Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium

Purpose: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced tra nsitional-cell carcinoma (TCC) of the urothelium. Patients and Methods: Patients with measurable, previously untreated, local ly advanced or metastatic TCC and with Eastern Cooperative Oncology Group p erformance status less than or equal to 2 and creatinine clearance greater than or equal to 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m(2). Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a ma ximum of six cycles. Results: Sixty-one patients were registered. In phase 1, 15 patients were e ntered at four different dose levels. Dose-limiting toxicity consisted of e arly onset (after the first cycle) grade 2 asthenia (two of six patients) a nd grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dos e of 80 mg/m(2) and gemcitabine 1,000 mg/m(2) wets recommended for phase If , and 46 additional patients were entered at this level for a total of 49 p atients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients , respectively. Overall, febrile neutropenia was seen in 11 patients, and o ne toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assess able for response; 16 complete responses (27.6%) and 29 partial responses ( 50%) were observed for an overall response rate of 77.6% (95% confidence in terval, 60% to 98%), The median survival time (MST) available for the phase I part of the study is 24.0 months. MST hers not been reached for the whol e group with the current follow-up. Conclusion: This combination of paclitaxel, cisplatin, and gemcitabine is f easible and highly active in patients with advanced TCC of the urothelium, further evaluation of this regimen in patients with TCC is warranted. (C) 2 000 by American Society of Clinical Oncology.