Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: December 14, 2010
Last updated: September 16, 2014
Last verified: May 2014

This phase I clinical trial studies the best dose of azacitidine and to see how well it works with mitoxantrone hydrochloride and etoposide in treating older patients with poor-prognosis acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, mitoxantrone hydrochloride, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Condition Intervention Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia in Remission
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(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Drug: azacitidine
Drug: mitoxantrone hydrochloride
Drug: etoposide
Other: laboratory biomarker analysis
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 I Study of Azacitidine Combined With Mitoxantrone and Etoposide (A-NOVE) Chemotherapy for Patients Age >/= 60 With Poor Prognosis Acute Myeloid Leukemia (AML)

Resource links provided by NLM:

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

Primary Outcome Measures:
  • Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy [ Time Frame: Up to 2 courses of treatment ] [ Designated as safety issue: Yes ]
    The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.

Secondary Outcome Measures:
  • Complete response rate [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
  • Changes in topoisomerase II levels [ Time Frame: Baseline to day 4 ] [ Designated as safety issue: No ]
    These will be compared between responders (i.e. those achieving either CR or morphologic leukemia-free state [MLFS]) vs. non-responders (those not achieving CR/MLFS after 1-2 induction cycles), with 95% confidence intervals and 2-tailed t-tests of significance. Similar, nonquantitative comparisons will be made between responders and non-responders with respect to changes in DNA methylation and gene expression.

  • Relapse-free survival [ Time Frame: From documentation of CR or MLFS to time of disease recurrence or last follow up, assessed up to 4 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From the start of study treatment until death from any cause or last follow up, assessed up to 4 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: December 2010
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (azacitidine, mitoxantrone hydrochloride, etoposide)
Patients receive induction therapy comprising azacitidine SC QD on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.
Drug: azacitidine
Given SC
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
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:


I. To determine the highest tolerated dose of two dosing schedules of azacitidine when combined with mitoxantrone (mitoxantrone hydrochloride) and etoposide (A-NOVE) chemotherapy in poor prognosis older patients with acute myeloid leukemia (AML).

II. To evaluate the toxicity of this regimen.


I. To determine the complete response (CR) rate and using this regimen. II. To evaluate changes in topoisomerase II activity, deoxyribonucleic acid (DNA) methylation and DNA expression arrays in leukemia cells during azacitidine treatment, and to correlate these changes with responses to A-NOVE chemotherapy.

III. To evaluate relapse-free survival (RFS) and overall survival (OS) in patients receiving post-remission consolidation with A-NOVE in patients achieving CR.

OUTLINE: This is a dose-escalation study of azacitidine.

Patients receive induction therapy comprising azacitidine subcutaneously (SC) once daily (QD) on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.

After completion of study treatment, patients are followed up every 3 months.


Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria, any subtype, de novo or secondary, except acute promyelocytic leukemia (APL)
  • One of the following:

    • Previously untreated, with adverse-risk cytogenetics, including any one of the following:

      • Complete or partial deletion of chromosome 7
      • Complete or partial deletion of chromosome 5
      • At least 3 numerical or structural abnormalities, other than t(15;17), t(8;21) or inv(16) or variant
      • 11q23 abnormalities
      • Inv(3) or variant such as t(3:3)
    • Previously untreated, transformed from prior myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) other than CML
    • Persistent leukemia following one cycle of 3+7 induction therapy (cytarabine plus either daunorubicin or idarubicin), any cytogenetic risk group
  • Left ventricular ejection fraction (LVEF) > 50% based on multi gated acquisition scan (MUGA) scan or 2-dimensional (2-D) echocardiogram
  • Serum creatinine =< 1.5 x upper limit of normal (ULN)
  • Serum bilirubin =< 1.5x ULN
  • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)
  • Patients with high initial white blood cell (WBC) should have the WBC reduced to below 50 x 10^9/L with hydroxyurea, to minimize the risk of leukostasis related-complications; hydroxyurea is permitted up to 24 hours prior to starting azacitidine
  • Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; men should not father a child while participating in this study
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy, radiotherapy or investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who have received prior radiation greater than 3000 cGy to marrow producing areas
  • Patients may not be receiving any other investigational agents
  • Patients with active central nervous system (CNS) leukemia; prior CNS leukemia is permitted provided the cerebrospinal fluid has cleared and there is no other evidence of active CNS leukemia
  • Prior therapy for AML with decitabine, azacitidine, mitoxantrone, or etoposide
  • Prior therapy with azacitidine or decitabine for pre-existing MDS
  • History of allergic reactions attributed to decitabine, azacitidine, etoposide, mitoxantrone, or compounds of similar chemical or biologic composition
  • Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Human immunodeficiency virus (HIV)-positive patients with cluster of differentiation (CD) counts less than 500/mm^3 and/or a history of HIV/acquired immune deficiency syndrome (AIDS)-related complications will be excluded from the study
  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 identifier: NCT01260714

Canada, Ontario
Juravinski Cancer Centre at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8V 5C2
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Principal Investigator: Joseph Brandwein University Health Network-Princess Margaret Hospital
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01260714     History of Changes
Other Study ID Numbers: NCI-2011-02559, NCI-2011-02559, CDR0000690647, PHL-074, 8331, N01CM00032, N01CM62203
Study First Received: December 14, 2010
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Erythroblastic, Acute
Leukemia, Monocytic, Acute
Hypereosinophilic Syndrome
Leukemia, Megakaryoblastic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Basophilic, Acute
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Leukocyte Disorders
Etoposide phosphate
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs processed this record on September 30, 2014