Phase I Study of Three-Times Daily Oral Etoposide in Patients with Refractory Solid Tumours

Abstract

Objective: The objective of this phase I study of oral etoposide in patients with refractory solid tumours was to determine the tolerability and pharmacokinetic profile and to establish the maximum tolerated dose (MTD) of the drug for this indication. Patients and Methods: 53 patients were enrolled, 37 of whom were evaluable for tumour response and tolerability. The male/female ratio was 17/20, the median age was 48 years (23–74) and the median Eastern Cooperative Oncology Group (ECOG) performance status was 1 (0–3). All patients had clinically progressive metastatic disease, which had not responded to standard treatment. 24 of 37 patients had previously received chemotherapy and 13 had been given radiotherapy. The initial dosage of oral etoposide was 15 mg/m2 three times daily for 14 days every 3 weeks. The dose was escalated, initially by 33% and by 25% thereafter, in groups of three to five patients until the MTD was reached. Plasma concentrations of the drug were determined by HPLC. Results: Three dosages levels were studied, 15 mg/m2 (dose level I), 20 mg/m2 (dose level II) and 25 mg/m2 (dose level III) three times daily for 14 consecutive days. The total number of evaluable courses was 130, with a median of 2 (range: 1–14) courses per patient. The MTD was 25 mg/m2 three times daily; severe neutropenia was the dose-limiting factor. Other adverse events included nausea and vomiting, alopecia and fatigue. In patients receiving dose level II (20 mg/m2) plasma etoposide concentrations ranged between 1 and 5 mg/L until 6 hours after administration. This dosage is recommended for use in phase II trials. One patient had a partial response, which has lasted for about 10 months. Six patients had minor responses. Conclusion: Preliminary pharmacokinetic data obtained in patients with refractory solid tumours suggest that an oral dosage of 20 mg/m2 three times daily for 14 days every 3 weeks provides satisfactory plasma concentrations of etoposide and could be recommended for phase II trials.