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/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 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 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 gastroinestinal toxicity, early signs of clinical activity and lack of hematologic toxicity make further exploration in combination trials warranted.