Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol.

Abstract

PURPOSE:

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: James P Thomas, Kendra D Tutsch, James F Cleary, Howard H Bailey, Rhoda Arzoomanian, Dona Alberti, Kris Simon, Chris Feierabend, Kimberly Binger, Rebecca Marnocha, Amy Dresen, George Wilding
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 50 Issue 6 Pg. 465-72 (Dec 2002) ISSN: 0344-5704 [Print] Germany
• PMID: 12451473 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Flavonoids
• Piperidines
• alvocidib
• Cyclin-Dependent Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacokinetics)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacokinetics)
• Female
• Flavonoids (pharmacokinetics)
• Flow Cytometry
• Half-Life
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Piperidines (pharmacokinetics)
• Safety
• Treatment Outcome