Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion

Abstract

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecln which is an Inhibitor of topolaomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicltiea of continuous Infusion (CI) topotecan. This phase I trial first explored a S day CI every 21 day schedule. Doses of topotecan Included 0.17, 0.34 and 0.68 mg/m²/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3–4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day Infusion in an effort to ameliorate toxicity and obtain greater dose Intensity (Dl). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 couraes. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3–4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1–2) In the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m²/week, whereas they received 1.08 mg/m²/week at the MTD on the 3 day schedule (24% Increase In relative dose Intensity). A atesdy-stste plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m²/day as a 3 day continuous Infusion. Minor responses were seen in two patienta with non-small cell lung cancer and three patients with ovarian cancer. In summary, a greater Dl can be achieved with topotecan given on a 3 day schedule than on a 5 day schedule.