Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46, 211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor Risk Acute Myelogenous Leukemias (AML)
Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46, 211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor Risk Acute Myelogenous Leukemias (AML)
This randomized phase II trial is studying two different schedules of alvocidib to compare how well they work when given together with cytarabine and mitoxantrone in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as alvocidib, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known which schedule of alvocidib is more effective when given together with cytarabine and mitoxantrone in treating patients with 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:
At least 50 years of age OR >= 18 years of age with >= 1 of the following poor-risk disease features:
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%