A Phase I-II study of 96-hour infusional topotecan and paclitaxel for patients with recurrent Mullerian tumors

BACKGROUND. Topotecan and paclitaxel are schedule dependent chemotherapeuti c agents with activity against ovarian carcinoma. A Phase I-II study in whi ch both drugs were administered concurrently by 96-hour, continuous, intrav enous infusion was performed to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy of the combination. METHODS. Women with ovarian or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. The dose of topotecan was es calated from 1.6 mg/m(2) while maintaining the paclitaxel dose constant at 100 mg/m(2). Plasma concentrations of both drugs were monitored daily durin g the first cycle of therapy. RESULTS. Forty-five patients with a median age of 54 years (range, 42-70 ye ars) received 181 cycles of therapy. Five patients were recruited to each o f four dose levels (topotecan 1.6 mg/m(2), 2.0 mg/m(2), 2.8 mg/m(2), and 3. 6 mg/m(2)), and an additional 25 patients were treated at the MTD (Phase II ). Neutropenia and thrombocytopenia became dose limiting toxicities (DLT) a t the fourth dose level. Emesis, mucositis, peripheral neuropathy, diarrhea , and alopecia were mild. Twenty patients (44%) had line-related occlusion, thrombosis, or infection. The mean values (+/- standard deviation) of the apparent steady-state plasma concentrations at the Phase II doses were 2.3 nM +/- 0.5 nM for topotecan lactone, 5.6 nM +/- 2.1 nM for total topotecan, and 40.1 nM +/- 16.8 nM for paclitaxel. There were seven partial responses (Phase II) contributing to an objective response rate of 28% and a median survival time of 11.7 months (range, 0.6-20.1 months). CONCLUSIONS. Topotecan at a dose of 2.8 mg/m(2) and paclitaxel at a dose of 100 mg/m(2) administered by concurrent, 96-hour, continuous intravenous in fusions shows activity against tumors of Mullerian origin. (C) 2001 America n Cancer Society.