Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To compare the efficacy of two different schedules (bolus vs "hybrid bolus-infusion") of
alvocidib followed by cytarabine and mitoxantrone hydrochloride in patients with newly
diagnosed acute myeloid leukemia (AML) with poor-risk features.

SECONDARY OBJECTIVES:

I. To compare the toxicities of these regimens. II. To determine the disease-free survival
and overall survival of patients who demonstrate a response to these regimens.

III. To compare the pharmacokinetics of alvocidib when administered in two different
schedules (bolus vs "hybrid bolus-infusion").

IV. To describe alvocidib-induced alterations in AML blast cell expression of selected target
mRNA and proteins.

V. To describe alvocidib-induced alterations in AML blast cell growth kinetic parameters.

OUTLINE: This is a multicenter study. Patients are stratified according to antecedent
hematologic disorder of >= 6 months duration prior to transformation to acute myeloid
leukemia (AML) and any prior antecedent therapy for myelodysplastic syndromes or
myeloproliferative disorder. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over
72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.

ARM II: Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours
on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.

Patients achieving partial or complete response (CR) after the first course of treatment may
receive a second course of treatment 35-63 days following blood count recovery and/or undergo
allogeneic bone marrow transplantation. Patients >= 50 years of age with t (8;21), inv (16),
or t(16;16) AML who achieve CR after the first course of treatment may receive 3-4 courses of
high-dose cytarabine consolidation therapy.

Bone marrow and/or blood samples are collected at baseline and periodically during study for
correlative laboratory studies, including pharmacokinetic studies by liquid chromatography
and tandem mass spectrometry, analysis of blast cell growth kinetic parameters by flow
cytometry, and blast cell expression of selected target mRNA and protein by quantitative
RT-PCR and western blotting.

After completion of study therapy, patients are followed periodically.

Inclusion Criteria:

- Pathologically confirmed newly diagnosed acute myeloid leukemia (AML) meeting the
following criteria:

- Subtypes M0, M1, M2, M4-7

- No acute promyelocytic leukemia (M3)

- At least 50 years of age OR >= 18 years of age with >= 1 of the following poor-risk
disease features:

- Antecedent hematologic disorder, including myelodysplastic syndromes
(MDS)-related AML or prior myeloproliferative disorder (MPD)

- Treatment-related AML, AML with trilineage dysplasia

- Myeloid sarcoma, myeloid proliferations related to Down Syndrome, or blastic
plasmacytoid dendritic cell neoplasm

- AML with trilineage dysplasia

- AML with adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q,
21q, or 17p; t[6;9]; t[9;22]; trisomy 8; trisomy 13, complex karyotypes [>= 3
unrelated abnormalities]),

- No hyperleukocytosis with >= 50,000 blasts/uL (leukapheresis or hydroxyurea allowed
for cytoreduction immediately prior to the first dose of alvocidib)

- No active CNS leukemia

- ECOG performance status 0-2

- Serum creatinine =< 2.0 mg/dL

- ALT/AST =< 5 times upper limit of normal

- Bilirubin =< 2.0 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- No active uncontrolled infection

- Infection that is under active treatment allowed provided it is controlled with
antibiotics

- No other life-threatening illness

- No mental deficits and/or psychiatric history that would preclude giving informed
consent or following study requirements

- At least 24 hours since prior leukapheresis or hydroxyurea for cytoreduction

- Prior non-cytotoxic therapies (e.g., thalidomide or lenalidomide, interferon,
cytokines, low-dose 5-azacytidine, or low-dose cytoxan) for MDS or MPD allowed

- Prior chemotherapy or bone marrow/stem cell transplantation for non-AML malignancy
allowed

- No prior alvocidib

- No other concurrent chemotherapy, radiotherapy, or immunotherapy

- No other concurrent investigational or commercially-available antitumor therapies for
AML

- LVEF >= 45%