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


Phase 1
18 Years
70 Years
Open (Enrolling)
Both
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

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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

Outcome Time Frame:

By day 42

Safety Issue:

Yes

Principal Investigator

Rebecca Klisovic

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02554

NCT ID:

NCT01249430

Start Date:

January 2011

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Ohio State University Medical CenterColumbus, Ohio  43210