PHASE-I AND PHARMACOKINETICS STUDY OF TOPOTECAN, A NEW TOPOISOMERASE-I INHIBITOR

Purpose: A phase I study with topotecan (SKF 104864-A, NSC 609699), a semisynthetic analog of camptothecin, was performed using a daily-times-5 regimen, given i.v. q 3 weeks, to evaluate the pharmacokinetics and toxicities of the compound. Patients and methods: Patients with a histologically confirmed diagnosis of a solid tumor no longer amenable to established forms of treatment were eligible for the study. Topotecan was given as a 30 min. infusion daily on 5 successive days, repeated every three weeks. In subsequent patient cohorts the dose was escalated from 0.5 to 1.5 mg/m2/day. Weekly evaluations included hematology and biochemistry. Response to treatment was assessed every 2 cycles. Pharmacokinetics were performed using a HPLC method. Results: Forty-eight patients were entered. The maximal tolerated dose was 1.5 mg/m2/day. The dose limiting toxicity was leucocytopenia. Other major toxicities were alopecia and moderate nausea/vomiting. Partial remissions were observed in one patient with pretreated small-cell lung cancer, one with non-small-cell lung cancer and one with no-pretreated pancreatic cancer, lasting 130-240 days. Pharmacokinetics showed a t1/2 (alpha) of 8.1 +/- 7.6 min., t1/2 (beta) of 132 +/- 48 min., V(d,ss) 72.7 +/- 26.9 L/m2 and Cl(tot) of 0.57 +/- 0.16 L/min/m2. Conclusion: Topotecan is an interesting new topoisomerase I inhibitor exerting antitumor activity in this phase I trial. Leucocytopenia is dose-limiting. The recommended dose for phase II studies is 1.5 mg/m2/day for 5 consecutive days every 3 weeks.