Phase I study of topotecan and cisplatin in patients with small cell lung cancer

Objective: A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. Methods: Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m²/day), and cisplatin at a fixed dose of 60 mg/m², 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. Results: A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m², respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m², respectively. The major toxicity in this combination was hematological events. Conclusions: For treatment-naive patients, the combined use of 0.65/60 mg/m² topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m² topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study.