A Phase 1 Study of Azacitidine in Combination With MEC (Mitoxantrone, Etoposide, Cytarabine) in Relapsed and Refractory Acute Myeloid Leukemia.
I. To determine the maximum-tolerated dose of azacitidine when combined with salvage
chemotherapy comprising mitoxantrone hydrochloride, etoposide phosphate, and cytarabine
(MEC) in patients with relapsed or refractory acute myeloid leukemia (AML).
I. To define the qualitative and quantitative toxicities of azacitidine in combination with
MEC with regard to organ specificity, time course, predictability, and reversibility.
II. To document the rate of complete remission (CR) and CR with incomplete blood count
recovery (CRi) in patients treated with this combination of agents.
III. To determine the overall survival, relapse-free survival, and event-free survival of
patients treated with this combination of agents.
IV. To evaluate the pharmacokinetics of azacitidine when given in combination with MEC in
patients enrolled on this study. (Exploratory) V. To measure R2 down regulation, including
changes in R2 target, AraCTP, and dNTP/NTP pools, of azacitidine when given in combination
with MEC and to correlate these pharmacodynamic endpoints with clinical response.
(Exploratory) VI. To evaluate hypomethylation, including DMNT1 expression, Sp1 expression,
global DNA methylation, gene expression profiling, and microRNA expression profiling, of
azacitidine when given in combination with MEC and to correlate these pharmacodynamic
changes with clinical response. (Exploratory)
OUTLINE: This is a dose-escalation study of azacitidine.
Patients receive azacitidine IV over 30 minutes on days 1-8 and mitoxantrone hydrochloride
IV over 10 minutes, etoposide phosphate IV over 30-60 minutes, and cytarabine IV over 6
hours on days 3-8 in the absence of disease progression or unacceptable toxicity. Treatment
may repeat every 8 days for 1 additional course. Blood and bone marrow samples are collected
at baseline and periodically during study for pharmacokinetic and pharmacodynamic studies.
After completion of study therapy, patients are followed up for 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose of azacitidine when combined with salvage chemotherapy (mitoxantrone hydrochloride, etoposide, and cytarabine [MEC]) via National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
Frequency distributions and other descriptive measures will form the basis of the analysis of these variables
By day 42
Ohio State University
United States: Food and Drug Administration
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