A Dose Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With Relapsed and Refractory Acute Leukemias
I. To determine the maximal tolerable dose of flavopiridol in relapsed or refractory acute
leukemia in adults (Stratum 1) and children (Stratum 2).
II. To define the qualitative and quantitative toxicities of flavopiridol in regard to organ
specificity, time course, predictability, and reversibility.
III. To determine the preliminary clinical activity of flavopiridol in adults (Stratum 1)
and children (Stratum 2) using this novel schedule in acute leukemia.
IV. To evaluate the plasma and cellular pharmacokinetics of flavopiridol in patients
enrolled on this study.
I. To measure pharmacodynamic measurements including effects on cell cycle; down modulation
of bcl-2, mcl-1, XIAP, bax, RNA polymerase II phosphorylation; and signaling via the VEGF
(VEGF, VEGF-R1, VEGF-R2, HIF-1), NF-Kappa B pathway, and PI3kinase pathway; and correlate
with Css and other pharmacokinetic features.
II. To assess drug induced apoptosis of acute leukemia cells in vitro and subsequent
relationship to clinical response based upon Css of flavopiridol attained in vivo.
II. To determine if increase in inflammatory cytokines (TNF-alpha, gamma-IFN, IL-6 and IL-8)
correlate with pharmacokinetics, pharmacodynamics, laboratory (decrease in serum albumin)
and clinical (hypotension observed with the first administration of flavopiridol) parameters
OUTLINE: This is a dose-escalation study. Patients are stratified according to age group
(adult [≥ 18 years] vs pediatric [1-17 years]).
Patients receive flavopiridol intravenously (IV) over 30 minutes followed by a 4-hour
infusion on days 1-3. Treatment repeats every 21 days for up to 6 courses in the absence of
unacceptable toxicity or disease progression. Cohorts of 3-6 patients receive escalating
doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is
defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience
Patients are followed up every 2 months for 1 year and then every 6 months for 4 years.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximal tolerable dose of flavopiridol
Ohio State University
United States: Food and Drug Administration
|Ohio State University Medical Center||Columbus, Ohio 43210|