Azacitidine in Combination With Mitoxantrone, Etoposide Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose of azacitidine (5-azaC) when combined with
mitoxantrone hydrochloride (mitoxantrone), etoposide phosphate (etoposide), and cytarabine
(MEC) as salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia
(AML).

SECONDARY OBJECTIVES:

I. To define the qualitative and quantitative toxicities of 5-azaC with MEC in combination
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) for this combination of agents as well as overall survival, relapse-free
survival, and event-free survival.

III. To evaluate the pharmacokinetics of 5-azaC when given in combination with MEC in
patients enrolled on this study.

IV. To measure R2 downregulation, including changes in R2 target, AraCTP, and dNTP/NTP pools,
of 5-azaC in combination with MEC and correlate these pharmacodynamic endpoints with clinical
response.

VI. To evaluate hypomethylation, including DMNT1 expression, Sp1 expression, global
deoxyribonucleic acid (DNA) methylation, gene expression profiling, and micro ribonucleic
acid (RNA) expression profiling, of 5-azaC when given in combination with MEC and correlate
these pharmacodynamic changes with clinical response.

OUTLINE: This is a dose-escalation study of azacitidine.

Patients receive azacitidine intravenously (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. Treatment continues for 1 course in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed relapsed or refractory
acute myeloid leukemia (AML) according to 2008 World Health Organization (WHO)
classification; must have failed at least one cycle of induction chemotherapy or
relapsed after achieving a complete remission following induction chemotherapy;
patients with prior autologous or allogeneic stem cell transplant are permitted

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 6 months for any comorbid conditions

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine =< 1.5 mg/dL

- Left ventricular ejection fraction >= 40%

- Ability to understand and the willingness to sign a written informed consent document

- Patients must have recovered from the non-hematologic toxicity of prior therapy to
less than grade 2

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study

- Patients receiving any other investigational agents or patients that have received any
other investigational agents within 14 days of enrollment

- Patients with active central nervous system disease or with granulocytic sarcoma as
sole site of disease

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to azacitidine, mannitol, or other agents used in study

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements; patients with active infection are permitted to enroll provided that the
infection is under control; myocardial infarction within 6 months prior to enrollment
or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities; prior to study entry, any
echocardiogram (ECG) abnormality at screening has to be documented by the investigator
as not medically relevant

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with azacitidine

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible