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    Summary
    EudraCT Number:2017-003377-34
    Sponsor's Protocol Code Number:54767414ALL2005
    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:2018-02-28
    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 number2017-003377-34
    A.3Full title of the trial
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Ensayo abierto, multicéntrico, de fase 2 que evalúa la eficacia y seguridad
    de Daratumumab en pacientes pediátricos y jóvenes adultos entre ≥1 y ≤
    30 años con leucemia linfoblástica aguda o linfoma linfoblástico de
    precursores de células B y T en recaída o refractarios al tratamiento.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Ensayo abierto, multicéntrico, de fase 2 que evalúa la eficacia y seguridad
    de Daratumumab en pacientes pediátricos y jóvenes adultos entre ≥1 y ≤
    30 años con leucemia linfoblástica aguda o linfoma linfoblástico de
    precursores de células B y T en recaída o refractarios al tratamiento.
    A.4.1Sponsor's protocol code number54767414ALL2005
    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 SponsorJanssen-Cilag International N.V.
    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 supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen Cilag, S.A
    B.5.2Functional name of contact pointGlobal Clinical Operations Spain
    B.5.3 Address:
    B.5.3.1Street AddressPaseo de las Doce Estrellas, 5-7
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28042
    B.5.3.4CountrySpain
    B.5.4Telephone number+314917228100
    B.5.5Fax number+314917228628
    B.5.6E-mailagonza45@its.jnj.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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code HuMax-CD38
    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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414 (Daratumumab)
    D.3.9.3Other descriptive nameHUMAX-CD38
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typehuman monoclonal antibody
    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/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Leucemia linfoblástica aguda o linfoma linfoblástico de precursores de
    células B y T en recaída o refractarios.
    E.1.1.1Medical condition in easily understood language
    Blood or bone cancer
    Cáncer de sangre o hueso.
    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 10000845
    E.1.2Term Acute lymphoblastic 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 10066109
    E.1.2Term Precursor B-lymphoblastic leukemia acute
    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 10066110
    E.1.2Term T-cell lymphoblastic leukemia acute
    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 main objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in relapsed/refractory B-cell ALL and T-cell ALL as measured by the complete response (CR) rate.
    El objetivo principal es evaluar la eficacia del daratumumab añadido a la quimioterapia estándar en leucemia linfoblástica aguda (LLA) de células B y T en recaída o refractaria, medida mediante la tasa de respuesta completa (RC).
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of daratumumab, including overall response rate (ORR), relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in pediatric and young adult subjects with B-cell and T-cell acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LL), and minimal residual disease (MRD) negative rate in subjects with B-cell and T-cell ALL
    - To assess the safety and tolerability of daratumumab in pediatric and young adult subjects with B-cell and T-cell ALL/LL
    - To assess the pharmacokinetics (PK) of daratumumab in pediatric and young adult subjects with B-cell and T-cell ALL/LL
    - To assess daratumumab immunogenicity in pediatric and young adult subjects with B-cell ALL and T-cell ALL/LL
    - To assess daratumumab concentration in cerebrospinal fluid (CSF)
    -Evaluar la eficacia de daratumumab, incluidas la tasa de respuesta
    global (TRG), la supervivencia sin recidiva (SSR), la supervivencia sin eventos (SSE) y la supervivencia global (SG) en sujetos pediátricos y adultos jóvenes con linfoma linfoblástico (LL) o LLA de células B y células T, y tasa negativa de enfermedad residual mínima (ERM) en sujetos con LLA de células B y células T
    -Evaluar la seguridad y tolerabilidad de daratumumab en sujetos
    pediátricos y adultos jóvenes con LLA o LL de células B y células T
    -Evaluar la farmacocinética (FC) de daratumumab en sujetos pediátricos y adultos jóvenes con LLA o LL de células B y células T
    -Evaluar la inmunogenicidad de daratumumab en sujetos pediátricos y
    adultos jóvenes con LLA o LL de células B y células T
    -Evaluar la concentración de daratumumab en el líquido cefalorraquídeo (LCR)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential subject must satisfy all the following criteria to be enrolled in the study:
    1. ≥1 and ≤30 years of age
    2. Documented ALL or LL as defined by the criteria below:
    a) B-cell cohort:
    Stage 1:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in second or greater relapse or refractory to 2 prior induction
    regimens and biopsy proven and with evidence of measurable disease
    by radiologic criteria and aged 1 to 30 years
    b) T-cell cohort:
    Stage 1:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in first relapse or refractory to 1 prior induction/consolidation
    regimen biopsy proven and with evidence of measurable disease by
    radiologic criteria and aged 1 to 30 years
    3. Performance status ≥70 by Lansky scale (for subjects <16 years of age) or Karnofsky scale (for subjects ≥16 years of age)
    4. Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:
    a. Hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion is permitted)
    b. Platelet count ≥10 × 109/L (prior platelet transfusion is permitted)
    5. Adequate renal function defined as normal serum creatinine for the subject’s age or creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m^2 at Cycle 1 Day 1 pre-dosing
    6. Adequate liver function at Cycle 1 Day 1 pre-dosing defined as:
    a. Alanine aminotransferase level ≤2.5x the upper limit of normal (ULN)
    b. Aspartate aminotransferase level ≤2.5xULN, and
    c. Total bilirubin ≤2x ULN or direct bilirubin level ≤2.0xULN
    7. Female subjects of reproductive potential prior to initiation of the study or during the study (should reproductive potential change during the study) must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 6 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. Birth control methods must include one highly effective method of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
    8. During the study and for 6 months after receiving the last dose of any component of the treatment regimen, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
    9. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 6 months after discontinuing study treatment (even after a successful vasectomy)
    10. Male subjects of reproductive potential must not donate sperm during the study or for 6 months after the last dose of study treatment
    11. The informed consent form (ICF) must be signed by a legally authorized representative or by the subject if at legal age of consent indicating understanding of the purpose of, and procedures required for, the study and willingness to participate in the study. Assent is also required of children capable of understanding the nature of the study according to country-specific or site-specific standards
    12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
    Cada paciente potencial debe cumplir con todos los siguientes criterios para participar en el estudio:
    1. ≥1 y ≤30 años de edad
    2. LLA o LL documentado según lo definido por los siguientes criterios:
    a) cohorte de células B:
    Fase 1:
    - LLA en segunda recaída o mayor o refractario a 2 regímenes de
    inducción previos con ≥5% de blastos en la médula ósea y de 1 a <18
    años.
    Etapa 2:
    - LLA en segunda recaída o mayor o refractario a 2 regímenes de
    inducción previos con ≥5% de blastos en la médula ósea y de 1 a 30
    años de edad.
    - LL en segunda recaída o mayor o refractario a 2 regímenes de
    inducción previos y biopsia comprobada y con evidencia de enfermedad medible mediante criterios radiológicos y en edades de 1 a 30 años.
    b) Cohorte de células T:
    Fase 1:
    -LLA en primera recaída o refractario a 1 régimen de inducción /
    consolidación previo con ≥5% de blastos en la médula ósea y edades de1 a <18 años.
    Fase 2:
    - LLA en primera recaída o refractario a 1 régimen de inducción /
    consolidación previo con ≥5% de blastos en la médula ósea y edades de 1 a 30 años.
    - LL en primera recaída o refractario a 1régimen de inducción /
    consolidación previa de biopsia demostrada y con evidencia de
    enfermedad apreciable mediante criterios radiológicos y edades de 1 a 30 años.
    3. Estado de rendimiento ≥70 por escala Lansky (para pacientes <16
    años de edad) o escala Karnofsky (para pacientes ≥16 años de edad)
    4. Valores adecuados de hematología en la pre-dosis del ciclo 1 día 1,
    definidos de la siguiente manera:
    a. Hemoglobina ≥7.5 g / dL (≥5 mmol / L; se permite la transfusión
    previa de glóbulos rojos )
    b. Recuento de plaquetas ≥10 × 109 / L (se permite la transfusión de
    plaquetas previa)
    5. Función renal adecuada definida como creatinina sérica normal para la edad del sujeto o aclaramiento de creatinina o tasa de radioisótopo glomerular de filtración (TFG) 70 ml / min / 1.73 m ^ 2 en el ciclo 1 Día
    1 pre-dosificación.
    6. Función hepática adecuada en la pre-dosis del ciclo 1 día 1 definida
    como:
    a. Nivel de alanina aminotransferasa ≤2.5x el límite superior de la
    normalidad (ULN)
    b. Nivel de aspartato aminotransferasa ≤2.5xULN, y
    c. Bilirrubina total ≤2x ULN o nivel de bilirrubina directa ≤2.0xULN
    7. Las mujeres con potencial reproductivo antes de iniciar el estudio o
    durante el estudio (si el potencial reproductivo cambia durante el
    estudio) deben comprometerse a abstenerse continuamente de las
    relaciones sexuales heterosexuales o utilizar 2 métodos de control de la natalidad de simultáneamente durante el período de tratamiento,
    durante cualquier interrupción de dosis, y durante 6 meses después de la última dosis de cualquier componente del régimen de tratamiento. La abstinencia sexual se considera un método altamente eficaz solo si se define como la abstención de las relaciones sexuales heterosexuales durante todo el período de riesgo asociado con el medicamento del estudio. Los métodos anticonceptivos deben incluir un método anticonceptivo altamente eficaz (ligadura de trompas, dispositivo intrauterino, hormonas [píldoras anticonceptivas, inyecciones, parches hormonales, anillos vaginales o implantes], o vasectomía de la pareja) y un método anticonceptivo efectivo adicional (condón de látex o sintético, diafragma o capuchón cervical). La anticoncepción debe comenzar 4 semanas antes de la administración del fármaco. La anticoncepción segura está indicada incluso cuando ha habido antecedentes de infertilidad, a menos que se deba a una histerectomía .
    8. Durante el estudio y durante 6 meses después de recibir la última
    dosis de cualquier componente del régimen de tratamiento, las mujeres deben aceptar no donar óvulos (óvulos, ovocitos) para fines de reproducción asistida.
    9. Los pacientes masculinos de potencial reproductivo que sean
    sexualmente activos con mujeres de potencial reproductivo siempre
    deben usar un condón de látex o sintético durante el estudio y durante 6 meses después de suspender el tratamiento del estudio (incluso después de una vasectomía exitosa)
    10. Los pacientes masculinos con potencial reproductivo no deben donar esperma durante el estudio o durante 6 meses después de la última dosis del tratamiento del estudio.
    11. El formulario de consentimiento informado (ICF) debe estar firmado por un representante legalmente autorizado o por el sujeto si la edad legal de consentimiento indica la comprensión del propósito y los procedimientos requeridos para el estudio y la voluntad de participar en el estudio. También se requiere la aprobación de niños capaces de comprender la naturaleza del estudio de acuerdo con los estándares específicos del país o del lugar.
    12. Debe estar dispuesto y ser capaz de cumplir con las prohibiciones y restricciones especificadas en este protocolo.
    E.4Principal exclusion criteria
    Any potential subject who meets any of the following criteria will be excluded from participating in the study:
    1. Received an allogeneic hematopoietic transplant within 3 months of screening
    2 Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease of Grade 2 or higher
    3. Received immunosuppression post hematopoietic transplant within 1 month of study entry.
    4. Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase inhibitor therapy
    5. Has either of the following:
    a. Evidence of dyspnea at rest or oxygen saturation ≤94%.
    b. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma may participate in the study
    6. Down syndrome, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
    7. Prior exposure to daratumumab or other anti-CD38 therapies
    8. Prior cancer immunotherapy (ie, CAR-T, inotuzumab) within 4 weeks prior to start of daratumumab treatment or blinatumomab within 2 weeks prior to the start of daratumumab treatment
    9. For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure must not exceed 400 mg/m^2 (each 10 mg/m^2 of idarubicin should be calculated as the equivalent of 30 mg/m^2 of doxorubicin)
    10. Subject is known to be seropositive for human immunodeficiency virus, hepatitis B (defined by a positive test for hepatitis B surface antigen or antibodies to hepatitis B surface and core antigens), or hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
    11. Screening 12-lead electrocardiogram (ECG) showing a baseline QT interval >470 msec or Grade 3 or higher cardiac disorders (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03)
    12. Known allergies, hypersensitivity, or intolerance to mannitol, glucocorticoid, doxorubicin, cytarabine, methotrexate, vincristine, cyclophosphamide, 6-mercaptopurine, mAb (IRR is not considered hypersensitivity) or human proteins, or their excipients, or known sensitivity to mammalian-derived products
    13. Received an investigational drug, was vaccinated with live attenuated vaccines, or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug, or is currently being treated in an investigational study.
    14. Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen
    15. Plans to father a child while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen
    16. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
    17. Major surgery within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration
    Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate
    18. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications listed in Section 8 of protocol.
    NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.
    Cualquier sujeto potencial que cumpla con alguno de los siguientes
    criterios será excluido de participar en el estudio:
    1.Recibió un trasplante alogénico hematopoyético dentro de los 3m
    antes de la selección.
    2.Enfermedad activa de injerto contra huésped de cualquier grado o
    enfermedad crónica de injerto contra huésped de Grado2 o sup.
    3.Recibió inmunosupresión después de un trasplante hematopoyético
    dentro de 1mes del ingreso al estudio.
    4.LLA de célulasB positivas para cromosoma Filadelfia(Ph+)elegibles
    para terapia con inhibidores de tirosina quinasa.
    5.Tiene cualquiera de los siguientes:
    a.Evidencia de disnea en reposo o saturación de oxígeno≤94%.
    b.Asma moderado o severo persistente conocido en los últimos 2añ o
    asma no controlada de cualquier clasificación.Tenga en cuenta que los
    pacientes que actualmente tienen asma intermitente controlada o asma persistente leve controlada pueden participar en el estudio.
    6.Sínd de Down,leucemia mielomonocítica juvenil,anemia de Fanconi,síndrome de Kostmann,síndrome de Shwachman o cualquier
    otro sínd conocido de insuficiencia de méd ósea.
    7.Exposición previa a daratumumab u otras terapias anti-CD38
    8.Inmunoterapia previa contra el cáncer(es decir,CART,
    inotuzumab)dentro de las 4sem previas al inicio del trat. con
    daratumumab o tratamiento de blinatumomab dentro de las 2sem
    anteriores al inicio del trat. con daratumumab.
    9.Para sujetos con LLA/LL de células T solamente: ¡a exposición
    acumulada previa a antraciclina no debe exceder400 mg/m^2(cada 10
    mg/m^2 de idarrubicina debe calcularse como el equivalente
    a30mg/m^2de doxorrubicina)
    10.Seropositividad conocida del paciente para virus de
    inmunodeficiencia humana,hep B(definido por una prueba positiva para el antígeno de superficie de hep B o anticuerpos contra antígenos de superficie y núcleo de hep B)o hep C(exc. en el caso de una respuesta virológica sostenida(SVR),definida como aviremia al menos 12sem después de finalización de terapia antiviral)
    11.Electrocardiograma 12derivaciones(ECG)que muestra un intervalo QT basal>470mseg o trastornos cardíacos de grado3 o superior(según
    Criterios de terminología común del Instituto Nacional del Cáncer para
    Eventos Adversos[NCI CTCAE]ver 4.03)
    12.Alergias conocidas,hipersensibilidad o intolerancia al
    manitol,glucocorticoides,doxorrubicina,citarabina,metotrexato,vincristina,ciclofosfamida,6-mercaptopurina,mAb(la reacción a la infusiónno se considera hipersensibilidad)o proteínas humanas o sus excipientes o sensibilidad conocida a los productos derivados-mamíferos.
    13.Recibió un fármaco en investigación,se vacunó con vacunas vivas
    atenuadas,utilizó un dispositivo médico de investigación invasivo dentro de las 4sem previas a la primera dosis planificada del fármaco del estudio,o está actualmente en tratamiento en un estudio de
    investigación.
    14.Embarazada,en periodo de lactancia o planeando quedarse
    embarazada mientras está incluida en este estudio o dentro de los 6m
    posteriores a la última dosis de cualquier componente del régimen de
    tratamiento.
    15.Planes para engendrar un hijo mientras está incluida en este estudio o dentro de los 6m posteriores a la última dosis de cualquier componente del régimen de tratamiento
    16.El sujeto padece cualquier condición o enfermedad médica o psiq
    concurrente(Ej. Inf sistémica activa,diab no controlada,enfermedad
    pulmonar infiltrativa difusa aguda)que es probable pueda interferir con procedimientos o resultados del estudio o que,en opinión del
    investigador,constituiría un peligro para participar en este estudio.
    17.Cirugía mayor dentro de las 2sem anteriores a la inclusión,o si no se hubiera recuperado completamente de la cirugía,o que planea una
    cirugía durante el tiempo que se espera que el sujeto participe en el
    estudio o dentro de las 2sem posteriores a la última dosis de la
    administración del medicamento del estudio.
    Nota:los sujetos con procedimientos quirúrgicos planificados que se
    realizarían bajo anestesia local pueden participar.
    18.Se sabe o se sospecha que el paciente no puede cumplir con el
    protocolo de estudio(Ej.Debido a alcoholismo,dependencia de drogas o trastorno psicológico).El paciente tiene alguna condición para la cual,en opinión del investigador,la participación no sería lo mejor para él mismo(Ej.comprometer el bienestar)o que podría prevenir,limitar o confundir las evaluaciones especificadas en el protocolo.El paciente está tomando cualquier medicamento prohibido enumerado en la Sección8del prot.
    NOTA:Los investigadores deben asegurarse de que se hayan cumplido
    todos los criterios de la incl. en el estudio. Si el estado clínico de un
    paciente cambia(incluidos los resultados de lab disponibles o la
    recepción de registros médicos adicionales)después de la inclusión, pero antes de que la 1ª dosis del medicamento del estudio se administre de manera tal que ya no satisfaga todos los criterios de elegibilidad,el sujeto debe ser excluido de su participación en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    1. Complete response (CR) rate
    1. Tasa de respuesta completa (RC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Within 2 cycles of therapy for B-cell ALL and at the end of Cycle 1 for T-cell ALL
    1. Dentro de los 2 ciclos de terapia para la ALL de células B y al final del
    Ciclo 1 para la LLA de células T.
    E.5.2Secondary end point(s)
    1. Overall response rate (ORR)
    2. Event-free survival (EFS)
    3. Relapse-free survival (RFS)
    4. Overall survival (OS)
    5. Minimal residual disease (MRD) negative rate
    6. Proportion of subjects who receive an allogeneic Hematopoietic stem cell transplant (HSCT) after treatment with daratumumab
    7. PK of daratumumab in pediatric and young adult subjects (Cmax and Cmin)
    8. Daratumumab immunogenicity incidence in pediatric and young adult subjects with B-cell T-cell ALL/LL
    9. Concentration of daratumumab in Cerebrospinal fluid (CSF)
    1. Tasa de respuesta global (ORR)
    2. Supervivencia sin eventos (EFS)
    3. Supervivencia sin recaídas (RFS)
    4. Supervivencia global (OS)
    5. Tasa negativa de enfermedad residual mínima (MRD)
    6. Proporción de pacientes que reciben un trasplante alogénico de
    células madre hematopoyéticas (TCMH) después del tratamiento con
    daratumumab
    7. PK de daratumumab en pacientes pediátricos y adultos jóvenes (Cmax
    y Cmin)
    8. Incidencia de inmunogenicidad de Daratumumab en sujetos
    pediátricos y adultos jóvenes con LLA/ LL de células T de células B
    9. Concentración de daratumumab en líquido cefalorraquídeo (LCR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.End of bothCycle(1&2)for B&T-cell cohort andDay28 of every other cycle from C4untilCR for B-ALL/LL
    2.Time from date of 1st treat.to 1st documented treat. failure,or date of relapse from CR,or death ,whichever occurs 1st
    3.Time from CR to relapse fromCR or death due to any cause,whichever occurs 1st
    4.Time from date of 1st treatment to date of death due to any cause
    5.End of both Cycle(1&2)for T-cell coh. and Day28 of every other cycle from C4untilCR forB-ALL/LL
    6.End of C1,2
    7.B-cell cohort-Predose & at endof infusion on D1ofC1,2,3,6,9,EoT,follow-up Tcell cohort-Predose & atend of infusion at
    C1D1,C2D1,22,EoT,follow-up
    8.Bcohort-Predose on D1ofC1,2,6,9, EoT,follow-up T cohort-Predose on
    D1ofC1,2, EoT,fu.
    9.Bcohort-Predose on D1ofC1,2,3,4,6,9 T cohort-Predose on
    C1D1,15,C2D2,15
    1.Fin de ciclos (C)1&C2 para cohorte de cél B&T y en día (D)28 de
    cualquier otro ciclo desde C4hastaCR para B-LLA/LL.
    2.Tiempo desde CR para recaer de CR o muerte por cualquier
    causa,cualquiera que ocurra 1º
    3.Tiempo desde fecha del 1er trat hasta fecha de muerte por cualquier
    causa.
    4.Fin de ambos Ciclos(C)1 y C2 para cohorte cél T y Día(D)28 a ciclos alt
    desdeC4hasta CR para B-LLA/LL.
    5.Fin de ambos C1,2.
    6.Cohorte de cél B:predosis y al final de infusión
    enD1deC1,2,3,6,9,EoT,seguimiento
    Cohorte de cél T:Predosis y al final de infusión en
    C1D1,C2D1,22,EoT,seguimiento
    7.Cohorte B:Predosis en D1 de C1,2,6,9,EoT,seguimiento
    Cohorte T:Predosis en D1 de C1,2,EoT,seguimiento
    8.Cohorte B:Predosis en D1 de C1,2,3,4,6,9
    Cohorte T:Predosis enC1D1,15,C2D2,15
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    Análisis de Inmunogenicidad y Biomarcadores
    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 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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA28
    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
    Canada
    Germany
    Israel
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will end 1 year after the last subject has initiated treatment. A futility analysis will be performed after Stage 1 of the study and could result in the trial ending prior to this if specific, protocol-defined efficacy events are not met.
    El estudio finalizará 1 año después de que el último sujeto haya iniciado el tratamiento. Se realizará un análisis de esterilidad después de la Etapa 1 del estudio y podría resultar en la finalización del ensayo antes de esto si no se cumplen los eventos específicos de eficacia definidos por el protocolo.
    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 months0
    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 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 Yes
    F.1.1Number of subjects for this age range: 54
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    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
    Children aged 1 year -18 years
    Niños de entre 1 y 18 años.
    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 28
    F.4.2.2In the whole clinical trial 69
    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)
    Standard of care treatment.
    Tratamiento estándar.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-10
    P. End of Trial
    P.End of Trial StatusOngoing
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