Phase II open-label study of oral piritrexim in patients with advanced carcinoma of the urothelium who have experienced failure with standard chemotherapy

Background: Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report the results of a multi-institutional, open-label, 2-stage, phase II study that further evaluates oral piritrexim in patients with urothelial carcinoma and who proved nonresponsive to standard chemotherapy. Patients and Methods: Eligible patients included those with bi-dimensionally measurable disease and an Eastern Cooperative Oncology Group performance status of 0-2, transitional cell carcinoma or adenocarcinoma of the urothelium, and nonresponse to ≥ 1 previous standard chemotherapy regimen. Patients received piritrexim orally at 25 mg 3 times daily (every 8 hours regularly) for 5 consecutive days each week for 3 weeks, followed by a 1-week rest period. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. Results: Of the 23 patients enrolled, 19 patients and 22 patients were assessable for toxicity and response, respectively. Two patients required dose reduction because of toxicity, 2 patients discontinued study because of toxicity, and 6 patients had ≥ 1 serious adverse event. Except for grade 1/2 pain and fatigue, gastrointestinal toxicities were the most commonly reported events, followed by fever, delirium, and myelosuppression. No objective responses were observed, with 2 patients demonstrating stable disease after 2-4 cycles. By the statistical design of the trial, further enrollment was halted because of lack of activity. Conclusion: Regardless of modest side effects, oral piritrexim in heavily pretreated patients is inactive at this dose and schedule, confirming the results of a recent cooperative group trial.