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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT01249430

Collaborator

(none)

Enrollment

Location

Arm

28.1

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

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

PRIMARY OBJECTIVES:

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:

To define the qualitative and quantitative toxicities of 5-azaC with MEC in combination with regard to organ specificity, time course, predictability, and reversibility.
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.
To evaluate the pharmacokinetics of 5-azaC when given in combination with MEC in patients enrolled on this study.
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.
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 Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

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 :

Jan 20, 2011

Actual Primary Completion Date :

May 24, 2013

Actual Study Completion Date :

May 24, 2013

Arms and Interventions

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 Names: 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

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 Names:

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

Outcome Measures

Primary Outcome Measures

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 [Up to day 42]
Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Secondary Outcome Measures

Clinical response according to the International Working Group criteria [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.
Qualitative and quantitative toxicities of azacitidine in combination with (mitoxantrone hydrochloride, etoposide, and cytarabine [MEC]) [Up to 30 days post-therapy]
Graded according to NCI CTCAE version 4.0.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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