A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer.

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.