MDS and JMML
Conditions
Interventions
In children older than 1 year of age and a body weight > 10 kg dosing will be
based on BSA, otherwise we will use a mg/kg dose. Three dose levels will be
studied.
Children >1 year of age and >10 kg
Sponsors
Erasmus MC, Universitair Medisch Centrum Rotterdam
Eligibility
Age
2 Years to 17 Years
Inclusion criteria
Inclusion criteria: • Diagnosis of relapsed advanced primary MDS or JMML, established at initial diagnosis by the diagnostic criteria as specified in the EWOG-MDS 2006 protocol (see appendix 1), and defined as: o Relapsed MDS: After a documented CR or PR, this designation is defined as - a reappearance of blasts in the peripheral blood, - or >=5% blasts in the bone marrow not attributable to any other cause (e.g. bone marrow regeneration after consolidation therapy), and confirmed with flowcytometry. o Relapsed JMML: After a documented CR or PR, this designation is defined as - reappearance of organomegaly - in combination with elevated WBC with peripheral blood monocytosis (greater than 1x109/l), - and/or the reappearance of a cytogenetic or molecular lesion indicative of prior disease. - In addition, clinical criteria may be used, which include objective parameters such as increase in spleen size of >50% from baseline, and/or the appearance of new skin lesions, and/or oxygen need, - and/or blast crises/transformation to AML. • 1 month to = 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 greater than 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. • Reproductive Function • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. • Female patients with infants must agree not to breastfeed their infants while on this study. • Male and female patients of child-bearing potential must agree to use an highly effective method of contraception approved by the investigator during the study and for 90 days after the last dose of azacitidine. • Highly effective methods of contraception include (but not exclusively) the following contraceptive methods: • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation • progestogen-only hormonal contraception associated with inhibition of ovulation • intrauterine device (IUD) • intrauterine hormone-releasing system ( IUS) • sexual abstinence. • Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.
Exclusion criteria
Exclusion criteria: • 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 azacitidine or mannitol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The current study aims to establish the recommended dose, safety and preliminary efficacy of azacitidine administered IV or SC in children with relapsed/refractory primairy or secondary MDS or JMML, in 2 different subgroups (strata) of patients. | — |
Secondary
| Measure | Time frame |
|---|---|
| • To determine the safety and tolerability of azacitidine per stratum. • 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 pharmacokinetics of azacitidine in plasma. • To study the pharmacodynamic effects of azacitidine in pediatric MDS and JMML. • To describe the number of patients transforming into AML | — |
Countries
Netherlands
Outcome results
None listed