Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as clofarabine and cytarabine, 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.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when
      given together with cytarabine and to see how well they work in treating young patients with
      refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia. (Phase I
      closed to enrollment as of 09/16/09)
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  To define the overall response rate (complete remission or remission without platelet
           recovery) in young patients with relapsed or refractory acute myeloid leukemia (AML) or
           acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with
           cytarabine.

      Secondary

        -  To determine the safety profile and tolerability of clofarabine when given in
           combination with cytarabine in patients with and without prior stem cell
           transplantation.

        -  To identify apoptosis specific genes that are important in mediating response to
           clofarabine and cytarabine.

        -  To quantitate the level of human equilibrative nucleoside transporter proteins (hENT1
           and hENT2) and human concentrative nucleoside transporter proteins (hCNT2 and hCNT3) in
           blasts of these patients.

        -  To determine gene expression profiles at study entry and at time of relapse in order to
           isolate profiles that may predict response and also to complement apoptosis specific
           protein arrays.

        -  To perform serial measurements of minimal residual disease (MRD) to provide an objective
           determination of the effectiveness of this treatment regimen and to correlate with post
           remission events (relapse, death).

        -  To perform FLT3/ITD analysis to help determine the prevalence and clinical significance
           of this somatic mutation in patients with relapsed AML.

      OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by a
      phase II study. Patients are stratified according to disease (acute lymphoblastic leukemia
      [ALL] vs acute myeloid leukemia [AML]). (Phase I closed to accrual as of 09/16/09)

        -  Intrathecal CNS prophylaxis (all patients with ALL and at physician's discretion for
           patients with AML or acute leukemia of ambiguous lineage): Patients receive intrathecal
           (IT) cytarabine on day 0 of the first course of induction therapy. Patients also receive
           IT methotrexate on day 1 of the second course of induction therapy and on day 1 of all
           courses of maintenance therapy.

        -  Induction therapy:

             -  Course 1: Patients receive cytarabine IV over 2 hours and clofarabine IV over 2
                hours on days 1-5. Patients with ≥ 5% blasts (i.e., M2 or M3 bone marrow) at days
                14-21 proceed immediately to course 2 of induction therapy. Patients with < 5%
                blasts (i.e., M1 bone marrow) may proceed to course 2 of induction therapy at blood
                count recovery or at day 42.

             -  Course 2: Patients receive clofarabine IV over 2 hours followed by cytarabine IV
                over 2 hours on days 1-5. After the second course of induction therapy, patients
                with M2 or M3 bone marrow at days 14-21 are removed from the study. Patients with
                M1 bone marrow proceed to maintenance therapy 14-42 days after the initiation of
                course 2.

        -  Maintenance therapy: Patients receive clofarabine and cytarabine as in induction
           therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of
           disease progression or unacceptable toxicity.

      Patients may undergo blood and bone marrow sample collection periodically for correlative
      laboratory studies.

      After completion of study therapy, patients are followed periodically for up to 5 years.

      PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.
    

Intervention name(s): clofarabine; cytarabine; methotrexate; laboratory biomarker analysis
Intervention type(s): Drug; Drug; Drug; Other
Intervention description(s): Given IV for 5 days; Given IV; Given intrathecally or IT age based dosage
Other intervention name(s): Cl-F-Ara-A; CAFdA; 2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine; Clolar; Evoltra; NSC# 606,869; IND # 73,789; Cytosine arabinoside; Ara-C; Cytosar; NSC #063878; MTX; amethopterin; Trexall; NSC #000740
Intervention MeSH terms: Cytarabine; Methotrexate; Clofarabine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent childhood acute lymphoblastic leukemia; recurrent childhood acute myeloid leukemia; acute undifferentiated leukemia; adult acute minimally differentiated myeloid leukemia (M0); childhood acute minimally differentiated myeloid leukemia (M0); adult acute myeloblastic leukemia without maturation (M1); childhood acute myeloblastic leukemia without maturation (M1); adult acute myeloblastic leukemia with maturation (M2); childhood acute myeloblastic leukemia with maturation (M2); adult acute myelomonocytic leukemia (M4); childhood acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); childhood acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); childhood acute monocytic leukemia (M5b); adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b); childhood acute erythroleukemia (M6); adult acute megakaryoblastic leukemia (M7); childhood acute megakaryocytic leukemia (M7); recurrent adult acute lymphoblastic leukemia; recurrent adult acute myeloid leukemia