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
Intervention: alvocidib; mitoxantrone hydrochloride; carboplatin; cytarabine; sirolimus; etoposide; topotecan hydrochloride
Intervention description: Given IV; Given IV; Given IV; Given IV; Given PO; Given IV; Given IV
Intervention MeSH terms: Cytarabine; Sirolimus; Carboplatin; Etoposide; Etoposide phosphate; Topotecan; Mitoxantrone; Alvocidib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 92.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Acute Myelogenous Leukemia (AML), Carboplatin, Topotecan, Flavopiridol, Mitoxantrone, Cytosine Arabinoside, Sirolimus, Etoposide

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.
    

Eligibility criteria:

        Inclusion Criteria

        Induction Therapy:

          -  Patients must have morphologic proof (from bone marrow aspirate, smears or touch preps
             of marrow biopsy) of acute myelogenous leukemia (AML) with >= 10% blasts within two
             weeks prior to induction randomization

               -  NOTE: Patients must be registered to E3903 (Ancillary Laboratory Protocol for
                  Collecting Diagnostic Material on Patients Considered for Eastern Cooperative
                  Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN]
                  Treatment Trials for Leukemia or Related Hematologic Disorders) and must undergo
                  eligibility testing for the study by multiparameter flow cytometry

               -  All immunodiagnoses are eligible for E1906, except acute promyelocytic leukemia
                  (APL) (proven by the presence of promyelocytic leukemia (PML)/retinoic acid
                  receptor (RAR) alpha); cases of APL can become eligible if the patient is
                  ineligible for an ECOG-ACRIN APL trial or if all-trans retinoic acid or arsenic
                  trioxide is not planned as part of the treatment regimen

          -  Patients must qualify for one of the following:

               -  Relapse =< 6 months after first CR, dated from documentation of CR to
                  documentation of relapse

               -  Relapse between 6-12 months after first CR

          -  Refractory to conventional initial induction chemotherapy (=< 2 courses) or to first
             reinduction (=< 1 course)

          -  Normal cardiac ejection fraction by pretreatment multi gated acquisition scan (MUGA)
             or echocardiogram within 4 weeks prior to randomization (resting ejection fraction >=
             50% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or
             to within the normal range of values for the institution

          -  Prior treatment to doses of any of the following:

               -  < 300 mg/m^2 of doxorubicin

               -  < 300 mg/m^2 of daunorubicin

               -  < 100 mg/m^2 of idarubicin

               -  < 100 mg/m^2 of mitoxantrone

          -  Serum creatinine =< 2.0 mg/dL

          -  Serum direct bilirubin < 2.0 mg/dL

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 4
             x upper limit of normal

               -  The above stipulation for normal hepatic function does not apply if liver
                  dysfunction is due to leukemia infiltration

          -  Prior to study entry, patients must have recovered from toxicities of prior
             chemotherapy and radiotherapy; for patients refractory to induction chemotherapy
             (patient subgroup outlined above), marrow documentation of residual leukemia post
             chemotherapy and qualification for remaining eligibility criteria are needed prior to
             study entry (this does not require >= 30% marrow blasts to be evident but a minimum of
             10% blasts must be present in the marrow)

               -  NOTE: Hydroxyurea is permitted within 4 weeks of study entry

          -  ECOG performance status 0, 1 or 2

          -  Patients with a history of central nervous system (CNS) leukemia are eligible if there
             is documentation of no current CNS involvement on cerebrospinal fluid (CSF)
             examination, (i.e., negative CSF by lumbar puncture)

        Consolidation therapy:

          -  Patients must have an ECOG performance status 0, 1 or 2

          -  Patients must have documented CR

          -  Patients must have an absence of infection or have infection controlled by
             antibiotics; patients who are septic will be excluded

          -  Patients must have a serum creatinine clearance > 50 cc/minute

          -  Patients must have a serum direct bilirubin < 2.0 mg/dl and alkaline phosphatase and
             SGOT (AST) < 4 x upper limits of normal

          -  Patients must have a normal cardiac ejection fraction by MUGA or echocardiogram prior
             to consolidation (resting ejection fraction >= 50% or >= 5% increase with exercise),
             shortening fraction by echocardiogram >= 24%, or to within normal range of values for
             the institution prior to the first and second cycle of consolidation for arms B and C

        Exclusion Criteria

        Induction therapy:

          -  Patients who have relapsed > 1 year after achieving first CR or are in >= second
             relapse

          -  Patients who have had a prior allogeneic OR autologous stem cell transplant

          -  History of recent myocardial infarction (within three months), uncontrolled congestive
             heart failure, or uncontrolled cardiac arrhythmia

          -  Prior treatment with carboplatin, topotecan, flavopiridol, or sirolimus

          -  Pregnant or breast feeding. Women of childbearing potential and sexually active males
             should use an accepted and effective method of contraception

          -  Intercurrent organ damage or medical problems that would prohibit therapy; no active
             or unresolved infection

          -  Current evidence of invasive fungal infection; such evidence includes positive blood
             or deep tissue cultures or stains

          -  Have another (i.e., prior) tumor which is currently active and likely to interfere
             with the patient's treatment for AML or which is likely to compromise the patient's
             morbidity or mortality substantially

        Consolidation therapy:

          -  Intercurrent organ damage or medical problems that will jeopardize the outcome of
             therapy

          -  For arms B and C, patients have exceeded the following anthracycline doses or their
             equivalents:

          -  < 300 mg/m^2 of doxorubicin

          -  < 300 mg/m^2 of daunorubicin

          -  < 100 mg/m^2 of idarubicin

          -  < 100 mg/m^2 of mitoxantrone