Tolerance and safety evaluation of topotecan hydrochloride capsule: a phase I clinical trial

Objective: To evaluate the safety and tolerability of domestic topotecan hydrochloride capsule for recommending safe and reasonable doses. Methods: The dose was escalated at three levels (1.5, 1.9 and 2.3 mg·m^-2) for 5 consecutive days of oral administration, and 21 days were designed as one cycle. With cohorts of 3~6 patients per dose level, in the first cycle subjects received topotecan capsule orally; in second cycle topotecan was given intravenously (1.5 mg·m^-2) in the first day and administered orally in 2~5 days. Blood sampled were collected at scheduled time points in the first and second days of second cycle. If dose-limiting toxicity (DLT) happened in 2 or more in the 3~6 subjects at a dose level, the dose climbing would stop. Results; Totally 13 patients with histologically confirmed malignancies were enrolled into 1.5 mg·m^-2group (n=6) and 1.9 mg·m^-2 group (n=7), and the maximum tolerated dose was reached if the patients completed the test. In 1.5 mg·m^-2dose group, no DLT appeared. In 1.9 mg·m^-2dose group, 5 DLTs appeared, which resulted from bone marrow suppression, including grade 4 thrombocytopenia, leukopenia and reduced hemoglobin. Non-hematological toxicities were grade 1~2 nausea, vomiting, anorexia, weakness and transaminase elevation. Severe adverse events occurred in 2 patients of 1.9 mg·m^-2 dose group; 1 patient was hospitalized due to severe thrombocytopenia and withdrawed from the trial, and 1 patient was off the study because tumor progression and then he died one week later. In 11 patients to evaluate the efficacy, 1 patient acquired partial remission, 5 patients with stable disease, and 5 patients in progressing. The 11 patients achieved pharmacokinetic data and absolute bioavailability. Conclusion; Domestic to-potecan capsule has antitumor activity. The DLT is bone marrow suppression. The maximum tolerated dose is 1.9 mg·m^-2, for 5 days, and 21 days a cycle. The patients show good tolerance to the 1.5 mg·m^-2 dose level. For the young patients with good physique and slight previous chemoradiotherapy, the 1.9 mg·m^-2 dose level deserves further study.