E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myeloid leukemia |
Leucemia mieloblástica aguda |
|
E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia |
Leucemia mieloblástica aguda |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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 |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |