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    Summary
    EudraCT Number:2015-004856-24
    Sponsor's Protocol Code Number:AC220-A-U302
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-27
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-004856-24
    A.3Full title of the trial
    A Phase 3, Double-Blind, Placebo-controlled Study of Quizartinib Administered in Combination with Induction and Consolidation
    Chemotherapy, and Administered as Continuation Therapy in Subjects 18 to
    75 Years Old with Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (QuANTUM First)
    Studio di fase 3, in doppio cieco, controllato verso placebo volto a valutare quizartinib somministrato in associazione con chemioterapia di induzione e consolidamento e somministrato come terapia di continuazione in soggetti di età compresa tra 18 e 75 anni con recente diagnosi di leucemia mieloide acuta FLT3-ITD(+) (QuANTUM First)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Trial Study of Quizartinib Administered in Combination with Induction and Consolidation Chemotherapy, and Administered as
    Continuation Therapy in Subjects 18 to 75 Years Old with Newly Diagnosed Acute Myeloid Leukemia
    Studio clinico di Quizartinib somministrato in combinazione con chemioterapia di induzione e di consolidamento, e sommministrato come terapia di continuazione in soggetti da 18 a 75 anni con nuova diagnosi di leucemia mieloide acuta.
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberAC220-A-U302
    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 SponsorDAIICHI SANKYO INC.
    B.1.3.4CountryUnited States
    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 supportDaiichi Sankyo Co. Ltd.
    B.4.2CountryJapan
    B.4.1Name of organisation providing supportDaiichi Sankyo Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo, Inc.
    B.5.2Functional name of contact pointSandra Hamelsky
    B.5.3 Address:
    B.5.3.1Street Address211 Mount Airy Road
    B.5.3.2Town/ cityBasking Ridge, NJ
    B.5.3.3Post code07920-2311
    B.5.3.4CountryUnited States
    B.5.4Telephone number0019089927021
    B.5.5Fax number0017329065690
    B.5.6E-mailshamelsky@dsi.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/622
    D.3 Description of the IMP
    D.3.1Product nameQuizartinib 20 mg
    D.3.2Product code AC220
    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 INNQuizartinib dihydrochloride
    D.3.9.1CAS number 1132827-21-4
    D.3.9.2Current sponsor codeAC220
    D.3.9.4EV Substance CodeSUB89721
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/9/622
    D.3 Description of the IMP
    D.3.1Product nameQuizartinib 30 mg
    D.3.2Product code AC220
    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 INNQuizartinib dihydrochloride
    D.3.9.1CAS number 1132827-21-4
    D.3.9.2Current sponsor codeAC220
    D.3.9.4EV Substance CodeSUB89721
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) (+) acute myeloid leukemia (AML)
    Leucemia mieloide acuta (LMA) con duplicazione tandem interna (ITD) (+) di FMS-tirosin chinasi 3 (FLT3)
    E.1.1.1Medical condition in easily understood language
    Acute Myeloid Leukemia (AML), a cancer of the blood.
    Leucemia Mieloide Acuta (LMA), un tumore del sangue.
    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 10000886
    E.1.2Term Acute myeloid 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 compare the effect of quizartinib vs placebo (administered with standard induction and consolidation chemotherapy, then administered as continuation therapy for up to 36 cycles) on eventfree survival (EFS) in subjects with newly diagnosed FLT3-ITD (+) AML.
    Confrontare l'effetto di quizartinib rispetto al placebo (somministrato con chemioterapia di induzione e di consolidamento standard e successivamente come terapia di continuazione per un massimo di 36 cicli) sulla sopravvivenza libera da eventi (EFS) in soggetti con recente diagnosi di AML FLT3-ITD(+).
    E.2.2Secondary objectives of the trial
    To compare the following in subjects treated with quizartinib vs placebo (administered with standard induction and consolidation chemotherapy,
    then administered as maintenance therapy for up to 12 cycles):
    ¿ Overall survival (OS);
    ¿ Complete remission (CR) rate;
    ¿ Composite complete remission rate (CRc = CR + CRp [Complete Remission with Incomplete Platelet Recovery] + CRi [Complete Remission with Incomplete Neutrophil Recovery]);
    ¿ Percentage of subjects achieving CR with no evidence of Minimal Residual Disease (MRD) following induction therapy.
    Other Secondary Objectives:
    To further characterize the safety profile of quizartinib administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 12 cycles.
    To assess the pharmacokinetics (PK) of quizartinib and its metabolite (AC886).
    Confrontare quanto segue in soggetti trattati con quizartinib rispetto a placebo (somministrato con chemioterapia di induzione e di consolidamento standard e successivamente come terapia di continuazione per un massimo di 36 cicli):
    ¿ sopravvivenza globale (OS);
    ¿ tasso di remissione completa (CR);
    ¿ tasso di remissione completa composita (CRc = CR + CR con recupero incompleto delle piastrine [CRp] + CR con recupero incompleto dei neutrofili [CRi]);
    ¿ percentuale di soggetti che raggiungono CR senza evidenza di malattia minima residua (MRD) dopo la terapia di induzione.
    Altri obiettivi secondari:
    Caratterizzare ulteriormente il profilo di sicurezza di quizartinib somministrato con chemioterapia di induzione e di consolidamento standard, e successivamente come terapia di mantenimento per un massimo di 12 cicli.
    Valutare la farmacocinetica (PK) di quizartinib e dei suoi metaboliti (AC886).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Up to 100 subjects will have intense pharmacokinetic (PK) sampling for plasma quizartinib (AC220) concentrations and its metabolite (AC886) at Cycle 1 during the Induction phase on Day 8, Day 15, and Day 21, within 10 minutes after the ECG is performed. This will be referred as the "PK-ECG-Biomarker Substudy".

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Fino a 100 soggetti avranno un intenso campionamento farmacocinetico (PK) per le concetrazioni di quizartinib (AC220) nel plasma e dei suoi metaboliti (AC886) al Ciclo 1 durante la fase di Induzione al Giorno 8, Giorno 15 e Giorno 21 entro 10 minuti dopo che l'ECG viene eseguito. Sar¿ indicato come "Sottostudio su PK-ECG-Biomarcatori"
    E.3Principal inclusion criteria
    1. Must be competent and able to comprehend, sign, and date an Ethics Committee or Institutional Review Board approved Informed Consent Form (ICF) before performance of any study-specific procedures or tests;
    2. =18 years or the minimum legal adult age (whichever is greater) and =75 years (at
    Screening);
    3. Newly diagnosed, morphologically documented primary AML or AML secondary to
    myelodysplastic syndrome or a myeloproliferative neoplasm based on the World Health Organization (WHO) 2008 classification (at Screening);
    4. Eastern Cooperative Oncology Group performance status 0-2 (at Screening);
    5. Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of =3% FLT3-ITD/total
    FLT3);
    6. Subject is receiving standard "7+3" induction chemotherapy regimen as specified in the protocol;
    7. Adequate renal function defined as: a. Creatinine clearance rate >50 mL/min, as
    calculated with the modified Cockcroft Gault equation;
    8. Adequate hepatic function defined as:
    a. Total serum bilirubin =1.5 × ULN;
    b. Serum alkaline phosphatase, aspartate transaminase and alanine transaminase =2.5 × ULN;
    9. Serum electrolytes within normal limits: potassium, calcium (total or corrected for serum albumin in case of hypoalbuminemia) and magnesium. If outside of normal limits, subject will be eligible when electrolytes are corrected;
    10. If a woman of childbearing potential, must have a negative serum pregnancy test upon entry into this study and must be willing to use highly effective birth control upon enrollment, during the treatment period and for 6 months following the last dose of investigational drug or cytarabine, whichever is later. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy
    or bilateral oophorectomy);
    11. If male, must be surgically sterile or willing to use highly effective birth control upon enrollment, during the treatment period, and for 6 months following the last dose of investigational drug or cytarabine, whichever is later.
    1. Capacità di comprendere, firmare e datare un modulo di consenso informato (ICF) approvato dal Comitato Etico o dal Consiglio di revisione istituzionale, prima dell'esecuzione di ogni procedura o esame specifico dello studio.
    2. Età =18 anni o la maggiore età (a seconda di quale delle due è maggiore) e =75 anni (allo screening).
    3. Recente diagnosi di AML primaria o AML secondaria a sindrome mielodisplastica documentata morfologicamente o di neoplasia mieloproliferativa in base alla classificazione dell'Organizzazione Mondiale della Sanità (OMS) del 2008 (allo screening).
    4. Stato di validità ECOG (Eastern Cooperative Oncology Group) di 0-2 (allo screening).
    5. Presenza di mutazione attivante FLT3-ITD nel midollo osseo (rapporto allelico di =3% FLT3-ITD/FLT3 totale).
    6. Soggetto sottoposto a regime di chemioterapia di induzione standard "7+3", come specificato nel protocollo.
    7. Funzionalità renale adeguata, definita come:
    a. clearance della creatinina > 50 ml/min, calcolata con l'equazione di Cockcroft Gault modificata.
    8. Funzionalità epatica adeguata, definita come:
    a. bilirubina sierica totale =1,5 × ULN;
    b. fosfatasi alcalina, aspartato transaminasi e alanina transaminasi nel siero =2,5 x ULN.
    9. Elettroliti sierici entro i limiti di normalità: potassio, calcio (totale o corretto per albumina sierica in caso di ipoalbuminemia) e magnesio. Se al di fuori dei limiti normali, il soggetto sarà idoneo quando gli elettroliti saranno corretti.
    10. Le donne in grado di procreare devono presentare un test di gravidanza su siero negativo al momento dell'ammissione a questo studio e devono essere disposte a utilizzare un metodo contraccettivo altamente efficace a partire dall’arruolamento, durante il periodo di trattamento e nei 6 mesi successivi all'ultima dose del farmaco sperimentale o di citarabina, qualsiasi duri più a lungo. Una donna è considerata in grado di procreare dopo il menarca e fino all’inizio della post menopausa (amenorrea per un minimo di 12 mesi), tranne se permanentemente sterile (sottoposta a isterectomia, salpingectomia bilaterale o ovariectomia bilaterale).
    11. Gli uomini devono essere chirurgicamente sterili o disposti a utilizzare un metodo contraccettivo altamente efficace a partire dall'arruolamento, nel periodo di trattamento e per 6 mesi successivi all'ultima dose del farmaco sperimentale o di citarabina, qualsiasi duri più a lungo.
    E.4Principal exclusion criteria
    1. Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); subjects who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).
    2. Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms;
    3. Prior treatment for AML, except for the following
    allowances:
    a. Leukapheresis;
    b. Treatment for hyperleukocytosis with hydroxyurea;
    c. Cranial radiotherapy for central nervous system (CNS) leukostasis;
    d. Prophylactic intrathecal chemotherapy;
    e. Growth factor/cytokine support;
    4. Prior treatment with quizartinib or other FLT3-ITD inhibitors;
    5. Prior treatment with any investigational drug or device within 30 days prior to Randomization
    (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures;
    6. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts;
    lumbar puncture is recommended for subjects with symptoms of CNS leukemia to rule out
    extramedullary CNS involvement;
    7. History of other malignancies, except adequately treated nonmelanoma
    skin cancer, curatively treated in-situ disease, or other solid
    tumors curatively treated with no evidence of disease for at least 2 years;
    8. Uncontrolled or significant cardiovascular disease, including any of the following:
    a. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
    b. QTcF interval >450 msec;
    c. Diagnosis of or suspicion of long QT syndrome (including family history of long QT
    syndrome);
    d. Systolic blood pressure =180 mmHg or diastolic blood pressure =110 mmHg;
    e. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia,
    ventricular fibrillation, or Torsade de Pointes);
    f. History of second (Mobitz II) or third degree heart block (subjects with pacemakers are
    eligible if they have no history of fainting or clinically relevant arrhythmias while using the
    pacemaker);
    g. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to
    Screening;
    h. History of New York Heart Association Class 3 or 4 heart failure;
    i. Known history of left ventricular ejection fraction (LVEF) =45% or less than the
    institutional lower limit of normal;
    j. Complete left bundle branch block;
    9. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy;
    10. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
    11. Known history of human immunodeficiency virus (HIV). Subjects should be tested for HIV prior to Randomization if required by local regulations or EC;
    1. Diagnosi di leucemia promielocitica acuta (APL), la classificazione francese-americana-britannica M3 o classificazione della APL dell'OMS con traslocazione, t(15;17)(q22;q12) o leucemia positiva per BCR-ABL (ossia leucemia mieloide cronica in crisi blastica); soggetti sottoposti a un controllo completo per APL e trattamento con acido all-trans retinoico (ATRA), ma per i quali non sia stata formulata una diagnosi di APL, saranno idonei (il trattamento con ATRA deve essere interrotto prima di iniziare la chemioterapia di induzione).
    2. Diagnosi di AML secondaria a precedente chemioterapia o radioterapia per altre neoplasie.
    3. Precedente trattamento per AML, fatta eccezione per i seguenti casi:
    a. leucaferesi;
    b. trattamento per iperleucocitosi con idrossiurea;
    c. radioterapia cranica per leucostasi del sistema nervoso centrale (SNC);
    d. chemioterapia intratecale profilattica;
    e. supporto per fattore di crescita/citochina.
    4. Precedente trattamento con quizartinib o altri inibitori di FLT3-ITD.
    5. Precedente trattamento con un farmaco o un dispositivo sperimentale nei 30 giorni precedenti la randomizzazione (entro 2 settimane per il farmaco sperimentale o l’immunoterapia approvata) o attuale partecipazione ad altre procedure sperimentali.
    6. Anamnesi di leucemia nota a carico dell'SNC, tra cui liquido cerebrospinale positivo per blasti di AML; è consigliata la puntura lombare per i soggetti con sintomi di leucemia a carico dell'SNC per escludere l'interessamento del SNC a livello extramidollare.
    7. Anamnesi di altre neoplasie, ad eccezione di tumore della pelle non melanomatoso adeguatamente trattato, malattia in situ trattata fino alla guarigione o altri tumori solidi trattati fino alla guarigione con nessuna evidenza di malattia da almeno 2 anni.
    8. Malattia cardiovascolare non controllata o significativa, tra cui qualsiasi condizione tra le seguenti:
    a. bradicardia inferiore a 50 battiti al minuto, a meno che il soggetto sia portatore di pacemaker;
    b. intervallo QTcF >450 msec;
    c. diagnosi o sospetto di sindrome del QT lungo (compresa anamnesi familiare di sindrome del QT lungo);
    d. pressione sistolica =180 mmHg e/o pressione diastolica =110 mmHg;
    e. anamnesi di aritmie ventricolari clinicamente significative (ad es., tachicardia ventricolare, fibrillazione ventricolare o torsione di punta);
    f. anamnesi di blocco cardiaco di secondo (Mobitz II) o terzo grado (i soggetti portatori di pacemaker sono idonei, se non presentano precedenti di svenimento o aritmie clinicamente significative durante l'utilizzo del pacemaker);
    g. anamnesi di angina pectoris o infarto del miocardio non controllato nei 6 mesi precedenti lo screening;
    h. anamnesi di insufficienza cardiaca di Classe 3 o 4 secondo la New York Heart Association;
    i. anamnesi nota di frazione di eiezione ventricolare sinistra (FEVS) =45% o inferiore al limite inferiore istituzionale della norma;
    j. Blocco di branca sinistra completo.
    9. Infezione fungina, batterica o virale attiva acuta o cronica sistemica non ben controllata con una terapia antimicotica, antibatterica o antivirale.
    10. Malattia epatica clinicamente significativa attiva nota (ad es., epatite B attiva o epatite C attiva).
    11. Anamnesi nota di infezione da virus dell’immunodeficienza umana (HIV). I soggetti devono essere sottoposti al test per l'HIV prima della randomizzazione, se richiesto dalle normative locali o comunitarie.
    12. Anamnesi di ipersensibilità a uno qualsiasi degli eccipienti delle compresse di quizartinib/placebo.
    13. Donne in gravidanza o che allattano al seno.
    14. Soggetti considerati in altro modo non idonei allo studio dallo sperimentatore.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is Event Free Survival in the Intent-to-treat (ITT) Analysis Set.
    L'endpoint primario di efficacia è l'EFS nel gruppo di analisi Intent-to-treat (ITT).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Date of earliest of any of the following:
    - Refractory disease (or treatment failure) which is determined at the end of the Induction Phase;
    - Relapse after CR, CRp or CRi;
    - Death from any cause at any time during the study.
    Data del primo di uno dei seguenti:
    • malattia refrattaria (o insuccesso del trattamento) che viene determinata alla fine della fase di induzione;
    • recidiva dopo CR, CRp o CRi;
    • decesso per qualunque causa, in qualsiasi momento durante lo studio.
    E.5.2Secondary end point(s)
    1. Overall survival, defined as the time from randomization until death from any cause;
    2. Complete remission rate which is the percent of subjects achieving CR after Induction;
    3. Composite complete remission rate, which is the percent of subjects achieving CRc after induction;
    4. Percent of subjects achieving CR with FLT3-ITD MRD negativity below
    a certain cutoff following induction therapy. Minimal or measurable
    residual disease is the presence of a small number of leukemic cells in
    the bone marrow of AML patients below the level of detection using
    conventional morphologic assessment. The FLT3-ITD MRD assay by Next
    Generation Sequencing will be used to detect and quantify residual FLT3-
    ITD mutations.
    ¿ sopravvivenza generale definita come il periodo che intercorre dalla randomizzazione al decesso per qualunque causa;
    ¿ tasso di remissione completa, che ¿ la percentuale di soggetti che raggiungono la CR dopo l'induzione;
    ¿ tasso di remissione completa composita, che ¿ la percentuale di soggetti che raggiungono la CRc dopo l'induzione;
    ¿ • percentuale di soggetti che raggiungono la CR con negatività di MRD FLT3-ITD sotto un certo livello limite dopo la terapia di induzione. La malattia residua minima o misurabile è la presenza di un piccolo numero di cellule leucemiche nel midollo osseo di pazienti con AML al di sotto del livello di rilevamento usando la valutazione morfologica standard. Per identificare e quantificare le mutazioni residue FLT3-ITD sarà utilizzato un saggio di sequenziamento di nuova generazione per MRD FLT3-ITD
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Lost to follow-up
    2. Outcome at the end of induction cycle 1 and the induction phase
    3. Same as point 2
    4. Same as point 2
    1. Soggetti irraggiungibili per il follow-up
    2. Outcome alla fine del Ciclo 1 di Induzione e la fase di Induzione
    3. Come il punto 2
    4. Come il punto 2
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned30
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA135
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Bulgaria
    Canada
    China
    Croatia
    Czechia
    France
    Germany
    Hong Kong
    Hungary
    India
    Israel
    Italy
    Korea, Republic of
    Malaysia
    Poland
    Portugal
    Romania
    Russian Federation
    Singapore
    Spain
    Taiwan
    Thailand
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will continue until the target number of EFS events is achieved and at least 14 months have elapsed since completion of enrollment; the end of the trial will be the date of the last subject visit.
    Lo studio continuer¿ fino al raggiungimento del numero target di sopravvivenza libera da eventi (EFS) e almeno trascorsi 14 mesi dal completamento dell'arruolamento; la fine della sperimentazione sar¿ la data della visita dell'ultimo soggetto.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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 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: 268
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 268
    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 state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 536
    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)
    An end of treatment visit (+7 days) is scheduled, followed by a 30 day (+7 days) safety follow-up visit, and then long-term visits will be performed as follows:
    - every 4 weeks for subjects who have NOT had an EFS event
    - every 12 weeks for subjects who have had an EFS event.

    All subjects will be followed for survival and subsequent anti-cancer therapy, if available.
    E' pianificata una visita di fine trattamento (+7 giorni) seguita da una visita di follow-up sulla sicurezza a 30 giorni (+ 7 giorni), e poi visite a lungo termine saranno eseguite come segue:
    - ogni 4 settimane per i soggetti che Non hanno manifestato un evento EFS
    - ogni 12 settimane per i soggetti che hanno manifestato un evento EFS

    Tutti i soggetti saranno seguiti per la sopravvivenza e conseguente terapia anti-tumorale, se disponibile.
    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 Decision2016-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-09
    P. End of Trial
    P.End of Trial StatusOngoing
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