Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors

Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days) was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day, and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity (DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2 for the b.i.d. schedule.