Phase I trial of topotecan in combination with gemcitabine in refractory solid tumor patients

Purpose. To determine maximum tolerated dose (MTD) and evidence of antitumor activity of topotecan in combination with gemcitabine in refractory cancer patients. Methods: This was a Phase I, prospective, dose-escalation trial that employed a novel-dosing schema to investigate clinical safety. Patients were treated in six cohorts with topotecan (T)+gemcitabine (G). The doses of T and G were administered by 30-minute IV infusion, T on days one through five (0.3 mg/m(2) to 1 mg/m(2)) and G on days one and 15 of a 28-day cycle (1000 mg/m2 to 1500 mg/m2). Toxicity was monitored. Results. Twenty-three cancer patients were enrolled (colorectal, n=5; lung, n=4; gastric, n=4; esophageal, n=2; other, n=8). Two of three patients developed grade 3 nonhematologic toxicity attributed to study regimen, thereby fulfilling dose limiting toxicity requirements at cohort 6 (T, 1 mg/m(2), G, 1500 mg/m(2)). Maximum tolerated dose (MTD) was established at cohort 5 (T, 1 mg/m(2), G, 1250 mg/m(2)). Ten patients were treated at cohort 5. Nonhematologic adverse effects (AEs) > grade 3 attributed to the study regimen were not observed. Hematologic toxicity was frequent. Twenty-five percent of patients in cohort 2 and 50% of patients in cohorts 4, 5, and 6 had a reduction of ANC to <500 mm(3). All neutropenic episodes were less than one week in duration. Five of the patients in the last three cohorts required delay and/or dose-reduction of G. Nineteen of 23 enrolled patients were evaluable for response. Two patients achieved a minimal response. Conclusions. The MTD was observed at a T dose of 1 mg/m(2) administered on days 1 through 15, and a G dose of 1250 mg/m(2) administered on days I and 15 via 30 minute intravenous (IV) infusion.