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Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2002 Oct 01; Vol. 20 (19), pp. 4074-82. - Publication Year :
- 2002
-
Abstract
- 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.<br />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/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules.<br />Results: Dose-limiting neutropenia developed at doses >/= 52.5 mg/m(2)/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 micro mol/L (range, 1.3 to 4.2 micro mol/L), 3.2 micro mol/L (range, 1.7 to 4.8 micro mol/L), and 3.9 micro mol/L (1.8 to 5.1 micro mol/L), respectively. Twelve patients had stable disease for >/= 3 months, with a median duration of 6 months (range, 3 to 11 months).<br />Conclusion: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/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.
- Subjects :
- Adult
Aged
Antineoplastic Agents adverse effects
Area Under Curve
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Flavonoids adverse effects
Humans
Infusions, Intravenous
Male
Maximum Tolerated Dose
Middle Aged
Neutropenia chemically induced
Piperidines adverse effects
Treatment Outcome
Antineoplastic Agents administration & dosage
Antineoplastic Agents pharmacokinetics
Flavonoids administration & dosage
Flavonoids pharmacokinetics
Neoplasms drug therapy
Piperidines administration & dosage
Piperidines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0732-183X
- Volume :
- 20
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 12351605
- Full Text :
- https://doi.org/10.1200/JCO.2002.01.043