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) |
Vergevorderde myelosyplastich syndroom (MDS) en Juveniele Myelomonocytraire leukemie (JMML) |
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E.1.1.1 | Medical condition in easily understood language |
MDS and JMML |
preleukemie en JMML |
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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 | 14.1 |
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 | 14.1 |
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. |
Het vaststellen van de aanbevolen dosering, veiligheid en de voorlopige effectiviteit van azacitidine in kinderen met MDS en JMML. |
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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
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-Het vaststellen van de veiligheid en verdraagzaamheid van azacitidine per stratum -Het vaststellen van de voorlopige hematologische remissie verhouding van azacitidine -Het omschrijven van de responseduur en lange termijn follow-up inclusief die van patiënten die een stamcel transplantatie na behandeling krijgen -Het vaststellen van de farmacokinetiek van azacitidine -Het bestuderen van de farmacodynamsiche effecten van azacitidine in MDS en JMML bij kinderen |
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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. |
• Hoog-gradige primaire of secundaire MDS of JMML volgens EWOG-MDS 2006 protocol criteria • 1 maand tot ≤ 18 jaar oud. • Lansky play score >= 60; of Karnofsky performance status >= 60. • Levensverwachting >= 3 maanden. • Normale nierfunctie gedefinieerd als minder dan NCI-CTCAE graad 1 (max 1.5 x ULN). • Normale leverfunctie gedefinieerd als minder dan NCI-CTCAE graad 1 (max 2.5 x ULN voor transaminases en bilirubine). • Geen andere chemo binnen 3 weken na start studie medicatie. • JMML: geen zuurstofbehoefte en saturatie >92% zonder zuurstof • JMML: perifere monocyten aantal >1.0x10E9/l • Recidief patiënten: minimaal 3 maanden na transplantatie na herstel van eerdere acute toxiciteit • Geen beperkingen voor follow-up • Op indicatie: negatieve zwangerschapstest • Op indicatie: anticonceptie tot 6 maanden na stop studie-medicatie • Schriftelijk informed consent |
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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.
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- Ernstige onderliggende ziekte - Genetische afwijkingen passend bij AML - JMML patienten bij wie op klinische gronden de diagnose Noonan syndroom wordt overwogen - Patienten met secundaire MDS met onderliggende beenmergfalen aandoening or met familiaire MDS - - Geisoleerde extramedullaire ziekte - Symptomatische CNS-lokalisatie - Bestaande ongecontrolleerde infectie - Cardiomyopathie met SF onder 28% - Behandeling met andere anti-kanker medicijnen - Zwangerschap of lactatie - Patiënten die niet kunnen deelnemen aan follow-up - Patiënten waarbij verwacht wordt dat er onvoldoende therapietrouw is |
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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.
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De huidige studie beoogt het vaststellen van de aanbevolen dosering, veligheid en de voorlopige effectiviteit van azacitidine (vidaza) per intraveneuze of subcutane toediening bij kinderen met nieuw gediagnosticeerde MDS of JMML en bij vergevorderde (recidief/refractair) MDS en JMML, verdeeld over 5 subgroepen. |
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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. |
Het primair eindpunt kan bij veel voorkomende DLT's al mogelijk worden vastgesteld. Bij normale inclusie en verloop is het primair eindpunt volledig evalueerbaar na inlusie van alle patiënten. |
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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. |
• het vaststellen van de veiligheid en verdraagzaamheid van azacitidine per stratum. • het vaststellen van de(preliminaire) hematologsiche remissie verhouding. • het omschrijven van de responseduur en lange termijn follow-up inclusief die van patiënten die stamceltransplantatie hebben gehad na azacitidine. • het vaststellen van de farmacokinetiek van azacitidine in plasma • het bestuderen van de pharmacodynamische effecten van azacitidine in MDS bij kinderen en JMML. |
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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 |
Voor de meeste eindpunten na 3 cycli, andere na 1 jaar na de de stamceltransplantatie of 1 jaar na laatste azacitidine in geval er geen stamceltransplantatie is gegeven. |
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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) | Yes |
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 |
historische data betreffende tijd tot transplantatie indien niet overbrugd met chemotherapie |
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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Laatste patiënt laatste visite |
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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 |