Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Condition: Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      This phase I trial studies the side effects and the best dose of cytarabine when given
      together with decitabine and vorinostat in treating patients with acute myeloid leukemia or
      myelodysplastic syndrome that has returned or has not responded to treatment. Drugs used in
      chemotherapy, such as cytarabine and decitabine, 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. Vorinostat may stop the growth of cancer cells by blocking some of the
      enzymes needed for cell growth. Giving cytarabine together with decitabine and vorinostat may
      kill more cancer cells.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of the combination of decitabine,
      vorinostat, and cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML)
      and select subsets of high risk leukemia/myelodysplastic syndromes (MDS).

      II. To define the specific toxicities and the dose limiting toxicity (DLT) of the
      combination.

      SECONDARY OBJECTIVES:

      I. To develop a platform for specifically targeting mixed-lineage leukemia partial-tandem
      duplication (MLL PTD), for future efficacy studies.

      II. To determine the overall response rate (ORR) of this regimen in relapsed/ refractory AML.

      III. To examine the role of decitabine and vorinostat in re-expression of mixed-lineage
      leukemia wild type (MLL- WT) in patients with MLL PTD via correlative studies specific to
      patients with MLL PTD and the preliminary relationship of this to clinical response in
      patients with MLL PTD+ AML.

      IV. To correlate the biological activity of decitabine as demethylating agent (changes in
      target gene methylation and gene expression, deoxyribonucleic acid [DNA]
      [cytosine-5-]-methyltransferase 1 [DNMT1] protein expression, global methylation) with
      clinical endpoints.

      V. To explore the biologic role of microribonucleic acids (RNAs) in determining clinical
      response to the combination and achievement of the other pharmacodynamic endpoints.

      OUTLINE: This is a dose-escalation study of cytarabine.

      INDUCTION THERAPY: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10;
      vorinostat orally (PO) on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14,
      and 16 in the absence of disease progression or unacceptable toxicity. Patients who achieve
      complete remission (CR) proceed to maintenance therapy. Patients who achieve CR with
      incomplete blood count recovery undergo bone marrow aspiration and biopsy at count recovery
      or day 42 before proceeding to maintenance therapy.

      MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and vorinostat PO
      on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Intervention name(s): Cytarabine; Decitabine; Laboratory Biomarker Analysis; Pharmacological Study; Vorinostat
Intervention type(s): Drug; Drug; Other; Other; Drug
Intervention description(s): Given IV; Given IV; Correlative studies; Correlative studies; Given PO
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; 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; L-001079038; MSK-390; SAHA; Suberanilohydroxamic Acid; Suberoylanilide Hydroxamic Acid; Zolinza
Intervention MeSH terms: Cytarabine; Decitabine; Vorinostat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment