An open-label, single-arm Phase II study of intravenous weekly (Days 1 and 8) topotecan in combination with carboplatin (Day 1) every 21 days as second-line therapy in patients with platinum-sensitive relapsed ovarian cancer.

OBJECTIVE: To evaluate clinical activity of weekly topotecan plus carboplatin in patients with platinum-sensitive recurrent ovarian, fallopian tube, or peritoneal carcinoma. METHODS: An open-label, single-arm, multicenter Phase I/II study. Phase II was the activity assessment phase, with overall response rate (ORR) as the primary endpoint. Eligible patients (females aged ≥18 years) received study treatment at the maximum-tolerated dose (MTD) identified in Phase I: intravenous topotecan 2.5mg/m(2) (Days 1 and 8), followed by carboplatin AUC 5 (Day 1), every 21 days. A two-stage Green-Dahlberg design was used to assess efficacy of treatment. An ORR of ≤30% was required to conclude that treatment was ineffective. RESULTS: Twenty-two patients in Phase I permitted identification of the MTD. In Phase II, 55 patients (median age 64.0 years) were enrolled and included in the intent-to-treat population. There were six complete responses (10.9%) and 11 partial responses (20.0%), giving an ORR of 30.9% (17 patients; 95% CI: 18.7%, 43.1%). Median time to response and progression-free survival were 6.57 weeks (95% CI: 5.86, 12.57) and 44.29 weeks (95% CI: 36.14, 52.14), respectively. Grade 3/4 hematological toxicity caused dose reductions, treatment delays and study discontinuation. Neutropenia (Grade 3: 29%; Grade 4: 11%) was the most common hematological adverse event (AE). Fatigue (71%) and nausea (71%) were the most common drug-related non-hematologic AEs. CONCLUSIONS: This study showed an acceptable benefit-risk profile for topotecan plus carboplatin. Further studies using alternative dose levels could help define an optimal dosing schedule for this treatment combination in patients with platinum-sensitive recurrent disease.

A phase I study to characterize the safety, tolerability, and pharmacokinetics of topotecan at 4 mg/m2 administered weekly as a 30-minute intravenous infusion in patients with cancer.

Topotecan pharmacokinetics at higher infusion rates (4 mg/m2 over 30 minutes) have not been studied. The authors report a pharmacokinetics and safety study of this dose in advanced cancer patients. Sixteen patients were given a 4-mg/m2 topotecan infusion intravenously (IV) over 30 minutes weekly for 3 weeks, repeated every 28 days. Pharmacokinetics were determined after the first dose. Plasma concentrations of total topotecan were measured to derive CL, V(ss), C(max), t(max), t(1/2), AUC(0-t), and AUC(0-infinity). Plasma total topotecan concentrations decreased biexponentially, with a mean CL value of 20.6 L/h, V(ss) value of 101 L, and t(1/2) value of 5.0 h. Nine significant adverse events (all hematologic) were topotecan related. Grade 3 or less adverse events included anemia, thrombocytopenia, leukopenia, and fatigue. Pharmacokinetics of the 4-mg/m2 infusion of topotecan over 30 minutes are comparable to findings from studies of lower and higher doses. Toxicities are similar to previous reports.