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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01249430
Recruitment Status : Completed
First Posted : November 29, 2010
Last Update Posted : September 21, 2017
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of azacitidine when given together with mitoxantrone, etoposide phosphate, and cytarabine in treating patients with acute myeloid leukemia that has returned after a period of improvement or does not respond to treatment. 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, by stopping them from dividing, or by stopping them from spreading. Azacitidine may help mitoxantrone, etoposide phosphate, and cytarabine work better by making cancer cells more sensitive to the drugs.

Condition or disease Intervention/treatment Phase
Recurrent Adult Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Drug: Cytarabine Drug: Etoposide Phosphate Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride Other: Pharmacological Study Phase 1

Detailed Description:


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).


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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Azacitidine in Combination With MEC (Mitoxantrone, Etoposide, Cytarabine) in Relapsed and Refractory Acute Myeloid Leukemia
Actual Study Start Date : January 20, 2011
Actual Primary Completion Date : May 24, 2013
Actual Study Completion Date : May 24, 2013

Arm Intervention/treatment
Experimental: Treatment (azacitidine, mitoxantrone, etoposide, cytarabine)
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. Treatment continues for 1 course in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Etoposide Phosphate
Given IV
Other Name: Etopophos

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantroni Hydrochloridum
  • Mitozantrone Hydrochloride
  • Mitroxone
  • Neotalem
  • Novantrone
  • Onkotrone
  • Pralifan

Other: Pharmacological Study
Correlative studies

Primary Outcome Measures :
  1. Maximum-tolerated dose of azacitidine when combined with salvage chemotherapy (mitoxantrone hydrochloride, etoposide, and cytarabine [MEC]) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: Up to day 42 ]
    Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Secondary Outcome Measures :
  1. Clinical response according to the International Working Group criteria [ Time Frame: Up to day 42 ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and lesser responses as well as stable and progressive disease.

  2. Qualitative and quantitative toxicities of azacitidine in combination with (mitoxantrone hydrochloride, etoposide, and cytarabine [MEC]) [ Time Frame: Up to 30 days post-therapy ]
    Graded according to NCI CTCAE version 4.0.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01249430

United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Alison Walker Ohio State University Comprehensive Cancer Center

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01249430     History of Changes
Other Study ID Numbers: NCI-2011-02554
NCI-2011-02554 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
OSU 10093
8803 ( Other Identifier: Ohio State University Comprehensive Cancer Center )
8803 ( Other Identifier: CTEP )
P30CA016058 ( U.S. NIH Grant/Contract )
U01CA076576 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: November 29, 2010    Key Record Dates
Last Update Posted: September 21, 2017
Last Verified: September 2017

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Etoposide phosphate
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents