Advanced Myelodysplastic Syndromes (MDS) and Juvenile Myelomonocytic Leukemia (JMML) MedDRA version: 16.1 Level: LLT Classification code 10054439 Term: Juvenile chronic myelomonocytic leukemia System Organ Class: 100000004864 MedDRA version: 16.1 Level: LLT Classification code 10068361 Term: MDS System Organ Class: 100000004864
Conditions
Sponsors
Erasmus MC
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under 18? yes Number of subjects for this age range: 65 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish the recommended dose and preliminary efficacy of azacitidine in children with newly diagnosed and relapsed advanced MDS or JMML.;Secondary Objective: -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 ;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. ;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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.;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 | — |
Countries
Austria, Czech Republic, Denmark, Germany, Ireland, Italy, Netherlands, Spain
Contacts
Public ContactS. Ramnarain
Trial Office
Outcome results
None listed