ORAL TOPOTECAN GIVEN ONCE OR TWICE-DAILY FOR 10 DAYS - A PHASE-I PHARMACOLOGY STUDY IN ADULT PATIENTS WITH SOLID TUMORS

Prolonged exposure to topotecan (TPT) in in vitro experiments and in v ivo studies in animals yielded the highest antitumor efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged adminis tration, Because of unpredictable diarrhea in the third week of the tw ice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the fi nding of optimal down-regulation of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of admini stration (10 days) was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tum ors that were refractory to standard forms of chemotherapy were entere d. Two dose schedules were studied: once daily (o.d.) and b.i.d. admin istration 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/m(2)/day, and dose levels were 0.5 , 0.6, 0.7, and 0.8 mg/m(2) with the 10-day b.i.d. schedule. Pharmacok inetics were performed on days 1 and 8 of the first course using a val idated highperformance liquid chromatographic assay and noncompartment al pharmacokinetic methods. Nineteen patients were entered in the 10-d ay o.d. schedule, with a total of 48 courses given. Dose-limiting toxi city (DLT) was reached at 1.6 mg/m(2)/day and consisted of common toxi city criteria (CTC) grade IV thrombocytopenia and CTC grade III diarrh ea. The maximum tolerated dose was 1.4 mg/ m(2)/day. In the 10-day b.i .d. administration of TPT, a total of 64 courses were studied in 20 pa tients. DLT was reached at a dose of 0.8 mg/m(2) b.i.d. and consisted of CTC grade IV myelosuppression and CTC grade TV diarrhea, The maximu m tolerated dose was 0.7 mg/m(2) b.i.d. Nonhematological toxicities wi th both schedules included mild nausea and vomiting, fatigue, and anor exia. Pharmacokinetics revealed a substantial variation of the area un der the plasma concentration-time curve of TPT lactone in both schedul es. Significant correlations were observed between the myelotoxicity p arameters and the area under the plasma concentration-time curve at da y 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 myelosu ppression and diarrhea for both schedules studied. The recommended dos es for Phase II, studies are 1.4 mg/m(2)/day for 10 days for the o.d. administration and 0.7 mg/m(2) for the b.i.d. schedule.