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    Summary
    EudraCT Number:2015-001901-15
    Sponsor's Protocol Code Number:NKCell_LMA_2015
    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:2015-11-05
    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 number2015-001901-15
    A.3Full title of the trial
    Natural Killer cell infusion as consolidation therapy in children and adolescents with acute myelogenous leukemia.
    Infusión de células Natural Killer como tratamiento de consolidación en niños y adolescentes con leucemia mieloblástica aguda.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Infusion of cells to treat myeloblastic leuciemia
    Infusion de celulas para tratar la leuciemia mieloblastica
    A.4.1Sponsor's protocol code numberNKCell_LMA_2015
    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 SponsorAntonio Pérez Martínez
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundación Mutua Madrileña
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital Universitario La Paz
    B.5.2Functional name of contact pointUCICEC
    B.5.3 Address:
    B.5.3.1Street AddressPaseo de la Castellana 261
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28049
    B.5.3.4CountrySpain
    B.5.4Telephone number34912071466
    B.5.5Fax number34912071466
    B.5.6E-mailmaria.posada@idipaz.es
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNK cells diferenciated adult allogeneic haploidentical ofexpanded periferic blood and activated with
    D.3.4Pharmaceutical form Injection
    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 INNNK cells diferenciated adult allogeneic haploidentical ofexpanded periferic blood and activated with IL
    D.3.9.3Other descriptive nameNK cells diferenciated adult allogeneic haploidentical ofexpanded periferic blood and activated with IL
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number50000000
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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 typeNK cells from haploidentical donor
    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 Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Farmaceutica S.A
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameProleukin
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINTERLEUKIN-2
    D.3.9.1CAS number 8000048-25-1
    D.3.9.3Other descriptive nameINTERLEUKIN-2
    D.3.9.4EV Substance CodeSUB14225MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000000
    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 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
    Acute myeloid leukemia
    Leucemia mieloblástica aguda
    E.1.1.1Medical condition in easily understood language
    Acute myeloid leukemia
    Leucemia mieloblástica aguda
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Reduce by 20% the probability of relapse at three years of pediatric patients with AML in first cytologic remission , without good prognosis cytogenetic alterations and without indication of progenitors hematopoietic allogeneic transplant.
    Disminuir un 20% la probabilidad de recaída a tres años de los pacientes pediátricos con LMA en primera remisión citológica, sin alteraciones citogenéticas de buen pronóstico y sin indicación de trasplante de progenitores hematopoyéticos alogénico.
    E.2.2Secondary objectives of the trial
    1. To determine the in vitro susceptibility of myeloid blasts to Natural Killer lymphocytes allogeneic.

    2. To determine the safety of infusion of NK cells along with the chemotherapy regimen.
    1. Determinar la susceptibilidad in vitro de los blastos mieloides a los linfocitos Natural Killer alogénicos.

    2. Determinar la seguridad de la infusión de células NK junto con el régimen de quimioterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients aged between 0 and 21 years diagnosed with AML in first cytologic remission who have completed induction and consolidation chemotherapy phase, and do not comply criteria for allogeneic HSCT. That is, patients who have responded well to induction lacking HLA identical related donor and have high-risk cytogenetic abnormalities
    2. Lansky / Karnofsky index > 60%.
    3. Functional disorders of organs (liver, kidney, respiratory) mild-moderate (<4), according to the criteria of the National Cancer Institute (NCI CTCAE v4).
    4. Left Ventricule ejection fraction> 39% .
    5. Grant informed consent in accordance with current legislation .
    6. Presence of a haploidentical donor.
    1. Pacientes de edad comprendida entre 0 y 21 años diagnosticados de LMA en situación clínica de primera remisión citológica que han completado la fase de inducción y consolidación de quimioterapia, y no tienen criterios para TPH alogénico. Es decir, pacientes que han respondido bien a la inducción, que carecen de donante familiar HLA idéntico y no tienen alteraciones citogéneticas de alto riesgo.
    2. Índice de Lansky/Karnofsky > 60%.
    3. Alteración funcional de órganos (hepática, renal, respiratorio) leve-moderada (<4), según los criterios del National Cancer Institute (NCI CTCAE v4).
    4. Fracción de eyección del ventrículo izquierdo >39%.
    5. Otorgar consentimiento informado de acuerdo con la normativa legal vigente.
    6. Presencia de un donante haploidéntico.
    E.4Principal exclusion criteria
    1. Patients with a history of poor compliance.
    2. Patients who after a psycho-social assessment are censored as unfit for the procedure:
    • psycho-social situation that makes it impossible proper participation in the study.
    • Patients with disease secondary to emotional or psychological problems such as PTSD, phobias, delusions, psychosis, with support request by specialists.
    • Evaluation of the involvement of the family in the patient's health.
    • Inability to understand information about the trial.
    3. Severe alteration of  functional organs (liver, kidney, respiratory) (4), according to the criteria of the National Cancer Institute (NCI CTCAE 4.3).
    4. Contraindications, interactions, precautions for use and dose reductions indicated in the corresponding summary of product characteristics should be considered.
    1. Pacientes con antecedentes de mal cumplimiento terapéutico.
    2. Pacientes que tras una evaluación psico-social se censuran como no aptos para el procedimiento.
    • Situación socio-familiar que imposibilite la correcta participación en el estudio.
    • Pacientes con problemas emocionales o psicológicos secundarios a la enfermedad como trastorno de estrés postraumático, fobias, delirios, psicosis, con requerimiento de soporte por especialistas.
    • Evaluación de la implicación de los familiares en la salud del paciente.
    • Imposibilidad de comprender la información sobre el ensayo.

    3. Alteración funcional de órganos (hepática, renal, respiratorio) grave (4), según los criterios del National Cáncer Institute (NCI CTCAE 4.3).
    4. Se deben considerar las contraindicaciones, interacciones, precauciones de uso y reducciones de dosis indicadas en las fichas técnicas correspondientes.
    E.5 End points
    E.5.1Primary end point(s)
    The main endpoint  is the probability of relapse in patients after infusion of NK cells. Each patient will be monitored according to clinical guidelines for detecting relapse. For evaluation, bone marrow aspirate will be performed after a month of treatment and subsequently at least annually, to complete three years of follow-up. The objective response rate will be set according to the criteria and cytomorphologic "minimal residual disease" (cytometry and / or real-time PCR).
    La variable principal es la probabilidad de recaída de los pacientes tras la infusión de células NK. Cada paciente será monitorizado de acuerdo a las guías clínicas para la detección de la recaída. Para su valoración se realizará un aspirado de médula ósea al mes de finalizado el tratamiento y posteriormente al menos de manera anual, hasta completar 3 años de seguimiento. La tasa de respuesta objetiva se establecerá según los criterios citomorfológicos y por ?enfermedad mínima residual? (citometría y/o PCR tiempo real).
    E.5.1.1Timepoint(s) of evaluation of this end point
    36 months
    36 meses
    E.5.2Secondary end point(s)
    1. The secondary endpoint will be the safety of infusion of NK cells along with the chemotherapy regimen. Patients will be monitored to detect potential adverse effects. For the NCI-CTC assessment criteria will be V4.0 and the proportion of patients with toxicity depending on the degree will be determined. Toxic effects can not be classified according to the criteria for toxicity of that system, they shall be classified as follows (MedDRA classification):
    a) Mild (asymptomatic);
    b) Moderate (symptom but does not significantly interfere with the function);
    c) Severe (causes significant interference function);
    d) life-threatening.
    2. HLA typing of patient and donor, haplotyping KIR functionality donor and donor NK leukemia patient.

    3. hematopoietic chimerism after infusion of NK cells. The expression of ligands for receptors activatorios (MICA, MICB, ULBPs) and inhibitory receptors (HLA-I) of NK cells was determined by multiparametric flow cytometry.
    4. The in vitro cytotoxic activity of NK cells against allogeneic leukemic blasts be another measured variable Eur real time fluorescence-TDA (Blomberg et al. J Immunol Methods 1986).
    1. La variable secundaria será la seguridad de la infusión de células NK junto con el régimen de quimioterapia. Los pacientes serán monitorizados para la detección de posibles efectos adversos. Para su valoración se seguirán los criterios NCI-CTC V4.0 y se determinará la proporción de pacientes que presentan toxicidad en función del grado. Los efectos tóxicos que no puedan clasificarse de acuerdo a los criterios para la toxicidad del citado sistema, se clasificarán de la siguiente manera (clasificación MedDRA):
    a) Leve (asintomático);
    b) Moderado (sintomático pero que no interfiere significativamente con la función);
    c) Severo (provoca una interferencia significativa de la función);
    d) Amenazante para la vida.
    2. Tipaje HLA de paciente y donante, determinación de haplotipo KIR en donante y funcionalidad de las NK del donante contra la leucemia del paciente.

    3. Quimerismo hematopoyético tras la infusión de células NK. La expresión de ligandos para los receptores activatorios (MICA, MICB, ULBPs) y para los receptores inhibitorios (HLA-I) de las células NK se determinará por citometría de flujo multiparamétrica.
    4. La actividad citotóxica in vitro de las células NK alogénicas frente a los blastos leucémicos será otra variable medida con fluorescencia a tiempo real Eur-TDA (Blomberg et al. J Immunol Methods 1986).
    E.5.2.1Timepoint(s) of evaluation of this end point
    36 months
    36 meses
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open 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 Yes
    E.8.1.7.1Other trial design description
    brazo unico
    single arm
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of Follow up (LVLS)
    Final de seguimiento
    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 months
    E.8.9.1In the Member State concerned days
    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: 35
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 35
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 35
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 35
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 35
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 35
    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
    Niños
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    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)
    Expected normal treatment of the disease
    Tratamiento normal esperado de esta enfermedad
    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 Decision2016-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-05
    P. End of Trial
    P.End of Trial StatusOngoing
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