1. Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.
- Author
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Creemers GJ, Gerrits CJ, Eckardt JR, Schellens JH, Burris HA, Planting AS, Rodriguez GI, Loos WJ, Hudson I, Broom C, Verweij J, and Von Hoff DD
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents pharmacokinetics, Camptothecin administration & dosage, Camptothecin adverse effects, Camptothecin blood, Camptothecin pharmacokinetics, Diarrhea chemically induced, Drug Administration Schedule, Female, Half-Life, Humans, Leukopenia chemically induced, Male, Middle Aged, Neoplasms blood, Thrombocytopenia chemically induced, Topotecan, Antineoplastic Agents administration & dosage, Camptothecin analogs & derivatives, Neoplasms drug therapy
- Abstract
Purpose: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies., Patients and Methods: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods., Results: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function., Conclusion: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.
- Published
- 1997
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