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    Summary
    EudraCT Number:2016-002919-18
    Sponsor's Protocol Code Number:AC220-A-U202
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-05-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-002919-18
    A.3Full title of the trial
    A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination with Re-Induction Chemotherapy, and as a Single-Agent Maintenance Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) with FLT3-ITD mutations.
    Estudio multicéntrico de fase 1/2, de aumento escalonado de la dosis, para evaluar la seguridad, la farmacocinética, la farmacodinámica y la eficacia de Quizartinib, en combinación con quimioterapia de reinducción y como tratamiento de mantenimiento con un solo agente, en pacientes pediátricos con MLA refractaria o en recaída de entre 1 mes y 18 años (y adultos jóvenes de hasta 21 años) con mutaciones de FLT3-ITD.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 clinical trial of the drug Quizartinib (AC220) to investigate the safety and efficacy in paediatric patients (aged 1 month to <18 years) and young adults (aged up to 21 years) with Acute Myeloid Leukemia (AML), a cancer of the blood.
    Estudio clinico de fase 1/2, de Quizartinib (AC220) para aumento evaluar la seguridad y eficacia en pacientes pediátricos ( entre 1 mes y 18 años ) y adultos jóvenes (de hasta 21 años) con Leucemia mieloide aguda (MLA) , un cancer de la sangre.
    A.4.1Sponsor's protocol code numberAC220-A-U202
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/102/2018
    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, 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 pointClinical Trial Information Contact
    B.5.3 Address:
    B.5.3.1Street Address211 Mt. Airy Road
    B.5.3.2Town/ cityBasking Ridge, New Jersey
    B.5.3.3Post code07920
    B.5.3.4CountryUnited States
    B.5.6E-maileu_cta@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
    D.3.2Product code AC220
    D.3.4Pharmaceutical form Powder for oral solution
    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.3.9.3Other descriptive nameQUIZARTINIB
    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 number60
    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 DaunoXome
    D.2.1.1.2Name of the Marketing Authorisation holderGalen Limited
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLiposomal Daunorubicin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDAUNORUBICIN
    D.3.9.1CAS number 20830-81-3
    D.3.9.4EV Substance CodeSUB06917MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Relapsed or Refractory acute myeloid leukemia (AML) in subjects aged ≥1 month to ≤21 years with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations following failure of front-line intensive chemotherapy
    Leucemia mieloide aguda (LMA) recidivante o refractaria en sujetos con edades comprendidas entre ≥1 mes y ≤21 años con mutaciones por duplicación en tándem interna (internal tandem duplication, ITD) en la tirosina cinasa 3 similar a FMS (FLT3) tras el fracaso de la quimioterapia intensiva de primera línea.
    E.1.1.1Medical condition in easily understood language
    Relapsed/Refractory acute myeloid leukemia (subjects aged ≥1month- ≤21years) with FMS-like tyrosine kinase 3 internal tandem duplication mutations after failure of front-line intensive chemotherapy
    LMA recidivante/refractaria (sujetos entre ≥1 mes y ≤21 años) con mutaciones por duplicación en tándem interna en tirosina cinasa 3 similar a FMS tras fracaso de quimioterapia intensiva de 1ª línea.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060558
    E.1.2Term Acute myeloid leukemia recurrent
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10076230
    E.1.2Term Fms-like tyrosine kinase 3 positive
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1 only:
    - To determine the recommended Phase 2 dose (RP2D) of quizartinib, in combination with chemotherapy, for subjects in the older (≥1 year old to ≤21 years old) and younger (≥1 month old to <12 months old) age groups.
    - To determine the composite complete remission (CRc) rate (i.e., complete remission [CR] + CR with incomplete recovery [CRi]) after completion of up to 2 Re-Induction Cycles.
    - To determine the safety and cumulative toxicity of quizartinib administered in combination with re-induction therapy for up to 2 cycles, with optional consolidation therapy, and as a single-agent maintenance therapy over ≤12 cycles.
    - To determine estimates of individual PK parameters of quizartinib and AC886 (metabolite of quizartinib).
    Fase I únicamente:
    - Determinar la dosis recomendada para la fase 2 (DRF2) de quizartinib, en combinación con quimioterapia para sujetos en los grupos de edad más mayor (de ≥1 año a ≤21 años de edad) y más joven (de ≥1 mes a <12 meses de edad).
    - Determinar la tasa de remisión completa compuesta (RCc) (es decir, la remisión completa [RC] + RC con recuperación incompleta [RCi]) tras completar un máximo de 2 ciclos de reinducción.
    - Determinar la seguridad y la toxicidad acumulada de quizartinib administrado en combinación con tratamiento de reinducción durante un máximo de 2 ciclos, con tratamiento de consolidación opcional, y como tratamiento de mantenimiento en monoterapia durante ≤12 ciclos.
    - Determinar las estimaciones de los parámetros FC individuales de quizartinib y AC886 (metabolito de quizartinib).
    E.2.2Secondary objectives of the trial
    •To determine:
    o CR rate after completion of up to 2 Re-Induction Cycles
    o Durations of CRc and CR
    • To assess:
    o Time to relapse, rate of relapse after 1, 2 and 3 years, and cumulative incidence of relapse at the EoT
    o To determine the rates of CR and CRc after completion of Re- Induction Cycle 1
    o OS and EFS at 1, 2, and 3 years
    o Number of subjects proceeding to high-dose conditioning therapy/ HSCT
    o Activity of quizartinib on FLT3-ITD and FLT3-wild- type autophosphorylation activity by an ex-vivo PIA during Re-Induction, Maintenance, and at time of relapse
    o FLT-ITD/FLT3-wild-type allelic ratio at Screening, during Re-Induction, and at time of relapse
    o To evaluate mutations in blasts at Screening and at time of refractory disease or relapse
    o MRD for subjects in CR or CRi at Screening, end of Re-Induction Cycle 1, end of Re- Induction Cycle 2 and at time of relapse by next generation sequencing
    o Acceptability including palatability of quizartinib formulations.
    Determinar:
    -Tasa RC tras completar máx 2 ciclos reinducción
    - Duraciones RCc y RC
    Evaluar:
    - Tiempo hasta recidiva, tasa recidiva tras 1, 2 y 3 años, e incidencia acumulada recidiva al fin de estudio
    - Determinar tasas RC y RCc tras completar C1 reinducción
    - SG y SSA al cabo de 1, 2 y 3 años
    - Nº sujetos continúan tto de acondicionamiento de dosis alta/TCMH
    - Actividad quizartinib sobre actividad autofosforilación de FLT3-ITD y FLT3 tipo salvaje mediante análisis actividad inhibitoria en plasma ex-vivo durante reinducción, mantenimiento y momento recidiva
    - Proporción alélica FLT-ITD/FLT3 tipo salvaje en selección, durante reinducción y momento recidiva
    - Mutaciones en blastos, selección y momento refracción o recidiva
    - EMR para sujetos en RC o RCi a partir de muestras en selección, al final C1 reinducción, al final C2 de reinducción y momento recidiva mediante secuenciación de última generación
    - Aceptabilidad, incluida palatabilidad de formulaciones de quizartinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must satisfy all of the following inclusion criteria prior to enrollment:
    1. Diagnosis of AML according to the World Health Organization (WHO) 2008 classification with >5% blasts in bone marrow, with or without extramedullary disease.
    2. Subjects must be in first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1−2 cycles of induction chemotherapy) at remission induction.
    3. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as confirmed by the central laboratory ≥3% FLT3-ITD/total FLT3). Subjects may be enrolled and begin treatment based upon the results of a local FLT3-ITD laboratory test (performed on or after the date of diagnosis of relapse/refractory disease), however, a sample must be sent to the central laboratory for confirmation.
    4. Subjects must be between 1 month and ≤21 years of age at the time the Informed Consent/Assent form is signed.
    5. Karnofsky performance status score of >50% for subjects >16 years of age, and a Lansky performance status score of >50% for subjects ≤16 years of age.
    6. Subjects must have fully recovered from the acute toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study:
    a. Myelosuppressive chemotherapy:
    - For subjects who relapse while they are receiving cytotoxic therapy, at least 21 days must have elapsed since the completion of cytotoxic therapy.
    - Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy. Subjects may also receive low dose cytarabine (100 mg/m2/dose once daily for 5 days) for cytoreduction.
    - Subjects who have received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib), with the exception of quizartinib, are eligible for this study.
    b. Hematopoietic growth factors: At least 3 days since the completion of therapy with a growth factor.
    c. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. However, for agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the medical monitor.
    d. ≥14 days for local external radiation therapy (XRT) for CNS chloromas.
    e. ≥90 days must have elapsed if prior total body radiation (TBI) or craniospinal XRT occurred.
    f. At least 90 days must have elapsed since HSCT; and subjects must not have active graft-versus-host disease (GVHD). Immunosuppressive therapy must be stable for ≥2 weeks in subjects with a history of ≤ Grade 2 GVHD and for ≥4 weeks in subjects with a history of Grade 3/4 GVHD.
    g. Investigational Drug/Device: at least 30 days or 5 half-lives since the completion of therapy, whichever is longer.
    7. Adequate renal and hepatic functions as indicated by the following laboratory values:
    a. Serum creatinine concentration ≤ institutional upper limit of nor al (ULN) based on the age and gender.
    b. Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin (unless related to leukemic involvement).
    c. Alanine transaminase (ALT) <5 × ULN (unless related to leukemic involvement).
    8. LV fractional shortening of ≥29% by echocardiogram, OR a left ventricular ejection fraction of ≥50% by radionuclide angiogram.
    9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment. Female subjects of childbearing potential must be willing to use highly effective birth control upon enrollment, during the treatment period, and for 6 months following the last dose of quizartinib or cytarabine, whichever is later. Female subjects are considered of childbearing potential following menarche, unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy).
    10. Female subjects with infants must agree not to breastfeed their infants while on this study.
    11. Male subjects must be surgically sterile or willing to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of quizartinib or cytarabine, whichever is later.
    12. Subjects and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks, and benefits of the study. All subjects and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines.
    Please refer to the protocol for a complete description of inclusion criteria for the maintenance phase.
    Los sujetos deben cumplir todos los siguientes criterios de inclusión antes de la inscripción:
    1. Diagnóstico de LMA según la clasificación de la Organización Mundial de la Salud (OMS) de 2008 con >5 % de blastos en la médula ósea, con o sin enfermedad extramedular.
    2. Los sujetos deben estar en la primera recidiva o ser refractarios a la quimioterapia de dosis alta de primera línea con no más de 1 intento (1−2 ciclos de quimioterapia de inducción) en la inducción de la remisión.
    3. Presencia de mutación activadora de FLT3-ITD en la médula ósea o en sangre periférica (proporción alélica confirmada por el laboratorio central ≥3 % FLT3-ITD/FLT3 total). Los sujetos podrán inscribirse y comenzar el tratamiento en función de los resultados de una prueba de laboratorio local de FLT3-ITD (realizada en la fecha del diagnóstico de enfermedad recidivante/refractaria o con posterioridad a esta fecha), aunque se debe enviar una muestra al laboratorio central para la confirmación.
    4. Los sujetos deben tener entre 1 mes y ≤21 años de edad en el momento de la firma del formulario de consentimiento/asentimiento informado.
    5. Puntuaciones en el estado funcional de Karnofsky de >50 % para sujetos >16 años de edad, y puntuación en el estado funcional de Lansky de >50 % para sujetos de ≤16 años de edad.
    6. Los sujetos deben haberse recuperado totalmente de los efectos de la toxicidad aguda de la quimioterapia, la inmunoterapia o la radioterapia previas a la entrada de este estudio:
    a. Quimioterapia mielosupresiva:
    − Para sujetos que experimenten una recidiva mientras estén recibiendo tratamiento citotóxico, deben haber transcurrido al menos 21 días desde la finalización del tratamiento citotóxico.
    − La citorreducción con hidroxiurea se puede iniciar y continuar durante un máximo de 24 horas antes del inicio del tratamiento sistémico del protocolo. Los sujetos también podrán recibir citarabina de dosis baja (dosis de 100 mg/m2/al día durante 5 días) para citorreducción.
    − Los sujetos que hayan recibido otros inhibidores de FLT3 (p. ej., lestaurtinib, sorafenib), con la excepción de quizartinib, son aptos para este estudio b. Factores de crecimiento hematopoyético: Al menos 3 días desde la finalización del tratamiento con un factor de crecimiento.
    c. Agente biológico (agente antineoplásico): Al menos 7 días desde la finalización del tratamiento con un agente biológico. Sin embargo, para agentes que tienen acontecimientos adversos (AA) conocidos que se produzcan después de los 7 días posteriores a la administración, este periodo debe ampliarse más allá del tiempo durante el que se sabe que se producen los AA. La duración de este intervalo debe comentarse con el supervisor médico.
    d. ≥14 días de radioterapia externa local (external radiation therapy, XRT) para cloromas en el SNC.
    e. Deben haber transcurrido ≥90 días si hubo radiación de todo el cuerpo (total body irradiation, TBI) o XRT craneoespinal previamente.
    f. Deben haber transcurrido al menos 90 días desde el TCMH; y los sujetos no deben tener enfermedad de injerto contra huésped (EICH) activa. El tratamiento inmunosupresor debe ser estable durante ≥2 semanas en sujetos con antecedentes de EICH de grado ≤2 y durante ≥4 semanas en sujetos con antecedentes de EICH de grado 3/4.
    g. Fármaco/dispositivo experimental: al menos 30 días o 5 semividas desde la finalización del tratamiento, lo que sea más largo.
    7. Funciones renal y hepática adecuadas, indicadas por los siguientes valores analíticos:
    a. Concentración de creatinina sérica ≤ límite superior de la normalidad (LSN) institucional en función de la edad y el sexo.
    b. Bilirrubina total <1,5 x LSN para la edad o bilirrubina conjugada normal (a menos que esté relacionada con la afectación leucémica).
    c. Alanina transaminasa (ALT) <5 × LSN (a menos que esté relacionada con la afectación leucémica).
    8. Acortamiento fraccional del VI de ≥29 % mediante ecocardiograma, O una fracción de eyección del ventrículo izquierdo de ≥50 % mediante angiografía de radionúclidos.
    9. Los sujetos de sexo femenino en edad fértil deben tener una prueba de embarazo en orina o en suero negativa confirmada dentro de las 2 semanas previas a la inscripción. Los sujetos de sexo femenino en edad fértil deben estar dispuestos a usar un método anticonceptivo altamente eficaz tras la inscripción, durante el periodo de tratamiento y durante 6 meses después de la última dosis de quizartinib o citarabina, la que sea más tarde. Se considera que los sujetos de sexo femenino están en edad fértil después de la menarquia, a menos que sean estériles de forma permanente (se han sometido a histerectomía, salpingectomía bilateral u ovariectomía bilateral).
    10. Los sujetos de sexo femenino con bebés deben acceder a no dar el pecho a sus bebés mientras estén en este estudio.

    Ver protocolo para descripción completa de principales criterios de inclusión para la fase de mantenimiento.
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria will be disqualified from entering the study:
    1. Diagnosis of isolated CNS relapse (CNS2/3 disease is allowed if treated with additional IT chemotherapy).
    2. Diagnosis of acute promyelocytic leukemia (APL), Juvenile myelomonocytic leukemia (JMML), FAB classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or myeloid proliferations related to Down syndrome.
    3. Uncontrolled or significant cardiovascular disease, including:
    a. Diagnosed or suspected congenital long QT syndrome.
    b. History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Medical Monitor prior to subject’s entry into the study.
    c. QT interval corrected >450 msec:
    • QTc interval corrected with Bazzet’s formula (QTcB) for subjects < 6 years of age at the time of enrollment.
    • QTc interval corrected with Fridericia’s formula (QTcF) for subjects ≥ 6 years of age at the time of enrollment.
    d. History of uncontrolled angina pectoris or myocardial infarction within 6 months.
    e. 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).
    f. Heart rate <50/minute on pre-entry ECG.
    g. Uncontrolled hypertension (i.e., systolic blood pressure and /or diastolic blood pressure that is, on repeated measurement, at or above the 95th percentile for sex, age, and height).
    h. History of complete left bundle branch block.
    i. History of New York Heart Association Class 3 or 4 heart failure.
    4. Subjects will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The subject needs to be off vasopressors and have negative blood cultures for at least 48 hours.
    5. Known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C).
    6. Known history of human immunodeficiency virus (HIV).
    7. History of hypersensitivity to any of the study medications or their excipients.
    8. Subject is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol.
    9. Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance, interfere with consent/assent, study participation, follow up, or interpretation of study results.
    10. Currently participating in other investigational interventional procedures (does not include observational procedures or long-term follow-up for previous interventional studies).
    11. Otherwise considered inappropriate for the study by the Investigator.
    Se considerará que los sujetos que cumplan cualquiera de los siguientes criterios no cumplen los requisitos para entrar en el estudio:
    1. Diagnóstico de recidiva del SNC aislado (se permite la enfermedad SNC2/3 si se trata con quimioterapia IT adicional).
    2. Diagnóstico de leucemia promielocítica aguda (LPA), leucemia mielomonocítica juvenil (LMMJ), clasificación M3 según la FAB o clasificación según la OMS de LPA con translocación, t(15;17)(q22;q12), o proliferaciones mieloides relacionadas con el síndrome de Down.
    3. Enfermedad cardiovascular no controlada o significativa, incluidos:
    a. Diagnóstico o sospecha de síndrome QT largo congénito.
    b. Antecedentes de arritmias ventriculares clínicamente significativas (como taquicardia ventricular, fibrilación ventricular o torsades de pointes [TdP]); cualquier antecedente de arritmia se comentará con el supervisor médico antes de la entrada del sujeto en el estudio.
    c. Intervalo QT corregido >450 ms:
    − Intervalo QTc corregido con fórmula de Bazzett (QTcB) para sujetos <6 años de edad en el momento de la inscripción.
    − Intervalo QTc corregido con fórmula de Fridericia (QTcF) para sujetos de ≥6 años de edad en el momento de la inscripción.
    d. Antecedentes de angina de pecho no controlada o infarto de miocardio dentro de los 6 meses anteriores.
    e. Antecedentes de bloqueo cardiaco de segundo (Mobitz II) o tercer grado (los sujetos con marcapasos son aptos si no tienen antecedentes de arritmias clínicamente relevantes mientras utilizan el marcapasos).
    f. Frecuencia cardiaca <50/minuto en la ECG antes de entrar en el estudio.
    g. Hipertensión no controlada (es decir, tensión arterial sistólica y/o tensión arterial diastólica que se encuentre, en mediciones repitas, en el percentil 95 o por encima para el sexo, la edad y la estatura).
    h. Antecedentes de bloqueo completo de la rama izquierda.
    i. Antecedentes de insuficiencia cardiaca de clase 3 o 4 según la Asociación del Corazón de Nueva York (New York Heart Association).
    4. Los sujetos serán excluidos si tienen una infección sistémica fúngica, bacteriana, vírica o de otro tipo que muestre signos/síntomas en curso relacionados con la infección sin mejoría a pesar del tratamiento con los antibióticos apropiados u otro tipo de tratamiento. El sujeto no debe estar recibiendo vasopresores y debe tener hemocultivos negativos durante al menos 48 horas.
    5. Hepatopatía clínicamente activa conocida (p. ej., hepatitis B activa o hepatitis C activa).
    6. Antecedentes conocidos de virus de la inmunodeficiencia humana (VIH)
    7. Antecedentes de hipersensibilidad a cualquiera de los medicamentos del estudio o sus excipientes.
    8. El sujeto está recibiendo o se prevé que recibirá quimioterapia, radiación o inmunoterapia distinta de lo especificado en el protocolo de manera concomitante.
    9. Cualquier enfermedad, afección, trastorno psiquiátrico o problema social concurrente significativo que pondría en peligro la seguridad o el cumplimiento del sujeto, interferiría con el consentimiento/asentimiento, la participación en el estudio, el seguimiento o la interpretación de los resultados del estudio.
    10. Estar participando actualmente en otros procedimientos intervencionistas experimentales (no incluye procedimientos observacionales o seguimiento a largo plazo para estudios intervencionistas previos).
    11. Ser considerado no apto de algún otro modo para el estudio por el investigador.
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
    - The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation
    therapy, and as a single-agent maintenance therapy over ≤12 cycles.
    - Phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1.

    Efficacy (i.e., the primary outcome measure):
    - CRc rate after completion of up to 2 Re-Induction Cycles.

    Pharmacokinetic:
    - Estimates of AUC, CL, and Vd for quizartinib and AC886 by the use of PopPK modeling or other applicable methods.
    Seguridad:
    - El perfil de seguridad de quizartinib administrado en combinación con quimioterapia de reinducción durante un máximo de 2 ciclos, con tratamiento de consolidación opcional, y como tratamiento de mantenimiento en monoterapia durante ≤12 ciclos.
    - Fase I únicamente: Número de TLD en cohortes de dosis en el ciclo 1 de reinducción.

    Eficacia (es decir, el criterio de valoración principal):
    - tasa de RCc después de completar hasta 2 ciclos de reinducción.

    Farmacocinética:
    - Estimaciones del ABC, aclaramiento (CL) y Vd para quizartinib y AC886 mediante la creación de modelos de FCPob y otros métodos aplicables.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Safety: From the time the Informed Consent/Assent Form signature and up to the 30-Day Safety Follow-up Visit
    • Efficacy: after completion of up to 2 Re-Induction Cycles.
    • PK: Re-Induction Cycles 1 and 2; Maintenance Cycle 1
    - Seguridad: desde momento de firma de consentimiento/ asentimiento y hasta D30 visita seguimiento seguridad.
    - Eficacia: tras completar hasta 2 ciclos de reinducción .
    - Farmacocinética: Ciclos 1 y 2 reinducción; Ciclo 1 mantenimiento.
    E.5.2Secondary end point(s)
    Efficacy (i.e., the secondary outcome measures):
    - Duration of CR.
    - Duration of CRc (i.e., from first documented CRc until documented
    relapse).
    - CR rate after completion of Re-Induction Cycle 1.
    - CR rate after completion of up to 2 Re-Induction Cycles.
    - CRc rate after completion of Re-Induction Cycle 1.
    - Time to relapse, the rate of relapse after 1, 2 and 3 years, and the cumulative incidence of relapse at the end of the study.
    - Overall survival, defined as the time from the start of Re-Induction
    therapy until death from any cause.
    - Number of subjects proceeding to high-dose conditioning therapy/HSCT (including transplant-related mortality).
    - Event-free survival defined as the time from the start of Re-Induction
    therapy until the earliest date of the following:
    - Refractory disease at the end of Re-Induction.
    - Relapse after CR or CRi.
    - Death from any cause at any time during the study.

    Pharmacodynamic:
    - Inhibition of FLT3-ITD and FLT3-wild-type autophosphorylation
    activity in an ex-vivo PIA during Re-Induction, Maintenance, and at the
    time of relapse.
    - FLT-ITD to FLT3-wild-type allelic ratio at Screening, during Re-
    Induction, and at the time of relapse.
    - Mutations present in blasts (e.g., in the kinase and juxtamembrane
    domains of FLT3-ITD and other mutations known to be associated with
    AML) at Screening and at the time of refractory disease or relapse.

    Biomarker:
    - MRD for subjects who are in CR or CRi at Screening, end of Re-Induction Cycle 1, end of Re-Induction Cycle 2, and at the time of relapse by next generation sequencing.

    Others:
    - Acceptability including palatability of quizartinib formulations.
    Eficacia (es decir, los criterios de valoración secundarios):
    - Duración de la RC.
    - Duración de la RCc (es decir, desde la primera RCc documentada hasta recidiva documentada).
    - Tasa de RC después de completar el ciclo 1 de reinducción.
    - Tasa de RC después de completar hasta 2 ciclos de reinducción.
    - Tasa de RCc después de completar el ciclo 1 de reinducción.
    - Tiempo hasta la recidiva, la tasa de recidiva después de 1, 2 y 3 años, y la incidencia acumulada de recidiva al final del estudio.
    - Supervivencia general, definida como el tiempo desde el inicio del tratamiento de reinducción hasta la muerte por cualquier causa.
    - Supervivencia sin acontecimientos, definido como el tiempo desde el inicio del tratamiento de reinducción hasta la fecha más reciente de las siguientes:
    − Enfermedad refractaria al final de la reinducción.
    − Recidiva después de RC o RCi.
    − Muerte por cualquier causa en cualquier momento durante el estudio.
    - Número de sujetos que continúan con el tratamiento de acondicionamiento de dosis alta/TCMH (incluida la mortalidad relacionada con el trasplante).

    Farmacodinámica:
    Inhibición de la autofosforilación de FLT3-ITD y de FLT3 de tipo salvaje mediante un PIA ex-vivo durante la reinducción, el mantenimiento y en el momento de la recidiva.
    Proporción alélica de FLT-ITD/FLT3 de tipo salvaje en la selección, durante la reinducción y en el momento de la recidiva.
    - Mutaciones presentes en blastos (p. ej., en los dominios cinasa y yuxtamembranoso de las mutaciones de FLT3-ITD y otras mutaciones conocidas por estar asociadas a la LMA) en la selección y en el momento de la refracción o la recidiva de la enfermedad.

    Biomarcador:
    - EMR para sujetos que están en RC o RCi en la selección, al final del ciclo 1 de reinducción, al final del ciclo 2 de reinducción y en el momento de recidiva mediante secuenciación de última generación.

    Otros:
    - Aceptabilidad incluida la palatabilidad de las formulaciones de quizartinib.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Efficacy
    o CR rate after completion of up to 2 re-induction cycles, and completion of C1 and 2
    o Time to relapse, the rate of relapse after 1, 2 and 3 years, and cumulative incidence of relapse at the EoT
    o OS, defined as the time from the start of Re-Induction therapy until death from any cause
    o Event-free survival from the start of Re-Induction therapy until the earliest date of: Refractory disease at the end of Re-Induction, Relapse after CR or Cri or death
    • PD: during Re-Induction, Maintenance, and at time of relapse
    • Biomarker: MRD measured after Re-Induction. Bone marrow aspirate samples collected at Screening, end of Re-Induction C1, end of Re-Induction C2, and at the time of relapse will be analyzed for MRD
    • Other: Palatability during Re-Induction C1 and Maintenance C1
    Eficacia
    - Tasa de RC tras completar hasta 2 Ciclos reinducción. Y Ciclos 1 y 2.
    - Tiempo hasta recidiva, tasa recidiva tras 1, 2 y 3 años, e incidencia acumulada recidiva a fin estudio.
    - SG, definida como tiempo desde inicio tto reinducción hasta la muerte por cualquier causa.
    - Supervivencia sin acontecimientos, definido como tiempo desde inicio tto reinducción hasta fecha más reciente de: enfermedad refractaria a final reinducción, Recidiva tras RC o RCi o muerte.
    Farmacodinámica: duración reinducción, mantenimiento y tiempo de recidiva.
    Biomarcador: EMR medida tras reinducción. Aspirado de médula ósea recogida en selección, fin de reinducción C1, fin reinducción C2, fin de recidiva se analizarán para EMR.
    Otros: palatabilidad durante Reinducción C1 y mantenimiento C1.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    1/2
    E.7.2Therapeutic exploratory (Phase II) No
    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 Yes
    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 trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Denmark
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Spain
    Sweden
    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
    LVLS
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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: 24
    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: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 9
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 28
    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
    Parent/guardian will sign in the case where a patient is not able to sign due to age
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 47
    F.4.2.2In the whole clinical trial 75
    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 the subject has ended his / her participation in the trial, 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 every 3 months for the first 2 years then once yearly thereafter until the last subject enrolled has been followed up for 3 years from the date of enrolment.
    Una vez que el paciente haya finalizado su participación en el ensayo está prevista visita de fin de tratamiento ( +7 dias) seguida por visita de seguimiento de seguridad de 30 días, ( +7 dias), después se realizarán visitas de seguimiento a largo plazo cada 3 meses durante los primeros 2 años y, posteriormente, una vez al año hasta que el último sujeto inscrito haya tenido al menos 3 años de seguimiento desde la fecha de la inscripción.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation ITCC
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Children’s Oncology Group
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-06
    P. End of Trial
    P.End of Trial StatusOngoing
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