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Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms

From the Center for Cancer Research, Developmental Therapeutics Program, and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda; Science Applications International Corporation–Frederick, National Cancer Institute, Frederick, MD; and Aventis Pharmaceuticals, Bridgewater, NJ.

Address reprint requests to Adrian M. Senderowicz, MD, Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bldg 30, Rm 211, 30 Convent Dr, Bethesda, MD 20892; email: asenderowicz{at}dir.nidcr.nih.gov

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks.

PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m²/d for 5 days; doses of 50 and 62.5 mg/m²/d for 3 days; and doses of 62.5 and 78 mg/m²/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules.

RESULTS: Dose-limiting neutropenia developed at doses 52.5 mg/m²/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 µmol/L (range, 1.3 to 4.2 µmol/L), 3.2 µmol/L (range, 1.7 to 4.8 µmol/L), and 3.9 µmol/L (1.8 to 5.1 µmol/L), respectively. Twelve patients had stable disease for 3 months, with a median duration of 6 months (range, 3 to 11 months).

CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m²/d for 5 days, 50 mg/m²/d for 3 days, and 62.5 mg/m²/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

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