title: Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol.
abstract: OBJECTIVE
  Flavopiridol (NSC 649890) is a synthetic flavone possessing significant antitumor activity in preclinical models. Flavopiridol is capable of inducing cell cycle arrest and apoptosis, presumably through its potent, specific inhibition of cyclin-dependent kinases. We conducted a phase I trial and pharmacokinetic study of flavopiridol given as a 72-h continuous intravenous infusion repeated every 2 weeks.
  
  
  METHODS
  A total of 38 patients were treated at dose levels of 8, 16, 26.6, 40, 50 and 56 mg/m(2)/24 h. During the first infusion, plasma was sampled at 24, 48 and 72 h to determine steady-state concentrations, and peripheral blood lymphocytes were assessed by flow cytometry for evidence of apoptosis. Additional postinfusion pharmacokinetic sampling was done at the 40 and 50 mg/m(2)/24 h dose levels.
  
  
  RESULTS
  Gastrointestinal toxicity was dose limiting, with diarrhea being the predominant symptom. Symptomatic orthostatic hypotension was also frequently noted. Several patients experienced tumor-specific pain during their infusions. The maximum tolerated dose (MTD) was determined to be 40 mg/m(2)/24 h. A patient with metastatic gastric cancer at this dose level had a complete response and remained disease-free for more than 48 months after completing therapy. Plasma concentrations at 24 h into the infusion were 94% of those achieved at steady state. Steady-state plasma flavopiridol concentrations at the MTD were 416.6+/-98.9 micro M. These concentrations are at or above those needed to see cell cycle arrest and apoptosis in vitro. The mean clearance of flavopiridol over the dose range was 11.3+/-3.9 l/h per m(2), similar to values obtained preclinically. Elimination was biphasic. The terminal half-life at the MTD was 26.0 h. No significant differences in pharmacokinetic parameters were noted between males and females. Patients taking cholestyramine to ameliorate flavopiridol-induced diarrhea had lower steady-state plasma concentrations. There was no significant change in the cell cycle parameters of peripheral blood lymphocytes analyzed by flow cytometry.
  
  
  CONCLUSIONS
  The MTD and recommended phase II dose of flavopiridol given by this schedule is 40 mg/m(2)/24 h. The manageable gastrointestinal toxicity, early signs of clinical activity and lack of hematologic toxicity make further exploration in combination trials warranted.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, University of Wisconsin Medical School, 600 Highland Ave, Madison, WI 53792, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Thomas
authors.forename: Kendra D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: James F
authors.initials: JF
authors.lastname: Cleary
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: Rhoda
authors.initials: R
authors.lastname: Arzoomanian
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Kris
authors.initials: K
authors.lastname: Simon
authors.forename: Chris
authors.initials: C
authors.lastname: Feierabend
authors.forename: Kimberly
authors.initials: K
authors.lastname: Binger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Amy
authors.initials: A
authors.lastname: Dresen
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005419:Flavonoids / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010880:Piperidines / Q000493:pharmacokinetics*; D012449:Safety; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases