Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes
      needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, work
      in different ways to stop the growth of cancer cells, either by killing the cells or by
      stopping them from dividing. Giving lestaurtinib together with cytarabine and idarubicin may
      kill more cancer cells.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of lestaurtinib
      when given together with cytarabine and idarubicin and to see how well they work in treating
      younger patients with relapsed or refractory acute myeloid leukemia.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine a safe, tolerable, and biologically active dose of lestaurtinib in combination
           with chemotherapy comprising cytarabine and idarubicin in younger patients with relapsed
           or refractory FLT3-mutant acute myeloid leukemia.

      Secondary

        -  Determine the overall response rate in patients treated with this regimen.

        -  Optimize dosing of lestaurtinib based primarily on biologic activity rather than
           toxicity.

        -  Correlate the clinical response to this regimen with the ability to achieve adequate
           FLT3 plasma inhibitory activity levels and the in vitro sensitivity of pretreatment
           leukemic cells to lestaurtinib in these patients.

        -  Determine the mechanisms of resistance to lestaurtinib in these patients.

        -  Assess the feasibility of using rapid central determination of FLT3 mutation status at
           study entry to determine induction therapy in future upfront protocols.

      OUTLINE: This is a multicenter, dose-finding study of lestaurtinib followed by an efficacy
      study.

        -  Dose-finding phase:

             -  Course 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4,
                idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on
                days 5-28. Patients achieving complete or partial response proceed to course 2.

      Cohorts of 6 patients receive escalating doses of lestaurtinib until a tolerable and
      biologically active dose (TBAD) is determined. The TBAD is defined as the dose at which no
      more than 2 of 6 patients experience DLT and biologic activity is confirmed by plasma
      inhibitory activity (PIA) assay.

        -  Course 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4
           and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28.
           Patients achieving complete or partial response proceed to continuation therapy.

        -  Continuation therapy: Patients receive oral lestaurtinib twice daily on days 1-28.
           Treatment repeats every 28 days for up to 6 courses in the absence of disease
           progression or unacceptable toxicity.

             -  Efficacy phase: Once the TBAD is determined, subsequent patients receive treatment
                as in course 1 and 2 with lestaurtinib at the TBAD. Patients may also receive
                continuation therapy as in the dose-finding phase.

      Blood samples are collected periodically during study treatment for pharmacokinetic and PIA
      assays.

      After completion of study treatment, patients are followed periodically for up to 5 years.

      PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.
    

Intervention name(s): cytarabine; idarubicin; lestaurtinib
Intervention type(s): Drug; Drug; Drug
Intervention description(s): given IV; Given IV; Given orally
Other intervention name(s): Cytosine arabinoside; Ara-C; Cytosar; NSC #063878; Idarubicin HCl; 4-Demethoxydaunorubicin; 4-DMD; DMDR; IdamycinPFS; benzodiazocin-1-one; IND#76431
Intervention MeSH terms: Cytarabine; Idarubicin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent childhood acute myeloid leukemia; adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); recurrent adult acute myeloid leukemia; secondary acute myeloid leukemia