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

This is an international, collaborative, prospective, open label, phase I/II trial to establish the recommended dose and preliminary efficacy of azacitidine in children with relapsed high-grade MDS or JMML. Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare malignant diseases of childhood. So far, stem cell transplantation is the only curative treatment option. No other agents are available to treat these diseases successfully, and HSCT results in approximately 50% survival only; hence there is clear unmet medical need. Over the past few years, we have increasing evidence that aberrant methylation contributes to the malignant phenotype of JMML and childhood advanced MDS. The demethylating agent azacitidine has been shown to improve survival in adults with MDS, but so far no studies are available in children with MDS or JMML. In the current study we want to establish the recommended dose and preliminary efficacy of azacitidine, in children with relapsed MDS or JMML in a pre-transplantation window. This study will provide a preliminary proof of concept whether a demethylating agent is able to induce responses in these diseases, and whether this agent indeed results in hypomethylation. Pharmacodynamic studies should provide this proof of concept. It needs to be mentioned that the HSCT procedure itself is not part of this protocol and should be performed under EWOG or institutional guidelines at the discretion of the principle investigator.



Two dose-levels will be studied:

1. Level 1: 75 mg/m2/day IV x 7 days with a 28-day interval;

2. Level 2: 100 mg/m2/day IV x 7 days with a 28-day interval.



In this study 2 subgroups of patients are eligible, which will be enrolled in 2 different strata:

1. Stratum 1: Relapsed patients with 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;

2. Stratum 2: 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.



The patients in the two strata need to be analyzed separately as there may be marked differences in tolerability and response.


For the MDS arm, if there is at least one patient achieving response (defined as CR or PR) and there
are no patients experiencing a dose-limiting toxicity among the three first patients in stage one,
another three patients will be treated at the next higher dose level, if applicable. In case of 1 dose-
limiting toxicity among the first three patients, the cohort will be expanded to 6 patients at the
starting dose-level. If there is at least one out of six patients achieving response and no more than
one patient experiences a dose-limiting toxicity in stage one, stage two shall open for enrolment. In
case of no responses the arm shall be closed to enrollment. In case there is more than one dose-
limiting toxicity in stage one, the dose is set to the previous level (if applicable), and stage 2 shall
open for enrolment if at least one patient responded at that dose-level. Otherwise, the arm shall be
closed to enrolment.


The dose will be increased only if <2 of the 6 evaluable patients (30%, across stage-one and stage-
two) achieve a response, and/or there are ≤ two dose-limiting toxicities; otherwise the therapy will
be deemed unpromising for further consideration.


For the JMML arm, the safety run-in will include 3 patients and the tolerability of the therapy will be
considered using a classic 3+3 design. Should the therapy be considered tolerable, stage one shall
enrol patients to a higher dose, or otherwise the patients in the safety run-in will be considered part
of stage one. During stage-one, if ≥ 1 of the 3 evaluable patients for the primary endpoint achieve a
response then stage two shall open to enrolment, or otherwise that arm shall be closed to
enrolment. At the end of stage two, the therapy will be considered positive for possible further
investigation if ≥ 2 of the 6 evaluable patients (30%, across stage-one and stage-two) achieve a
response; or otherwise considered unpromising for further consideration.

We will recruit a maximum of 12 patients in each stratum, and hence 24 patients in total. Including
screen failures or drop-outs or in case of DLTs we may need to recruit a maximum of 28 patients.



The study will last approximately 8 years from first patient first visit (FPFV) to last patient last visit (LPLV).

There is clear medical need in pediatric high-grade MDS and JMML to control disease pre-SCT without the disadvantages associated with intensive chemotherapy. So far no agents have been successfully applied in this window, or are specifically registered for use in these disease conditions.



Based on adult data in MDS using the hypomethylating agent azacitidine regarding efficacy, and the favorable safety profile, we feel that a study in pediatric MDS is warranted. There are unpublished data suggesting that hypermethylation is also an important mechanism of disease pathogenesis in JMML, which is a subentity of pediatric MDS.



There are available pediatric safety data using azacitidine dosages that are much higher than proposed in this study, therefore we decided not to dose-reduce azacitidine in this study but to use a similar dose as has been shown to be safe and effective in adult MDS. Apparently this dose results in adequate hypomethylation, whereas the leukemia studies in the past have focused on the use of azacitidine as a regular cytotoxic compound (hence MTD-based).



We aim at determining a recommended dose for pediatric MDS and JMML and provide preliminary efficacy data, as well as pharmacokinetics and dynamics.

Response and safety will be evaluated at differen time-points according to the stratum the patient is included is. DLTs are limited to the 1st course of treatment.

28-nov-2018: Inclusion stratum 1 (relapsed MDS) closed.

Vidaza will be given IV for 7 days with a 28-day interval.


In this study 2 subgroups of pediatric MDS and JMML patients are eligible, and will be enrolled in 2 different strata:

1. Stratum 1: Relapsed patients with 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;

2. Stratum 2: 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.