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Abstract Objective: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. Patients and methods: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m2/day according to a 5 days on/2 days off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. Results: Twenty patients received a total of 57 cycles (range 18). Grade 34 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 34 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. Conclusions: RFS2000 could be administered orally as a 5 days on/2 days off schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population. [ABSTRACT FROM AUTHOR]