Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia
Condition: Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myelomonocytic Leukemia (M4); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Monocytic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Basophilic, Acute; Leukemia, Eosinophilic, Acute; Leukemia, Megakaryoblastic, Acute; Hypereosinophilic Syndrome; Recurrence
Study type: Interventional
Phase: Phase 2

Summary: 
      This phase II trial is studying the side effects and best dose of bortezomib and to see how
      well it works when given together with combination chemotherapy in treating younger patients
      with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop
      the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used
      in chemotherapy, such as idarubicin, cytarabine, and etoposide, 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) together with bortezomib may
      kill more cancer cells
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To determine the toxicities and tolerability of bortezomib in combination with
      standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in
      pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

      II. To estimate the complete response rate to the Arm A and Arm B regimens.

      SECONDARY OBJECTIVES:

      I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces
      apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of
      measuring AML stem cells in relapsed and recovering bone marrow.

      OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified
      according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²).
      Patients are assigned to 1 of 2 groups.

      GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative
      exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days
      1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and
      8.

      GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400
      mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1
      hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib
      IV on days 1, 4, and 8.

      NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10.

      All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment
      repeats every 28 days for up to 2 courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study therapy, patients are followed periodically for at least 5 years.
    

Intervention name(s): idarubicin; cytarabine; bortezomib; etoposide; laboratory biomarker analysis
Intervention type(s): Drug; Drug; Drug; Drug; Other
Intervention description(s): Given IV; Given IV or IT; Given IV; Given IV; Correlative studies
Other intervention name(s): 4-demethoxydaunorubicin; 4-DMDR; DMDR; IDA; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; LDP 341; MLN341; VELCADE; EPEG; VP-16; VP-16-213
Intervention MeSH terms: Cytarabine; Etoposide; Idarubicin; Etoposide phosphate; Bortezomib
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment