Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy

Purpose: Twenty-one-day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our pr ior favorable phase I experience) to determine its activity, time to progre ssion, and pharmacodynamics. Patients and Methods: Ovarian cancer patients with measurable lesions and o ne prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m(2)/d 21-day continuous ambulatory intravenous infusion, with appropriate dose m odifications for toxicity, was administered every 28 days, Weekly blood lev els of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mo nonuclear cells (PBMCs) were determined for pharmacodynamic correlation. Results: Twenty-four patients were entered onto the study (six cisplatin-re fractory, five relapsing within < 6 months and 13 relapsing > 6 months afte r platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One ep isode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the p atients herd anemia that required transfusions. Eight of 23 patients with m easurable disease (35%; 95% confidence interval [CI], 15% to 54%) had parti al responses (PRs) lasting longer than 1 month. Two of these patients had m inor residual computed tomographic changes but had clinical complete remiss ions that lasted up to 53 weeks while they were not undergoing further ther apy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) t hat lasted 6 months, for on overall response rate of 38% in nine of 24 pati ents (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pha rmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model. Conclusion: Twenty-one-day infusion is a well-tolerated method of administe ring topotecan. Pharmacodynamic studies demonstrate correlations between (1 ) the week of infusion and the PBMC topo-1 level,(2) the AUC of topotecan a nd the decrease in topa-1 levels, and (3) the change in topa-1 level and th e neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administ ration therefore warrants further investigation in larger, randomised studi es comparing this 21-day schedule with the once-daily-for-5-days schedule. (C) 1999 by American Society of Clinical Oncology.