Azacitidine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With High-Risk Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To establish the recommended phase II dose of 5-azacytidine (azacitidine) when combined
with high-dose cytarabine (HiDAC) and mitoxantrone (mitoxantrone hydrochloride) chemotherapy
in high-risk acute myeloid leukemia (AML) patients.

SECONDARY OBJECTIVES:

I. To determine the complete remission (CR) rate following the use of induction chemotherapy
regimen of 5-azacytidine followed by high-dose cytarabine (HiDAC) and mitoxantrone
chemotherapy in high-risk AML patients.

II. To determine the toxicity of the combination regimen. III. To determine the disease-free
survival (DFS) and overall survival (OS) of the patient population.

IV. To determine the gene expression levels of topoisomerase II and deoxycytidine kinase in
leukemia blasts pre-treatment and following therapy with 5-azacytidine.

V. To collect specimens for banking for use in future research studies with a view to
elucidating the predictors of response to epigenetic therapies.

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

INDUCTION: Patients receive azacitidine intravenously (IV) over 10-40 minutes or
subcutaneously (SC) once daily (QD) on days 1-5, cytarabine IV over 4 hours on days 6 and 10,
and mitoxantrone hydrochloride IV over 60 minutes on days 6 and 10.

CONSOLIDATION: Patients receive azacitidine IV over 10-40 minutes or SC QD on days 1-5.
Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity. Patients ineligible for allogeneic stem cell transplantation continue
on to maintenance.

MAINTENANCE: Patients receive azacitidine IV over 10-40 minutes or SC QD on days 1-5. Courses
repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have one of the following disease characteristics:

- Therapy-related myeloid neoplasm (t-MN) age >= 18 years

- Patients must have received cytotoxic chemotherapy, radiation, or a drug
known to affect the properties of deoxyribonucleic acid (DNA) or cell
growth, prior to current diagnosis of therapy-related myeloid neoplasm
(t-MN); this broad definition is meant to include any prior therapy with
chemicals that affect DNA replication, DNA integrity, or DNA structure, or
chemicals that alter cell growth; this includes traditional cytotoxic
chemotherapy, newer immunologic agents that have been shown to have
cytotoxic activities in addition to immunosuppressive functions, and other
chemicals; note that patients with primary AML could be diagnosed with a t-
MN if morphology/cytogenetic analysis clearly indicated that the second
process is not a relapse of the original disease

- AML arising from an antecedent hematological disorder age >= 18 years

- De novo AML in patients age >= 60 years

- Relapsed and/or refractory AML >= 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment

- Male and female patients must use an effective contraceptive method during the study
and for at least 6 months after study treatment

- Patients must be at least 2 weeks from major surgery, radiation therapy, participation
in other investigational trials and must have recovered from clinically significant
toxicities of these prior treatments

- Ability to understand and willingness to sign the informed consent form

Exclusion Criteria:

- Concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified
in this protocol

- Diagnosis of acute promyelocytic leukemia (APL)

- Use of investigational agents/any anticancer therapy within 2 weeks before study entry
with the exception of hydroxyurea (note: for patients with hyperleukocytosis [white
blood cell (WBC) > 20,000/uL], hydroxyurea [and leukapheresis, if clinically
indicated] will be initiated and these patients will receive 5-azacytidine when the
WBC count has decreased to =< 20,000/uL; hydroxyurea can be overlapped with
5-azacytidine in selected cases, after consultation with the study chair; hydroxyurea
must be discontinued before the initiation of the HiDAC/mitoxantrone chemotherapy)

- Prior treatment with 5-azacytidine followed immediately by HiDAC and mitoxantrone as
proposed in this study (note: prior therapy with 5-azacytidine or decitabine or HiDAC
or mitoxantrone would be allowed-in patients with relapsed/refractory disease- unless
the prior therapy was identical to the schema/schedule proposed in this study)

- Active second cancer other than specified; active cancer refers to cancer that
requires systemic chemotherapy or biological therapy within 6 months of the study
entry; patients who have received only hormonal therapy in the neoadjuvant or adjuvant
setting in the past 6 months may participate in this study

- Have any other severe concurrent disease, or have a history of serious organ
dysfunction (e.g. uncontrolled or severe cardiovascular disease, diabetes, pulmonary
disease, infection, psychiatric illness) that may in the judgment of the treating
physician/ principal investigator place the patient at undue risk to undergo treatment

- Pregnant or lactating patients

- Any significant concurrent illness that would, in the judgment of the treating
physician/principal investigator, compromise patient safety or compliance, or study
participation