Phase-I study of a new schedule based on increasing days of topotecan administration associated with dose individualisation

Background: The most commonly prescribed schedule of topotecan administration is daily for five days, every 21 days. Both pre-clinical and clinical studies suggest that a more protracted schedule may increase its therapeutic index. The current study was undertaken to determine the maximum tolerated number of days with 30-minute i.v. infusion of topotecan daily at fixed area under the plasma concentration-time curve (AUC) (i.e., 35 μg/L×h). Patients and methods: Topotecan was administered i.v. over 30 min. The planned levels of number of days of administration were: 7, 10, 13, 15 and 17. The dose was individualized according to the patient’s individual topotecan clearance observed after the first infusion of each cycle. Results: Twenty-three patients were enrolled and received 71 cycles of therapy. The 13-day level was defined as the maximum number of days of administration. The main side effects were thrombocytopenia and anaemia, whereas neutropenia was infrequent. The mean (coefficient of variation) observed AUC was 34.6 (21%), and 33.4 (19%) μg/L×h, for the last day of cycle 1, and of cycle 2, respectively. Confirmed partial responses were observed in one patient with metastatic desmoplastic tumour and in two patients with small round metastatic endocrine carcinoma. Conclusion: The recommended number of topotecan administration is 10 days. Beyond the potential clinical interest of topotecan administered for a 10-day period, this is the first trial showing the feasibility of a phase-I study exploring a number of administrations of daily AUC rather than a total dose in mg/m².