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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01249430
First received: November 25, 2010
Last updated: October 9, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: mitoxantrone hydrochloride
Drug: etoposide
Drug: cytarabine
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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.

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

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


Secondary Outcome Measures:
  • 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.


Enrollment: 23
Study Start Date: January 2011
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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.
Drug: azacitidine
Given IV
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01249430

Locations
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Rebecca Klisovic Ohio State University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01249430     History of Changes
Other Study ID Numbers: NCI-2011-02554, NCI-2011-02554, CDR0000689575, OSU-10093, OSU 10093, 8803, U01CA076576, P30CA016058
Study First Received: November 25, 2010
Last Updated: October 9, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 22, 2014