Azacitidine in Combination With Mitoxantrone, Etoposide Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Azacitidine; Cytarabine; Etoposide Phosphate; Laboratory Biomarker Analysis; Mitoxantrone Hydrochloride; Pharmacological Study
Intervention type(s): Drug; Drug; Drug; Other; Drug; Other
Intervention description(s): Given IV; Given IV; Given IV; Correlative studies; Given IV; Correlative studies
Other intervention name(s): 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; .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; Etopophos; CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan
Intervention MeSH terms: Cytarabine; Etoposide; Mitoxantrone; Azacitidine; Etoposide phosphate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment