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/m2 to 1 mg/m2) 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/m2, G, 1500 mg/m2). Maximum tolerated dose (MTD) was established at cohort 5 (T, 1 mg/m2, G, 1250 mg/m2). 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 mm3. 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/m2 administered on days 1 through 15, and a G dose of 1250 mg/m2 administered on days 1 and 15 via 30 minute intravenous (IV) infusion.