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

Primary Purpose

Recurrent Adult Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Azacitidine

Cytarabine

Etoposide Phosphate

Laboratory Biomarker Analysis

Mitoxantrone Hydrochloride

Pharmacological Study

About this trial

This is an interventional treatment trial for Recurrent Adult Acute Myeloid Leukemia

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (azacitidine, mitoxantrone, etoposide, cytarabine)

Arm Description

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.

Outcomes

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

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

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])

Graded according to NCI CTCAE version 4.0.

Full Information

NCT ID

NCT01249430

First Posted

November 25, 2010

Last Updated

September 20, 2017

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01249430

Brief Title

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

Official Title

A Phase 1 Study of Azacitidine in Combination With MEC (Mitoxantrone, Etoposide, Cytarabine) in Relapsed and Refractory Acute Myeloid Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Completed

Study Start Date

January 20, 2011 (Actual)

Primary Completion Date

May 24, 2013 (Actual)

Study Completion Date

May 24, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

5. 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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Recurrent Adult Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (azacitidine, mitoxantrone, etoposide, cytarabine)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Other Intervention Name(s)

5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Other Intervention Name(s)

.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

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Etoposide Phosphate

Other Intervention Name(s)

Etopophos

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

Mitoxantrone Hydrochloride

Other Intervention Name(s)

CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

Pharmacological Study

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Description

Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Time Frame

Up to day 42

Secondary Outcome Measure Information:

Title

Clinical response according to the International Working Group criteria

Description

Responses will be summarized by simple descriptive summary statistics delineating complete and lesser responses as well as stable and progressive disease.

Time Frame

Up to day 42

Title

Qualitative and quantitative toxicities of azacitidine in combination with (mitoxantrone hydrochloride, etoposide, and cytarabine [MEC])

Description

Graded according to NCI CTCAE version 4.0.

Time Frame

Up to 30 days post-therapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alison Walker

Organizational Affiliation

Ohio State University Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ohio State University Comprehensive Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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