E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Myelodysplastic Syndromes (MDS) and Juvenile Myelomonocytic Leukemia (JMML) |
Síndrome mielodisplásico avanzado (SMD) y Leucemia Mielomonocítica Juvenil (LMMJ) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054439 |
E.1.2 | Term | Juvenile chronic myelomonocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068361 |
E.1.2 | Term | MDS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish the recommended dose and preliminary efficacy of azacitidine in children with newly diagnosed and relapsed advanced MDS or JMML. |
Establecer la dosis recomendada y la eficacia preliminar de azacitidina en niños con SMD o LMMJ de nuevo diagnóstico, avanzado y en recaída |
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E.2.2 | Secondary objectives of the trial |
-To determine the safety and tolerability of azacitidine in newly diagnosed and relapsed advanced MDS and JMML -To determine (preliminary) the hematological remission rate in these patients -To describe the durability of response and long-term follow-up, including that of patients undergoing stem-cell transplant after treatment with azacitidine -To determine the plasma pharmacokinetic parameters of azacitidine -To study the pharmacodynamic effects of azacitidine in pediatric advanced MDS or JMML |
- Determinar la seguridad y tolerancia de azacitidina en SMD (primario o secundario) o LMMJ de nuevo diagnóstico, avanzado, o en recaída. - Determinar (de forma preliminar) la tasa de remisión hematológica en estos pacientes. - Describir la duración de la respuesta y el seguimiento a largo plazo, incluyendo el de los pacientes sometidos a trasplante de células madre hematopoyéticas tras el tratamiento con azacitidina. - Determinar los parámetros farmacocinéticos de azacitidina en plasma. - Estudiar los efectos farmacodinámicos de azacitidina en pacientes pediátricos con SMD o LMMJ avanzado |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In this study 4 subgroups of patients are eligible, which will be enrolled in 4 different strata:
?stratum 1: newly diagnosed patients with advanced MDS (RAEB or RAEB-t) in a ?pre stem cell transplantation window?. ?stratum 2: relapsed patients with advanced MDS in a ?re-transplantation window?. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment. ?stratum 3: newly diagnosed patients with JMML in a ?pre-stem cell transplantation window?. ?stratum 4: relapsed patients with JMML in a ?re-transplantation window?. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment. ?straum 5:newly diagnosed or relapsed patients with secondary advanced MDS, occurring after chemotherapy, radiotherapy and or stem-cell transplantation, or secondary cases after prior treatment for aplastic anemia. Note: secondary MDS cases after bone-marrow failures or familial cases are not eligible
General conditions: ?Advanced primary or secondary MDS or JMML confirmed by the diagnostic criteria as specified in the EWOG-MDS 2006 protocol (see appendix 1) ?1 month to ? 18 years old ?Lansky play score ? 60; or Karnofsky performance status ? 60 (appendix 2) ?Life expectancy ? 3 months ?Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN). ?Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin) ?No chemotherapy within 3 weeks of start of study medication. For 6-MP or low-dose cytarabine in JMML patients 1 week wash-out time is sufficient. ?For JMML patients: saturation >92% without additional supply of oxygen ?For JMML patients: peripheral blood monocyte count > 1.0x109/l ?For relapsed patients following HSCT: recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation. ?Able to comply with scheduled follow-up and with management of toxicity. ?For patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study. If applicable, use of an effective contraceptive method. ?Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations. |
En este estudio existen 5 subgrupos de pacientes elegibles que se incluirán en 5 estratos diferentes: ? estrato 1: pacientes con diagnóstico reciente de SMD primario avanzado (RAEB o RAEB-t) en una ?ventana pre-trasplante de células madre hematopoyéticas? ? estrato 2: pacientes en recaída con SMD primario avanzado en una ?ventana de re-trasplante?. En la recaída se puede continuar la administración de azacitidina si el segundo trasplante no es viable, siempre y cuando exista un beneficio para el paciente. ? estrato 3: pacientes con LMMJ de diagnóstico reciente en una ?ventana de pre-trasplante de células madre hematopoyéticas?. ? estrato 4: pacientes con LMMJ en recaída en una ?ventana re-trasplante?. En la recaída se puede continuar la administración de azacitidina si el segundo trasplante no es viable, siempre y cuando exista un beneficio para el paciente. ? estrato 5: pacientes de diagnóstico reciente o recaída de SMD secundario, tras quimioterapia, radioterapia y/o trasplante de células madre hematopoyéticas o casos secundarios tras el tratamiento previo de anemia aplásica. Condiciones generales: ? SMD o LMMJ primario o secundario confirmado por los criterios diagnósticos especificados en el protocolo EWOG-MDS de 2006 (véase anexo 1). ? desde 1 mes hasta ? 18 años de edad ? puntuación de Lansky ? 60; o la puntuación de Karnofsky ? 60 (anexo 2) ? Esperanza de vida? 3 meses ? Función renal normal definida como menos de, o igual, a grado 1 NCI-CTCAE (máx 1.5 x ULN). ? Función hepática normal definida como menos de o igual, a grado 1 NCI-CTCAE (máx 2.5 x ULN para transaminasas y bilirrubina) ? Sin quimioterapia en las 3 semanas previas al inicio de la medicación del estudio. El periodo de 1 semana de lavado es suficiente para pacientes con LMMJ que reciben 6- MP o bajas dosis de citarabina. ? Para pacientes con LMMJ: saturación de O2 >92% sin aporte adicional de oxígeno ? Para pacientes con LMMJ: recuento de monocitos en sangre periférica superior a 1.0x109/l ? Para pacientes en recaída tras el trasplante: recuperación de todos los efectos tóxicos de quimioterapia previa/trasplante de células madre hematopoyéticas. ? Capaces de cumplir con el seguimiento programado y con el manejo de la toxicidad. ? Para pacientes en edad fértil, debe obtenerse un test de embarazo negativo antes de entrar en el estudio. Si es necesario, se utilizará un método anticonceptivo eficaz. ? Consentimiento informado por escrito de los pacientes o de los padres/tutores legales de menores de edad, de acuerdo con la legislación y normas locales. |
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E.4 | Principal exclusion criteria |
Prior or current history: ?Other serious illnesses or medical conditions ?Genetic abnormalities indicative of AML ?JMML patients in whom a diagnosis of Noonan syndrome is suspected based on clinical history and/or presenting symptoms ?Patients with secondary MDS with underlying bone-marrow failure syndromes or with familial MDS ?Isolated extramedullary disease ?Symptomatic CNS-involvement ?Current uncontrolled infection ?Cardiac toxicity (shortening fraction below 28%) ?Concurrent treatment with any other anti-cancer therapy is not allowed ?Pregnant or lactating patients ?Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons ?Patient with expected non compliance to toxicity management guidelines ?Prior treatment with a demethylating agent ?Allergy to azicitidine or mannitol. |
Historia clínica previa o actual: ? Otras enfermedades o condiciones médicas graves ? Anomalías genéticas indicativas de LMA ? Pacientes con LMMJ en los que existe sospecha del síndrome de Noonan en base a la historia clínica y/o síntomas ? Pacientes con SMD secundarios con fallo de médula ósea subyacente o SMD familiar ? Enfermedad extramedular aislada ? Infiltración sintomática del SNC ? Infección actual no controlada ? Toxicidad cardiaca (fracción de acortamiento por debajo de 28%) ? No está permitido ningún tratamiento concomitante con otra terapia anti-cáncer ? Pacientes embarazadas o en periodo de lactancia ? Pacientes cuyo seguimiento no puede realizarse regularmente debido a motivos psicológicos, sociales, familiares o geográficos ? Pacientes que no podrán cumplir las guías de manejo de toxicidades ? Tratamiento previo con un agente dimetilante ? Alergia a azicitidina o manitol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to establish a recommended dose and preliminary efficacy of azacitidine in children with newly diagnosed or relapsed advanced MDS or JMML. |
El objetivo principal de este estudio es establecer la dosis recomendada y la eficacia preliminar de azacitidina en niños con SMD o LMMJ de nuevo diagnóstico, avanzado, o en recaída. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint may be limited by Dose Limiting toxicities in cycle 1 but otherwise full evaluation of the primary endpoint is possible after of treatment and after end of study. |
La variable principal puede estar limitada por las toxicidades limitantes de dosis en el ciclo 1 pero la evaluación completa de la variable principal es posible después del tratamiento y tras el final del estudio. |
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E.5.2 | Secondary end point(s) |
Other objectives concern: ?To determine the safety and tolerability of azacitidine in newly diagnosed and relapsed MDS and/or JMML. ?To determine (preliminary) the hematological remission rate in these patients. ?To describe the durability of response and long-term follow-up (at least 1 year after end of treatment), including that of patients undergoing stem-cell transplant after treatment with azacitidine. ?To determine the plasma pharmacokinetic parameters of azacitidine. ?To study the pharmacodynamic effects of azacitidine in pediatric MDS or JMML. |
Otras variables son: ? Determinar la seguridad y tolerancia de azacitidina en SMD y/o LMMJ de nuevo diagnóstico, avanzado, o en recaída. ? Determinar (de forma preliminar) la tasa de remisión hematológica en estos pacientes. ? Describir la duración de la respuesta y el seguimiento a largo plazo, incluyendo el de los pacientes sometidos a trasplante de células madre hematopoyéticas tras el tratamiento con azacitidina. ? Determinar los parámetros farmacocinéticos de azacitidina en plasma. ? Estudiar los efectos farmacodinámicos de azacitidina en pacientes pediátricos con SMD o LMMJ . |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For most endpoints after 3 cycles, and others after 1 year after HSCT or 1 year after last treatment with azacitidine when no HSCT is given |
Para la mayoría de las variables, después de 3 ciclos y otros, después de un año tras el trasplante o 1 año después del último tratamiento con azacitidina cuando no se realiza el trasplante |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
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 | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
datos históricos cuando el tiempo al trasplante no se solapó con quimioterapia |
historical data when time to transplant was not bridged with chemotherapy |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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
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Last patient last visit |
Ultimo paciente última visita |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |