Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol
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/m2/24 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/m2/24 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/m2/24 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 µM. 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 m2, 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/m2/24 h. The manageable gastroinestinal toxicity, early signs of clinical activity and lack of hematologic toxicity make further exploration in combination trials warranted.
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