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.
• Stratum 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 EWOG-MDS-Azacitidine-2010 protocol 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 >1.0x10^9/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 |