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    Summary
    EudraCT Number:2008-002260-33
    Sponsor's Protocol Code Number:CA180-226
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2012-01-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2008-002260-33
    A.3Full title of the trial
    A Phase II Study of Dasatinib Therapy in Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib.

    Decision number of Paediatric Investigation Plan: P/31/2010 & P/200/2011 + P/0118/2013

    Revised Protocol 06 incorporating Protocol Amendment 17

    + Amendment Number 02, Country-Specific - United Kingdom (version 1.0 dated 14-Jul-09)

    + Protocol Amendment 09 - UK Specific (v1.0 date 12-Oct-2010)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II Study of Dasatinib in Children and Adolescents With Newly
    Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or
    Intolerant to Imatinib
    A.4.1Sponsor's protocol code numberCA180-226
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00777036
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/200/2011
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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 supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointEU Start Up Department
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance, Avenue de Finlande, 8
    B.5.3.2Town/ cityBraine l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name SPRYCEL®
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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/3/05/338-339
    D.3 Description of the IMP
    D.3.1Product nameBMS-354825-03
    D.3.2Product code BMS-354825-03
    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 INNDasatinib
    D.3.9.1CAS number 863127-77-9
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name SPRYCEL®
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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/3/05/338-339
    D.3 Description of the IMP
    D.3.1Product nameBMS-354825-03
    D.3.2Product code BMS-354825-03
    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 INNDasatinib
    D.3.9.1CAS number 863127-77-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/338-339
    D.3 Description of the IMP
    D.3.1Product nameBMS-354825-03
    D.3.2Product code BMS-354825-03
    D.3.4Pharmaceutical form 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 INNDasatinib
    D.3.9.1CAS number 863127-77-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/05/338-339
    D.3 Description of the IMP
    D.3.1Product nameDasatinib
    D.3.2Product code BMS-354825
    D.3.4Pharmaceutical form Powder for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNDasatinib
    D.3.9.1CAS number 863127-77-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib
    E.1.1.1Medical condition in easily understood language
    Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10034877
    E.1.2Term Philadelphia chromosome positive
    E.1.2System Organ Class 100000004848
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10024329
    E.1.2Term 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
    The primary objective is to estimate:
    - The major cytogenetic response (MCyR) rate to dasatinib therapy in
    children and adolescents with CP-CML subjects who prove resistant to or
    intolerant to imatinib.
    - The complete hematologic response (CHR) rate in children and
    adolescents with Ph+ ALL, AP-CML and BP-CML, who are resistant,
    intolerant to, or relapse after prior imatinib therapy.
    - The complete cytogenetic response (CCyR) rate to dasatinib therapy in
    children and adolescents with newly diagnosed CP-CML who are
    treatment-naive
    E.2.2Secondary objectives of the trial
     To assess the safety and tolerability of dasatinib in children and
    adolescents treated with dasatinib for relapsed or refractory Ph+
    leukemias
     To assess the safety and tolerability of dasatinib in children and
    adolescents with newly diagnosed Ph+ CP-CML who are treatment-naive.
     To evaluate additional measures of efficacy in children and adolescents
    with newly diagnosed CP-CML or subjects with relapsed or refractory
    Ph+ leukemias treated on a given regimen of dasatinib including:
    – best cytogenetic rates and hematological response rates
    – time to response and duration of response
    – disease free survival (DFS)
    – progression-free survival (PFS) and overall survival (OS)
    – rates of complete (CMR) and major (MMR) molecular response
     To describe the spectrum of the BCR-ABL mutations at baseline, at
    progression or end of treatment, and to explore the role of mutations as
    predictors of response
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed Written informed consent from subject, or from parents minor subjects, according to local law and regulation.
    2) Target Population
    a) Diagnosis:
    i) Cohort #1: Subjects must have Ph+ CML in CP which presence of all the following criteria:
    (a) < 15% blasts in peripheral blood and bone marrow
    (b) < 20% basophils in peripheral blood
    (c) < 30% blasts + promyelocytes in peripheral blood and bone marrow
    (d) ≥ 100 X 109 platelets/L unless thrombocytopenia secondary to recent treatment
    (e) No extramedullary involvement other than liver and/or spleen
    (f) Ph+ (with 9:22 translocation) must be demonstrated by bone marrow cytogenetics
    ii) Cohort #2: Subjects must have Ph+ ALL or Ph+ AP- or Ph+ BP-CML:
    (1) Ph+ ALL have to be in first or subsequent relapse [defined as loss of a complete hematologic response as defined in Section 4.3.1.1] or fail to achieve a complete hematological remission [as defined in Section 4.3.1.1].
    (2) Ph+ AP-CML must meet at least one of the following criteria:
    (a) ≥ 15% but < 30% blasts in peripheral blood or bone marrow
    (b) ≥ 30% blasts + promyelocytes in peripheral blood and in bone marrow (but percent alone has to be < 30%)
    (c) ≥ 20% basophils in peripheral blood or bone marrow
    (d) < 100 X 109/L platelets unrelated to therapy
    (3) Ph+ BP-CML has to meet either of the following criteria:
    (a) ≥ 30% blasts in peripheral blood or bone marrow
    (b) Presence of extramedullary blastic disease other than lymph nodes, liver or spleen
    iii) Cohort #3: Subjects must have been newly diagnosed with Ph+ CML
    in CP which is defined by the presence of all the following criteria:
    (a) < 15% blasts in peripheral blood and bone marrow
    (b) < 20% basophils in peripheral blood
    (c) < 30% blasts + promyelocytes in peripheral blood and bone marrow
    (d) ≥ 100 X 109 platelets/L unless thrombocytopenia secondary to recent treatment
    (e) No extramedullary involvement other than liver and/or spleen
    (f) Ph+ (with 9:22 translocation) must be demonstrated by bone marrow cytogenetics
    b) Subjects in Cohort #1 or Cohort #2 have to be proven resistant or intolerant to imatinib:
    i) Intolerance Definition: Cohort #1 and Cohort #2, intolerance to imatinib is defined as the occurrence of any toxicity grade ≥ 3 considered at least possibly related to imatinib and that led to
    discontinuation of previous imatinib therapy.
    ii) For Cohort #1, resistance to imatinib must meet at least one of the following criteria:
    (a) Failure to achieve, or loss of, CHR after ≥ 3 months of imatinib at a daily dose of 260 mg/m2 or greater (refer to Section 4.3.2 for CHR loss criteria). Capping the dose at 400 mg QD in chronic phase CML subjects with a BSA > 1.5 m2 is accepted.
    (b) Failure to achieve MCyR after ≥ 6 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (refer to Section 4.3.1.2 for cytogenetic response definitions) Capping the dose at 400 mg QD in chronic phase CML subjects with a BSA > 1.5 m2 is accepted;
    (c) Failure to achieve CCyR after ≥ 12 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (refer to Section 4.3.1.2 for cytogenetic response definitions) Capping the dose at 400 mg QD in
    chronic phase CML subjects with a BSA > 1.5 m2 is accepted;
    (d) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases,
    confirmed at 2 - 4 weeks, after prior MCyR to imatinib at a daily dose of
    260 mg/m2 or greater. Capping the dose at 400 mg QD in chronic phase
    CML subjects with a BSA > 1.5 m2 is accepted.
    iii) For Cohort #2, resistance to imatinib must meet at least one of the
    following criteria:
    (a) Failure to achieve CHR while on imatinib after a ≥ 4-week treatment
    or a ≥ 50% increase in peripheral blood blasts over a 2-week period
    (b) Subjects who achieved a CHR subsequently no longer meet the
    criteria consistently over a consecutive 2-week period while receiving
    imatinib
    (c) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases,
    confirmed at ≥ 6 week interval, after prior MCyR to imatinib.
    (d) For subjects with Ph+ ALL, first or subsequent relapse [≥ 25% bone
    marrow blasts] or failure to achieve remission after prior imatinib
    exposure.
    c) Lansky or Karnofsky scale > 50
    d) Life expectancy ≥ 12 weeks
    e) Subjects must have recovered to baseline or Grade 1 (NCI CTCAE,
    version 3.0) from the toxicities (except alopecia) resulting from recent
    therapies, including chemotherapy, hormonal therapy, immunotherapy,
    biological therapy or investigational product and radiation therapy.
    f) Serum Na, HCO3, PO4 and Ca levels ≤ grade 1 and adequate hepatic
    and renal function defined as AST, ALT, bilirubin and creatinine ≤ Grade
    2 (NCI CTCAE, Version 3.0).
    3) Age and Sex
    a) Men and women, age 0 to 18 years
    b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.
    For additional details, refer to the protocol, section 4.2.1
    E.4Principal exclusion criteria
    1) Sex and Reproductive Status
    a) WOCBP who are unwilling or unable to use a highly effective method to avoid pregnancy for the entire study period and for up to 1 month after the last dose of investigational product.
    b) Women who are pregnant or breastfeeding or likely to becomepregnant
    c) Women with a positive pregnancy test on enrollment or prior to
    investigational
    product administration.
    d) Sexually active fertile men not using effective birth control if their
    partners are
    WOCBP who are unwilling or unable to use an acceptable method to
    avoid
    pregnancy for the entire study period and for up to 4 weeks after the last
    dose of
    investigational product.
    2) Target Disease Exceptions
    a) Subjects for whom potentially-curative therapy is available, including hematopoietic stem-cell transplantation (HSCT) at the time when subject
    is
    assessed for enrollment
    b) Subjects with isolated central nervous system disease are excluded
    from study.
    Subjects with CNS-1 (no detectable blast cells in a sample of
    cerebrospinal fluid),
    CNS-2 (< 5 leukemic blast cells in a sample with < 10 erythrocytes per
    cubic
    millimeter) and CNS-3 disease (> 5 leukemic blasts per cubic millimeter
    in a
    sample with < 10 erythrocytes per cubic millimeter) are eligible for
    study,46
    provided this is a combined relapse which also involves the bone marrow
    in
    addition to CNS and they are asymptomatic (no convulsions or other
    neurological
    symptoms).
    c) Isolated extramedullary disease, with < 5% blasts in bone marrow
    3) Medical History and Concurrent Diseases
    a) Any serious uncontrolled medical disorder that would impair the
    ability of the
    subject to receive protocol therapy, including:
    i) Ongoing uncontrolled infection
    ii) Clinically-significant disorder of platelet function (eg. von
    Willebrand's
    disease) or ongoing gastrointestinal bleeding
    iii) Clinically-significant cardiovascular disease, congenital long QT
    syndrome,
    history of ventricular arrhythmias or heart block, or prolonged QTc
    interval
    > 450 ms (Fridericia correction) on baseline electrocardiogram
    iv) Subjects diagnosed with the T315I mutation (mutation testing should
    be
    performed according to the investigator's standard practice and is not
    mandatory at sites without BCR-ABL testing available).
    v) Subjects who have experienced hypersensitivity to dasatinib or to any
    of the
    excipients. Inactive ingredients in dasatinib tablets include: lactose
    monohydrate, microcrystalline cellulose, croscarmellose sodium,
    hydroxypropyl cellulose, and magnesium stearate. The tablet coating
    consists
    of hypromellose, titanium dioxide, and polyethylene glycol.
    vi) Subjects with hereditary problems of galactose intolerance or Lapp
    lactase
    deficiency or glucose-galactose malabsorption.
    vii)Uncorrected hypokalemia or hypomagnesemia.
    b) Expected non-compliance to protocol schedule or unable to have
    regular
    follow-up due to psychological, social, familial or geographic reasons
    4) Prohibited Treatments and/or Therapies
    a) Prior therapy with dasatinib.
    b) Any investigational agent or any other anti-cancer agent within 14
    days prior to
    treatment start.
    i) Imatinib mesylate may be continued up to 7 days before treatment
    start, or, in
    the presence of rising peripheral blast cells, imatinib may be continued
    up to
    2 days before treatment start.
    ii) If required for control of peripheral blast cells or WBCs, 6-mercaptopurine or
    6-thioguanine may be given up to 2 days before treatment start and
    corticosteroids or hydroxyurea can be given during the period
    immediately
    prior to treatment start and during the first month of study therapy,
    these
    agents will be discontinued (or tapered in the case of corticosteroids) as
    soon
    as possible.
    c) Subjects requiring ongoing medications which may:
    i) Have a known risk of causing QTc prolongation - see Section 5.5.1.2
    ii) Irreversibly inhibit platelet function, or anticoagulants - see Section
    5.5.1.3
    (Does not apply to low-dose heparin for prophylaxis or to heparin
    flushes for
    i.v. lines)
    d) For Cohort #3: Prior chemotherapy, immunotherapy, or radiotherapy
    for CML
    with the exception of hydroxyurea.
    5) Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated
    b) Subjects who are compulsorily detained for treatment of either a
    psychiatric or
    physical (eg, infectious disease) illness
    E.5 End points
    E.5.1Primary end point(s)
    • Cohort #1: Major Cytogenetic Response (MCyR) rate, defined as the
    proportion of all
    treated subjects who achieve a complete or partial cytogenetic response
    on study.
    • Cohort #2: Complete Hematologic Response (CHR) rate, defined as the
    proportion of
    all treated subjects who achieve a confirmed CHR on study.
    • Cohort #3: Complete Cytogenetic Response (CCyR) rate, defined as the
    proportion of
    all treated subjects who achieve a CCyR on study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohort #1: Every 3 months during the first two years. Yearly thereafter
    and at the end of protocol therapy;
    Cohort #2: Every week for the first eight weeks. Then every 3 months
    during the first two years. Every three months thereafter and at the end
    of protocol therapy;
    Cohort #3: Every 3 months until complete cytogenetic response (CCyR)
    is achieved and then yearly (or as clinically indicated) once a subject has
    achieved a CCYR.
    E.5.2Secondary end point(s)
    (1) To assess the safety and tolerability of dasatinib in children and
    adolescents treated with dasatinib for relapsed or refractory Ph+
    leukemias
    (2) To assess the safety and tolerability of dasatinib in children and
    adolescents with newly diagnosed Ph+ CP-CML who are treatment-naive.
    (3) To evaluate additional measures of efficacy in children and
    adolescents with newly diagnosed CP-CML or subjects with relapsed or
    refractory Ph+ leukemias treated on a given regimen of dasatinib
    including: best cytogenetic and hematological response rates (Cohorts 1
    & 3);
    (4) time to response and duration of response;
    (5) disease free survival (DFS);
    (6) progression-free survival (PFS) and overall survival (OS);
    (7) rates of complete (CMR) and major (MMR) molecular response.
    (8) To describe the spectrum of the BCR-ABL mutations at baseline, at
    progression or end of treatment, and to explore the role of mutations as
    predictors of response
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1)/(2)/(4)/(5)/(6) Every week for the first eight weeks. Then every 3
    months during the first two years. Every three months thereafter and at
    the end of protocol therapy.
    (3) Best cytogenetic response rates: every 3 months during the first 2
    years, then yearly. Hematologic response rates: Cohort 1 and Cohort 3 -
    Every week for the first eight weeks, monthly until month 6, every 3
    months thereafter.
    (7) Every 3 months during the first two years. Then every three months
    thereafter and at the end of protocol therapy
    (8) At baseline, every 3 months during the first two years, then at every
    6 months, at progression or end of treatment
    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 Yes
    E.6.13.1Other scope of the trial description
    Palatability
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    France
    Germany
    India
    Italy
    Korea, Republic of
    Mexico
    Netherlands
    Romania
    Russian Federation
    Singapore
    South Africa
    Spain
    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
    Subjects will be followed yearly for survival for up to 5 years after discontinuation of study therapy.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 122
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 50
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 71
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    pediatric subjects
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    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)
    After 24 months of treatment, subjects who complete the study and continue to demonstrate clinical benefit will be eligible to receive study drug up to 12 months after the approval of study drug within the pediatric population by the responsible health authority or until the study drug becomes commercially available within the country, whichever occurs sooner.
    Pls refer to Protocol Amendment 02, Section 4.1, for further details.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Italy
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