes) avant randomisation
    •Syndrome du QT long, antécédents familiaux de mort subite idiopathique ou de syndrome congénital du QT long ou l’une des anomalies suivantes :
    • Facteurs de risque pour les torsades de pointes incluant une hypokaliémie ou une hypomagnésémie non corrigée, des antécédents d’insuffisance cardiaque ou des antécédents de bradycardie cliniquement significative/symptomatique
    • Médicaments concomitants avec un risque connu de torsades de pointes selon qtdrugs.org qui ne peuvent pas être arrêtés ou remplacés par une alternative sûre
    • Incapacité à déterminer l’intervalle QTcF
    5. Tout problème médical concomitant sévère et/ou non contrôlé qui pourrait, selon l’opinion du médecin-investigateur, provoquer des risques de sécurité inacceptables ou compromettre la conformité au protocole (par ex. diabète non contrôlé, infection active ou non contrôlée, hyperlipidémie cliniquement significative non contrôlée et amylase sérique élevée).
    6. Antécédents de pancréatite aigüe dans l’année précédant la randomisation ou antécédents médicaux de pancréatite chronique.
    7. Antécédents de maladies hépatiques aigües ou chroniques.
    8. Antécédents de cancer dans les 3 ans précédant la randomisation, à l’exception du carcinome basocellulaire, du cancer de la prostate indolente et du carcinome in situ traité de manière curative.
    9. Antécédents connus d’infection par le virus de l’immunodéficience humaine (VIH), le virus de l’hépatite B (VHB) ou C (VHC). Un dépistage de l’antigène de surface de l’hépatite B (HBsAg) et de l’anticorps nucléocapsidique de l’hépatite B (HBcAb) sera réalisé lors de l’inclusion dans l’étude.
    10. Troubles de la fonction gastrointestinale ou maladie gastrointestinale qui pourraient entraver de façon significative l’absorption du traitement à l’étude (par ex. maladies ulcéreuses, nausées non contrôlées, vomissements, diarrhée, syndrome de malabsorption, résection de l’intestin grêle ou bypass gastrique).
    11. Patients recevant un des traitements suivants qui ne peut pas être arrêté, remplacé par un autre traitement au moins 1 semaine avant le début du traitement à l’étude et pendant toute la durée de l’étude :
    • Inducteurs ou inhibiteurs forts de CYP3A
    • Substrats de CYP3A4/5 avec un index thérapeutique étroit
    12. Eviter toute consommation de pamplemousses, d’oranges amères ou de produits contenant leur jus pendant toute la durée de l’étude et de préférence dans les 7 jours précédant la première dose du traitement à l’étude, à cause de l’interaction possible de CYP3A4 avec les traitements à l’étude. Le jus d’orange est autorisé.
    13. Antécédents de réactions d’hypersensibilité à l’un des traitements à l’étude ou à leurs excipients ou à un traitement de même classe chimique.
    14. Participation à une étude antérieure, dans les 30 jours avant randomisation ou les 5 demi-vies du traitement expérimental (selon le délai le plus long).
    15. Femmes enceintes ou qui allaitent.
    Les femmes en âge d’avoir des enfants, c’est-à-dire toutes les femmes physiologiquement aptes à être enceintes, sauf si elles utilisent une méthode de contraception très efficace pendant toute la durée du traitement et pendant les 14 jours suivant l’arrêt du traitement. Les méthodes de contraception très efficaces incluent :voir les détails dans le protocol section 5.2.
    E.5 End points
    E.5.1Primary end point(s)
    • Molecular Response (MR)4.5 rate at 48 weeks
    Taux de réponse moléculaire (RM)4,5 à 48 semaines
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks
    48 semaines
    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
    •- Taux de RM4,5 à 48 semaines
    - Différence dans le taux de RM4,5 à 48 semaines
    •- Taux de RM4,5 à 96 semaines
    - Taux de RM4,5 jusqu’à 48 et 96 semaines
    - Taux de RM4,5 soutenue à 96 semaines
    - Durée nécessaire pour atteindre une RM4,5
    •Fréquence/sévérité des effets indésirables, changements des résultats de laboratoire, anomalies cliniquement significatives dans les électrocardiogrammes (ECG) et dans les signes vitaux.
    •Concentrations plasmatiques de l’asciminib et de l’imatinib administrés en association. Les paramètres PK incluent entre autres : Cmax, Tmax, Cmin, AUClast et 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
    Les évaluations sont effectuées pour chaque paramètre selon les visites indiquées dans le calendrier des visites. Pour plus de détails, merci de vous reporter au calendrier des visites tableau 8-1 et 8-2 du protocol.
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 fin de l'étude est définie suivant 96 semaines après que le dernier patient randomisé ait reçu la première dose de traitement + 30 jours de suivi de la tolérance, ou ... pour plus de détails voir le protocole section 9.2.
    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 months8
    E.8.9.1In the Member State concerned days25
    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 state5
    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.
    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 Decision2018-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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