Daily oral topotecan: Utilization of a metronomic dosing schedule to treat recurrent or persistent solid tumors

Abstract

2571 Background: Topotecan has antiangiogenic properties when administered on a metronomic schedule. This study investigated the safety, efficacy, and pharmacokinetics of oral topotecan, utilizing continuous low dose daily therapy without drug free intervals. Methods: This phase I, single-center, open-label, dose-ranging study consisted of 30-day treatment cycles of daily oral topotecan at dose levels of 0.25, 0.50, 0.75, 1.00, and 1.25 mg. Because our intent was to administer a continuous daily dose, the dose-limiting toxicity (DLT) was defined as a grade 2 adverse event. At least 3 patients (pts) were enrolled at each dose level. If 1 of 3 pts treated at a given dose level experienced a DLT, the level was expanded to 6 pts. If more than 2 of 6 pts had a DLT at that dose level, the previous dose level was considered the MTD. Results: 16 heavily pretreated pts with various solid tumors were enrolled, with an average of 4 prior regimens (range 2–11). Mean cycles received on protocol were 2 (range 1–6). 3 pts were enrolled at the 0.25 mg dose, 4 at 0.5 mg (one withdrew consent), 3 at 0.75 mg, 4 at 1.0 mg (one withdrew after new biliary obstruction secondary to rapid tumor growth), and 2 at 1.25 mg. The topotecan Cmax increased linearly with dose and the median (range) Tmax was 2 h (1–7). The DLT was reached at 1.25 mg (2 pts had Gr.3 GI toxicities). 2 pts (14% response) had stable disease (1 pt with a minor response and 1 pt with cervical cancer has stable disease for 7 months on therapy after multiple recurrences on prior regimens). The remaining pts had disease progression. The MTD for phase II evaluation was defined at 1.0 mg daily. Pending thrombospondin levels and circulating endothelial obtained on study patients may elucidate the most beneficial daily dose. Conclusions: This is the first phase I trial utilizing a continuous daily dosing of oral topotecan in this metronomic fashion. This 28-day cycle was well tolerated at a MTD dose of 1 mg orally daily. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline