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

• Maximum-tolerated dose of azacitidine when combined with salvage chemotherapy comprising mitoxantrone hydrochloride, etoposide phosphate, and cytarabine (MEC) [ Designated as safety issue: Yes ]
• Tolerability of azacitidine in combination with MEC [ Designated as safety issue: Yes ]

• Qualitative and quantitative toxicities of azacitidine in combination with MEC graded via NCI CTCAE v4.0 [ Time Frame: Up to 30 days post-therapy ] [ Designated as safety issue: Yes ]
• Clinical response according to the International Working Group criteria [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
  Responses will be summarized by simple descriptive summary statistics delineating complete and lesser responses as well as stable and progressive disease.

This phase I clinical trial is studying the side effects and best dose of azacitidine when given together with mitoxantrone, etoposide phosphate, and cytarabine in treating patients with relapsed or refractory acute myeloid leukemia. Azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide phosphate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Azacitidine may help mitoxantrone, etoposide phosphate, and cytarabine work better by making cancer cells more sensitive to the drugs.

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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.

• Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
• Adult Acute Myeloid Leukemia With Del(5q)
• Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
• Recurrent Adult Acute Myeloid Leukemia

• Drug: azacitidine
  Given IV
  Other Names:

  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
• Drug: mitoxantrone hydrochloride
  Given IV
  Other Names:

  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
• Drug: etoposide
  Given IV
  Other Names:

  • EPEG
  • VP-16
  • VP-16-213
• Drug: cytarabine
  Given IV
  Other Names:

  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
• Other: laboratory biomarker analysis
  Correlative studies
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

Inclusion Criteria:

• Histologically or cytologically confirmed acute myeloid leukemia

  • Relapsed or refractory disease according to 2008 WHO classification
• Must have failed ≥ 1 course of induction chemotherapy or relapsed after achieving a complete remission after induction therapy
• No active central nervous system disease or granulocytic sarcoma as sole site of disease
• ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• Life expectancy > 6 months for any comorbid conditions
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 mg/dL
• LVEF ≥ 40%
• Not pregnant or nursing
• Negative pregnancy test
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to azacitidine, mannitol, or other agents used in the study

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Serious cardiac arrhythmia
  • Psychiatric illness and/or social situations that would limit compliance with study requirements

• None of the following:

  • Myocardial infarction within the past 6 months
  • NYHA class III or IV heart failure
  • Uncontrolled angina
  • Severe uncontrolled ventricular arrhythmias
  • Electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Patients with active infection allowed provided the infection is controlled
• No other concurrent anticancer agents or therapies, including chemotherapy, radiotherapy (including palliative), or biologic response modifiers
• Prior autologous or allogeneic stem cell transplantation allowed
• Recovered from non-hematologic toxicity to < grade 2
• More than 2 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C)
• More than 14 days since prior and no other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients