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)
- 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.
- To compare the toxicities of these regimens.
- To determine the disease-free survival and overall survival of patients who demonstrate
a response to these regimens.
- To compare the pharmacokinetics of alvocidib when administered in two different
schedules (bolus vs "hybrid bolus-infusion").
- To describe alvocidib-induced alterations in AML blast cell expression of selected
target mRNA and proteins.
- 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 21-63 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.
Allocation: Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Judith E. Karp, MD
Sidney Kimmel Comprehensive Cancer Center
United States: Food and Drug Administration
|Fred Hutchinson Cancer Research Center||Seattle, Washington 98109|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|
|Hollings Cancer Center at Medical University of South Carolina||Charleston, South Carolina 29425|