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    Summary
    EudraCT Number:2008-002260-33
    Sponsor's Protocol Code Number:CA180-226
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2008-12-19
    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
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2008-002260-33
    A.3Full title of the trial
    A Phase II Study of Dasatinib Therapy in Children and Adolescents with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia or with Ph+ Leukemias Resistant or Intolerant to Imatinib Revised Protocol 02 incorporating Administrative Letter 01, 02 & Protocol Amendment 03 and 07 (04- Oct-2010)
    Studio di fase II con Dastinib in bambini e adolescenti con leucemia mieloide cronica in fase corica di nuova diagnosi o con leucemie Ph+ resistenti o intolleranti ad Imatinib. Revised Protocol 02 che incorpora l'Administrative Letter 01, 02 e gli emendamenti al Protocollo 03 e 07 (04-Ottobre-2010)
    A.4.1Sponsor's protocol code numberCA180-226
    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 SponsorBristol-Myers Squibb Internaltional 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 Unit 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 AuthorisationUnited Kingdom
    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.3.4Pharmaceutical 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.3.9.2Current sponsor codeBMS-354825-03
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 AuthorisationUnited Kingdom
    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.3.4Pharmaceutical 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.3.9.2Current sponsor codeBMS-354825-03
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 nameDasatinib
    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.3.9.2Current sponsor codeBMS-354825-03
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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 Newly Diagnosed Chronic Phase CML or with Ph+ Leukemias Resistant to or Intolerant to Imatinib
    Bambini ed adolescenti con leucemia mieloide cronica in fase cronica di nuova diagnosi o con leucemia Ph+ resistenti o intolleranti ad Imatinib
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLGT
    E.1.2Classification code 10024324
    E.1.2Term Leukaemias
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    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 study objective is to estimate the complete cytogenetic response(CCyR)rate to dasatinib therapy in children and adolescents with newly diagnosed CP-CML in first chronic phase with no prior therapy (except hydroxyurea) and to estimate the major cytogenetic response (MCyR) rate to dasatinib therapy in subjects who prove resistant to or intolerant to imatinib. Additionally, an estimate of the complete hematologic response (CHR) rate in children and adolescents with Ph+ ALL, AP-CML and BP-CML, who are resistant to, intolerant to, or relapse after prior imatinib therapy.
    L obiettivo primario e` di stimare la risposta citogenetica completa (CCyR) alla terapia con Dastinib in bambini e adolescenti con CP-CML di nuova diagnosi senza alcuna precedente terapia (eccetto idrossiurea) e stimare la percentuale di risposta citogenetica maggiore (MCyR) alla terapia con dasatinib in soggetti che sono resistenti, intolleranti a Imatinib. Inoltre, una stima della percentuale di risposta ematologia completa (CHR) in bambini e adolescenti con Ph+ALL, AP`ˆ'e BP`ˆ'CML, che sono resistenti, intolleranti a imatinib o hanno presentato recidive dopo precedente terapia con Imatinib.
    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 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
    `ˆ' Verificare la sicurezza e la tollerabilita` di dasatinib in bambini e adolescenti trattati con dasatinib per leucemie Ph+ recidivanti o refrattarie `ˆ' Verificare la sicurezza e la tollerabilita` del dasatinib in bambini e adolescenti con Ph+ CP-CML di nuova diagnosi che sono naive al trattamento `ˆ' Valutare misure aggiuntive di efficacia in bambini e adolescenti con CP-CML di nuova diagnosi o soggetti con leucemie Ph+ recidivante o refrattaria trattati con un regime di dasatinib che include:`ˆ'percentuale di risposta citogenetica ed ematologica `ˆ'tempo di risposta e durata di risposta `ˆ'sopravvivenza libera dalla malattina(DFS)`ˆ'sopravvivenza libera da progressione(PFS)e sopravvivenza globale(OS)`ˆ'percentuale di risposta molecolare completa(CMR)e percentuale di risposta molecolare maggiore(MMR)`ˆ' Descrivere lo spettro delle mutazioni BCR`ˆ'ABL al baseline,alla progressione o alla fine del trattamento,e analizzare il ruolo delle mutazioni per la previsione della risposta.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed Written Informed Consent a) 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 or spleen (f) Ph+ or variant must be demonstrated by bone marrow cytogenetics ii) Cohort #2: Subjects must have Ph+ ALL or Ph+ AP- or 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) 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) < 10 X 109/L platelets unrelated to therapy (3) 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 or spleen (f) Ph+ or variant 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 for further informations refear to protocol
    1.Consenso informato firmato a) Consenso informato scritto da parte dei soggetti, o dai genitori dei pazienti minorenni, in base alle leggi e normative locali 2.Popolazione target a)Diagnosi: i) Gruppo#1: I pazienti devono avere Ph+CML in CP, che si definisce grazie alla presenza dei seguenti criteri: •&lt;15% di blasti nel sangue periferico e nel midollo osseo •&lt;20% di basofili nel sangue periferico •&lt;30% di blasti+promielociti nel sangue periferico e nel midollo osseo •maggiore o uguale a 100x109 piastrine/L, eccetto trombocitopenia secondaria da recente trattamento •assenza di coinvolgimento extramidollare diverso da quello del fegato o della milza •Ph+ o varianti devono essere dimostrate dalla citogenetica del midollo osseo ii) Gruppo#2: I pazienti devono avere Ph+ALL o Ph+ AP`ˆ'o BP`ˆ'CML: •I pazienti Ph+ ALL devono essere in prima o successive recidive [definita come una mancanza della risposta ematologia completa come riportatp nella Seione 4.3.1.1] o non raggiungere la remissione [come riportato nella Sezione 4.3.1.1] •I pazienti AP`ˆ'CML devono soddisfare almeno uno dei seguenti criteri: (a) e 15% ma &lt;30% di blasti nel sangue periferico o nel midollo osseo (b) e 30% di blasti + promielociti nel sangue periferico e nel midollo osseo (ma ogni singola percentuale deve essere &lt;30%) (c) e 20% di basofili nel sangue periferico o nel midollo osseo (d) &lt; 10 X 109/ L piastrine non correlate alla terapia •BP`ˆ'CML devono soddisfare tutti i seguenti criteri: (a) `‰¥ 30% blasti nel sangue periferico o nel midollo osseo (b) Presenza di malattia extramidollare blastica diversa da linfonodi, fegato o della milza iii) Gruppo#3: I pazienti devono avere Ph+CML in CP, che si definisce grazie alla presenza dei seguenti criteri: •&lt;15% di blasti nel sangue periferico e nel midollo osseo •&lt;20% di basofili nel sangue periferico •&lt;30% di blasti+promielociti nel sangue periferico e nel midollo osseo •maggiore o uguale a 100x109 piastrine/L, eccetto trombocitopenia secondaria da recente trattamento •assenza di coinvolgimento extramidollare diverso da quello del fegato o della milza •Ph+ o varianti devono essere dimostrate dalla citogenetica del midollo osseo b) I pazienti del Gruppo#1 e del Gruppo#2 devono dimostrare resistenza o intolleranza a imatinib: i) Definizione di intolleranza: per il Gruppo #1 e il Gruppo #2 l`intolleranza a imatinib e` definita come il verificarsi di qualsiasi tossicita` di grado maggiore o uguale a 3 considerate almeno possibilmente correlate a imatinib e che hanno portato all`interruzione della precedente terapia con imatinib. ii) Per il Gruppo# 1: la resistenza a imatinib deve soddisfare almeno uno dei seguenti criteri: (a) Il mancato conseguimento o la perdita di CHR dopo un periodo `‰¥ 3 mesi di imatinib a una dose giornaliera di 260 mg/m2 o superiore (rif. alla Sezione 4.3.1.2 per le definizioni di risposta citogenetica). Una dose di 400 mg al giorno in pazienti affetti da LMC in fase cronica con una BSA&gt;1.5 m2 sono accettabili; (b) Il mancato raggiungimento di MCyR dopo un periodo `‰¥ 6 mesi o CCyR dopo un periodo e 12 mesi della terapia con imatinib a una dose giornaliera di 260 mg/m2 o superiore; (rif. alla Sezione 4.3.1.2 per le definizioni di risposta citogenetica). Una dose di 400 mg al giorno in pazienti affetti da LMC in fase cronica con una BSA&gt;1.5 m2 sono accettabili; (c) Il mancato raggiungimento di CCyR dopo un periodo `‰¥ 12 mesi della terapia con imatinib a una dose giornaliera di 260 mg/m2 o superiore; (rif. alla Sezione 4.3.1.2 per le definizioni di risposta citogenetica). Una dose di 400 mg al giorno in pazienti affetti da LMC in fase cronica con una BSA&gt;1.5 m2 sono accettabili; per ulteriori informazioni consultare il protocollo
    E.4Principal exclusion criteria
    1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of investigational product. b) Women who are pregnant or breastfeeding 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. This criterion relates to subjects with CNS-3 disease (`‰¥ 5 leukemic blasts per cubic millimeter in a sample with < 10 erythrocytes per cubic millimeter). Subjects with CNS-1 (no detectable blast cells in a sample of cerebrospinal fluid) and CNS-2 (< 5 leukemic blast cells in a sample with < 10 erythrocytes per cubic millimeter) are eligible for study.46 Subjects with a combined relapse which also involves the CNS are eligible, provided this is 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 (e.g. 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. b) Expected non-compliance to protocol schedule or unable to have regular followup 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. 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. If required for control of peripheral blast cells, hydroxyurea, corticosteroids, 6-mercaptopurine or 6-thioguanine may be given up to 2 days before treatment start. c) Subjects requiring ongoing medications which may: i) Have a known risk of causing QTc prolongation - see Section 5.5.3.2 ii) Irreversibly inhibit platelet function, or anticoagulants - see Section 5.5.3.3 (Does not apply to low-dose heparin for prophylaxis or to heparin flushes for i.v. lines) for further informations refear to protocol
    1) Sesso e Stato riproduttivo a) WOCBP che non desiderano o non possono utilizzare un metodo contraccettivo adeguato per evitare la gravidanza per l`intero periodo di studio e fino a 12 settimane dopo l`ultima dose di farmaco in studio. b) Le donne in gravidanza o che allattano al seno c) Donne con test di gravidanza positivo all`arruolamento o prima della somministrazione del farmaco in studio d) Uomini sessualmente attivi e fertili che non utilizzano un efficace metodo di controllo delle nascite con una partner fertile WOCBP che non desiderano o non possono utilizzare un metodo contraccettivo adeguato per evitare la gravidanza per l`intero periodo di studio e fino a 4 settimane dopo l`ultima dose di farmaco in studio. 2) Eccezioni a) I pazienti per i quali e` potenzialmente disponibile una terapia`ˆ'curativa, compreso il trapianto delle cellule staminali ematopoietiche (HSCT) b) I pazienti con casi isolati di patologie al sistema nervoso centrale (CNS) sono esclusi dallo studio. Questo criterio si riferisce a quei soggetti con malattia CNS-3 (`‰¥ 5di blasti leucemici per millimetro cubo in un campione con &lt; 10 eritrociti per millimetro cubo). I pazienti con CNS-1 (in cui non si osservano cellule blastiche in un campione di fluido spinale) e CNS-2 (&lt; 5 di blasti leucemici per millimetro cubo in un campione con &lt; 10 eritrociti per millimetro cubo) possono essere arruolati nello studio. 29 46 pazienti con ricaduta combinata in cui sia coinvolto anche il CNS, purche` sia asintomatico (nessuna convulsione o altri sintomi neurologici), sono arruolabili. c) Malattia extramidollare isolata, con una percentuale &lt;5% di blasti nel midollo osseo 3) Storia medica e malattie concomitanti a) Qualsiasi grave disturbo medico incontrollato che potrebbe compromettere la capacita` dei pazienti a ricevere la terapia di studio, tra cui: i) infezione incontrollata in corso ii) disturbi della funzione piastrinica clinicamente significative (come la malattia di von Willebrand`s) o sanguinamento gastrointestinale in corso iii) malattie cardiovascolari clinicamente significative, sindrome congenita dell`intervallo QT prolungato, storia di aritmie ventricolari o blocco cardiaco, o prolungato intervallo QTc &gt; 450 ms (correzione Fridericia) sull`elettrocardiogramma al baseline iv) pazienti diagnosticati con la mutazione T315I (l`esame per la valutazione della mutazione dovrebbe essere effettuato secondo la pratica standard dello sperimentatore e non e` mandatario per quei centri sperimentali senza la disponibilita` del test BCR-ABL). v) pazienti in cui si e` gia` manifestata ipersensibilita` al dasatinib o ad uno degli eccipienti. Gli eccipienti nelle compresse di dasatinib sono: lattosio monoidrato, cellulosa monocristallina, sodio croscaramelloso, cellulosa idrossipropile e magnesio stearato. Il rivestimento delle compresse e` costituito da: ipromellosa, biossido di titanio, glicole polietilenico. vi) pazienti con problemi ereditari di intolleranza al lattosio e deficienza di Lapp lattasi o malassorbimento di glucosio-galattosio. b)il mancato rispetto del programma del protocollo o impossibilita` di ricevere regolare monitoraggio a causa di ragioni legate a problemi psicologici, sociali, familiari o motivi geografici 4)trattamenti e / o terapie proibite a)Precedenti terapie con dasatinib. b) qualsiasi farmaco in fase di sperimentazione o qualsiasi altro farmaco anti-cancro entro 14 giorni prima iniziare il trattamento. Imatinib mesilato puo` essere continuato fino a 7 giorni prima di iniziare il trattamento, o, in presenza di aumento delle cellule blastiche periferiche, imatinib puo` essere continuato fino a 2 giorni prima di iniziare il trattamento. Se necessario per il controllo delle cellule blastiche periferiche, idrossiurea, per ulteriori informazioni consultare il protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is MCyR for Cohort #1 and CHR for Cohort #2, and CCyR for Cohort #3. Cytogenetic response will be based on the percentage of Ph+ metaphases among `‰¥ 20 analyzed metaphases in bone marrow aspirate. CHR will be assessed regularlythrough hematology tests. Molecular responses will also be assessed. Mutation analyses will be reported descriptively. To assess safety, adverse events will be reported continuously and graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Safety will be summarized by cohort, by reporting AEs, laboratory abnormalities, dose interruptions and reductions, treatment discontinuation for toxicity, and use of concomitant medications.
    L endpoint primario e` la valutazione della MCyR per il gruppo 1 e della CHR per il gruppo 2 e della CCyR per il gruppo 3. La risposta citogenetica sara` valutata sulla percentuale di metafasi Ph+ 20 analizzate fra le metafasi nell aspirato di midollo osseo. CHR verra` valutato regolarmente attraverso analisi ematologiche del siero. Verra` anche valutata la risposta molecolare. Le analisi di mutazione verranno riportate descrittivamente. Per valutare la sicurezza, gli eventi avversi verranno osservati di continuo e classificati in accordo ai NCI Common Terminology Criteria per gli Eventi Avversi (CTCAE) versione 3.0. La sicurezza sara` riassunta per gruppi riportando gli AEs, i valori anormali di laboratorio, le interruzioni o riduzioni di dose, la discontinuazione per tossicita` e uso di terapie concomitanti.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 Yes
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    I pazienti saranno seguiti annualmente per la sopravvivenza fino a 5 anni dopo l`interruzione della terapia.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months70
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months70
    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: 0
    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.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 109
    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)
    I pazienti che completano lo studio e continuano a mostrare dei benefici clinici saranno eleggibili per ricevere il farmaco in studio oltre i 12m dopo l`approvazione del farmaco nella popolazione pediatrica dall`AC responsabile o fino a quando il farmaco diventa commerciabile in quel paese (quale evento accade prima). Il farmaco sara` fornito tramite uno studio di rollover richiedendo l`approvazione dell`AC e del CE responsabili, o tramite un altro meccanismo a discrezione dello sponsor.
    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 Decision2009-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-11-28
    P. End of Trial
    P.End of Trial StatusRestarted
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