Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      This randomized phase II trial is comparing three different combination chemotherapy regimens
      to see how well they work in treating patients with relapsed or refractory acute myeloid
      leukemia. Drugs used in chemotherapy 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. It is not yet known which
      combination chemotherapy regimen is more effective in treating patients with relapsed or
      refractory acute myeloid leukemia.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To determine the complete remission (CR) + cytogenic complete remission (CRc) +
      morphologic complete remission with incomplete blood count recovery (CRi) rate of carboplatin
      and topotecan; flavopiridol, mitoxantrone and cytosine arabinoside and sirolimus,
      mitoxantrone, etoposide and cytosine arabinoside in adult patients with refractory or
      relapsed acute myeloid leukemia (AML).

      NOTE: Since the CRc patients are required to be either CR or CRi, we only report the rate of
      CR+CRi in the results section.

      II. To determine the rate of treatment failure of these regimens. III. To determine the
      incidence and severity of toxicities of these regimens. IV. To analyze the predictive value
      of blast cell properties that have been suggested to determine response. (Correlative
      laboratory studies) V. To determine whether pretreatment levels of B-cell chronic lymphocytic
      leukemia (CLL)/lymphoma 2 (Bcl-2) or, alternatively, whether a therapy-induced change in
      topoisomerase I levels correlates with response to this regimen. (Correlative laboratory
      studies) VI. To assess the impact of clonal evolution by comparing cytogenetic abnormalities
      at the time of relapse with those at initial diagnosis and correlating these abnormalities
      and changes with response to the treatment regimens in this protocol. (Cytogenetic and
      fluorescent in situ hybridization [FISH] studies) VII. Panel FISH studies for common AML
      rearrangements will be performed on relapse AML specimens to determine the presence of these
      recurrent AML abnormalities and to evaluate for subtle additional abnormalities consistent
      with clonal evolution in these relapse specimens. (Cytogenetic and FISH studies)

      OUTLINE: Patients are randomized to 1 of 3 treatment arms.

      INDUCTION THERAPY:

      ARM A: Patients receive carboplatin and topotecan hydrochloride intravenously (IV)
      continuously over 24 hours on days 1-5.

      ARM B: Patients receive alvocidib IV over 4.5 hours once daily (QD) on days 1-3, cytarabine
      IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours
      on day 9.

      ARM C: Patients receive sirolimus orally (PO) QD on days 2-9, mitoxantrone hydrochloride IV
      over 15 minutes QD, etoposide IV over 1 hour QD, and cytarabine IV over 3 hours QD on days
      4-8 or 5-9. (Closed to accrual)

      After completion of induction therapy, patients in all arms undergo bone marrow aspirate and
      biopsy. Patients with persistent leukemia (i.e., leukemic blasts >= 10%) are removed from
      study and are offered alternative therapy at the discretion of the investigator. Patients who
      achieve CR proceed to consolidation therapy or receive alternative therapy at the discretion
      of the investigator.

      CONSOLIDATION THERAPY: Beginning within 2-6 weeks after documentation of CR, patients may
      receive up to 2 additional courses of the same treatment they received during induction
      therapy. Courses repeat every 4-10 weeks in the absence of disease progression or
      unacceptable toxicity.

      After completion of study therapy, patients are followed periodically for up to 3 years.
    

Intervention name(s): alvocidib; mitoxantrone hydrochloride; carboplatin; cytarabine; sirolimus; etoposide; topotecan hydrochloride
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Given IV; Given IV; Given IV; Given IV; Given PO; Given IV; Given IV
Other intervention name(s): FLAVO; flavopiridol; HMR 1275; L-868275; CL 232315; DHAD; DHAQ; Carboplat; CBDCA; JM-8; Paraplat; Paraplatin; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; AY 22989; Rapamune; rapamycin; SLM; EPEG; VP-16; VP-16-213; hycamptamine; Hycamtin; SKF S-104864-A; TOPO
Intervention MeSH terms: Cytarabine; Sirolimus; Carboplatin; Etoposide; Etoposide phosphate; Topotecan; Mitoxantrone; Alvocidib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myelogenous Leukemia (AML), Carboplatin, Topotecan, Flavopiridol, Mitoxantrone, Cytosine Arabinoside, Sirolimus, Etoposide