Clinical Trials /

Decitabine Followed by Mitoxantrone Hydrochloride, Etoposide, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

NCT01729845

Description:

This phase I/II trial studies the side effects and best dose of decitabine followed by mitoxantrone hydrochloride, etoposide, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Decitabine Followed by Mitoxantrone Hydrochloride, Etoposide, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
  • Official Title: Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming With Decitabine in Adults With Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS): A Phase 1/2 Study

Clinical Trial IDs

  • ORG STUDY ID: 2652.00
  • SECONDARY ID: NCI-2012-02224
  • SECONDARY ID: 2652
  • SECONDARY ID: FH#2652
  • SECONDARY ID: 2652.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01729845

Conditions

  • Previously Treated Myelodysplastic Syndrome
  • Recurrent Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.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-28453Treatment (decitabine, MEC)
Decitabine5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, MEC)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (decitabine, MEC)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (decitabine, MEC)

Purpose

This phase I/II trial studies the side effects and best dose of decitabine followed by mitoxantrone hydrochloride, etoposide, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate the maximum tolerated dose (MTD) of decitabine priming followed by sequential
      mitoxantrone hydrochloride/etoposide/cytarabine (MEC) chemotherapy in adults with
      relapsed/refractory acute myeloid leukemia (AML).

      SECONDARY OBJECTIVES:

      I. Determine, within the limits of a Phase 1/2 study, disease response and duration of
      remission.

      II. Identify biomarkers (e.g., deoxyribonucleic acid [DNA] methylation and/or gene expression
      changes) associated with treatment responses.

      OUTLINE: This is a phase I, dose-escalation study of decitabine followed by a phase II study.

      Patients receive decitabine intravenously (IV) on days -9 to -5 (dose level 1), days -11 to
      -5 (dose level 2), or days -14 to -5 (dose level 3).

      INDUCTION THERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-5, etoposide IV
      on days 1-5, and cytarabine IV on days 1-5. Patients achieving complete response (CR) or CR
      with incomplete platelet count recovery (CRp) may receive up to 2 courses of induction
      therapy and up to 2 courses of consolidation therapy.

      After completion of study treatment, patients are followed up every 3 months for up to 5
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, MEC)ExperimentalPatients receive decitabine IV on days -9 to -5 (dose level 1), days -11 to -5 (dose level 2), or days -14 to -5 (dose level 3). INDUCTION THERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-5, etoposide IV on days 1-5, and cytarabine IV on days 1-5. Patients achieving CR or CR with CRp may receive up to 2 courses of induction therapy and up to 2 courses of consolidation therapy.
  • Cytarabine
  • Decitabine
  • Etoposide
  • Mitoxantrone Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Prior diagnosis of "high-risk" myelodysplastic syndrome (MDS) (>= 10% blasts) or AML
             other than acute promyelocytic leukemia (APL) with t(15;17) (q22;q12) or variants
             according to the 2008 World Health Organization (WHO) classification; patients with
             biphenotypic AML are eligible

          -  Relapsed/persistent disease according to standard criteria requiring salvage therapy;
             outside diagnostic material is acceptable as long as peripheral blood and/or bone
             marrow slides are reviewed at the study institution; flow cytometric analysis of
             peripheral blood and/or bone marrow should be performed according to institutional
             practice guidelines

          -  Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT)
             are eligible if relapse occurs provided symptoms of graft-versus host disease are well
             controlled with stable use of immunosuppressive agents

          -  Treatment-related mortality (TRM) score =< 9.2 as calculated with simplified model

          -  Should be off any active therapy for AML with the exception of hydroxyurea for at
             least 14 days prior to study registration unless patient has rapidly progressive
             disease, and all grade 2-4 non-hematologic toxicities should have resolved

          -  May have previously received monotherapy with demethylating agents for MDS or AML

          -  May have previously received chemotherapy with MEC for MDS or AML

          -  Patients with symptoms/signs of hyperleukocytosis or white blood cells (WBC) >
             100,000/uL can be treated with leukapheresis or may receive up to 2 doses of
             cytarabine (up to 500 mg/m^2/dose) prior to enrollment

          -  Bilirubin =< 2 x institutional upper limit of normal (IULN) unless elevation is
             thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
             (assessed within 7 days prior to study day 1)

          -  Serum creatinine =< 1.5 x IULN (assessed within 7 days prior to study day 1)

          -  Left ventricular ejection fraction >= 40%, assessed within 3 months prior to study day
             1, e.g. by multi gated acquisition (MUGA) scan or echocardiography, or other
             appropriate diagnostic modality and no clinical evidence of congestive heart failure;
             if the patient had anthracycline-based therapy since the most recent cardiac
             assessment, cardiac evaluation should be repeated if there is clinical or
             radiographical suspicion of cardiac dysfunction, or if the previous cardiac assessment
             was abnormal

          -  Women of childbearing potential and men must agree to use adequate contraception

          -  Provide written informed consent

        Exclusion Criteria:

          -  Refractory/relapsing myeloid blast crisis of chronic myeloid leukemia (CML), unless
             patient is not considered candidate for tyrosine kinase inhibitor treatment

          -  Concomitant illness associated with a likely survival of < 1 year

          -  Active systemic fungal, bacterial, viral, or other infection, unless disease is under
             treatment with anti-microbials and/or controlled or stable (e.g. if specific,
             effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis,
             human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined
             as being afebrile and hemodynamically stable for 24 hours; patients with fever thought
             to be likely secondary to leukemia are eligible

          -  Known hypersensitivity to any study drug

          -  Pregnancy or lactation

          -  Patients may not be receiving any other investigational agents
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Most Efficacious and Tolerated Dosage of Decitabine (Period 1)
Time Frame:through day 45
Safety Issue:
Description:MTD (most tolerated dose) of decitabine, measured in number of dose limiting toxicities. MTD defined as the highest dose in which the incidence of dose limiting toxicity is < 33%, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)

Secondary Outcome Measures

Measure:Remission Rate Including CR and CRp
Time Frame:Up to 5 years
Safety Issue:
Description:Complete remission (CR) and Complete remission with incomplete platelet recovery (CRp) categorized according to criteria recommended by International Working Groups: Complete resolution of disease-related symptoms and signs including palpable hepatosplenomegaly; hemoglobin level at least 110 g/L, platelet count at least 100x10^9/L, and absolute neutrophil count at least 1.0 x10^9/L. In addition, all 3 blood counts should be no higher than the upper normal limit; Normal leukocyte differential; Bone marrow histologic remission defined as the presence of age-adjusted normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no higher than 1.
Measure:Duration of Relapse-free Survival (for Patients Achieving CR or CRp)
Time Frame:Up to 5 years
Safety Issue:
Description:Categorized according to criteria recommended by International Working Groups.
Measure:Overall Survival
Time Frame:Up to 5 years
Safety Issue:
Description:Survival measured as of day of last contact. Categorized according to criteria recommended by International Working Groups.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated