The objective of this phase I study was to investigate the safety of an all-oral combination chemotherapy regimen: topotecan and capecitabine. Topotecan was administered once a day for 5 consecutive days followed by 2 days of rest and was administered again for 5 consecutive days. The starting dose of topotecan was 0.5 mg/m2/d(-1). Capecitabine was administered concurrently at an oral dose of 1800 mg/m2/d(-1) divided twice daily for 14 concurrent consecutive days. Each cycle of treatment was 21 days. Topotecan pharmacokinetic studies were performed on day 1 of cycles 1 and 2. Nineteen patients with refractory cancer were treated. Dose-limiting toxicity (thrombocytopenia, diarrhea) was observed in 2 of 3 patients at a topotecan dose of 2.0 mg/m2/d(-1). A total of 10 patients were treated at the maximum-tolerated dose of topotecan (1.5 mg/m2/d(-1)) and only 1 treatment-related grade 3 nonhematologic toxic event was demonstrated; however, grade 3 hematologic toxicity was observed in 8 of 10 patients at the maximum-tolerated dose, although no correlated clinical sequela resulted. One patient achieved a partial response and 7 achieved stable disease for 4 months or longer. Measurement of plasma topotecan showed pharmacokinetics consistent with no alteration by capecitabine. In conclusion, we recommend further investigation of oral topotecan (1.5 mg/m2/d(-1)) on days 1 to 5 of each week for 2 weeks in combination with capecitabine (180 mg/m2 twice daily) on days 1 to 14 within a 21-day cycle.