A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma

Background. As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeut ic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. Methods. Eligibility included platinum-/paclitaxel-resistant ovarian carcin oma, measurable disease, and adequate hematologic, renal, and hepatic funct ion. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determ ined prior to and at the completion of each weekly course. Results. Twenty-four patients were entered and 23 patients were evaluable f or toxicity and response. Two hundred eighteen weekly courses of therapy we re administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial r esponses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topoteca n lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lacton e concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng /ml for partial response, stable disease, and progressive disease, respecti vely. An analysis of variance of steady state plasma topotecan concentratio ns after the first week of infusion over all administered cycles demonstrat ed a significant difference in steady state plasma topotecan lactone concen trations between patients with partial response and stable disease and betw een partial response and no response (significant at the 0.05 level after a djustment for multiple comparisons). Controlling for cycle number, steady s tate topotecan lactone concentrations are significantly greater for patient s with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of greater than or equal to 1.9 ng/ml (95% confidence level). Conclusion. Steady state topotecan lactone concentrations are associated wi th responding or stable disease in platinum- and paclitaxel-resistant ovari an cancer. Steady state topotecan concentrations could potentially be utili zed to modify tumor exposure and response, (C) 2000 Academic Press.