A Phase I/II study of Azacitidine (Vidaza®) in pediatric patients with relapsed high-grade pediatric MDS or JMM

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 3

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 <= 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 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

• 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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The current study aims to establish the recommended dose, safety and<br /><br>preliminary efficacy of azacitidine administered IV or SC in children with<br /><br>relapsed/refractory primairy or secondary MDS or JMML, in 2 different subgroups<br /><br>(strata) of patients.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>• To determine the safety and tolerability of azacitidine per stratum.<br /><br>• To determine (preliminary) the hematological remission rate in these patients.<br /><br>• To describe the durability of response and long-term follow-up, including<br /><br>that of patients undergoing stem-cell transplant after treatment with<br /><br>azacitidine.<br /><br>• To determine the pharmacokinetics of azacitidine in plasma.<br /><br>• To study the pharmacodynamic effects of azacitidine in pediatric MDS and JMML.<br /><br>• To describe the number of patients transforming into AML</p><br>