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) |
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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 | 16.1 |
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 | 16.1 |
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. |
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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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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. |
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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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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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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. |
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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. |
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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 |
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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 |
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 | 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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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 |