Phase II trial of cisplatin (C), fixed-dose rate gemcitabine (G) and gefitinib for advanced transitional cell carcinoma (TCC) of the urothelial tract: Preliminary results of CALGB 90102.

4540 Background: The GC combination has become a standard of care for advanced TCC. The epidermal growth factor receptor (EGFR) is frequently expressed in TCC and is associated with a poor prognosis. While gefitinib alone has minimal activity in advanced TCC, C has demonstrated pre-clinical synergy with gefitinib. The combination of GC and gefitinib has been shown to be safe. Because a fixed dose rate infusion of G appears to be more effective compared to standard dosing for the treatment of pancreatic cancer, we sought to test the efficacy of C, fixed dose-rate G and gefitinib in the treatment of patients with advanced TCC. METHODS: Eligible patients had measurable N2, N3 or M1 disease; PS of 0-2; CrCl of > 50 ml/min; adequate hematologic and liver function; no brain metastases; no prior systemic combination chemotherapy. The treatment regimen consisted of C 70mg/m2 D1, G 1000mg/m2 D1+8 administered at a fixed dose rate of 10 mg/m2/min every 3 weeks concurrent with gefitinib 500 mg/day PO for a maximum of 6 cycles. Responders were continued on maintenance gefitinib 500 mg/day until progression. RESULTS: A total of 27 patients were accrued before the study was halted because dose-limiting toxicity (DLT) exceeded pre-established stopping rules. The DLT events observed were 2 Gr 5 (1 neutropenic infection, 1 CVA) and 3 Gr 4 non-hematologic toxicities (1 hyperuricemia, 1 fatigue, 1 dyspnea). Grade 3 diarrhea and skin rash were observed in 2 (8%) and 4 (16 %) patients respectively. Of 24 evaluable patients there were 12 responses for an ORR of 50 % (95% CI= 29 -71%). Median time to progression is 6.9 months (95% CI: 3.8-8.9). CONCLUSIONS: The combination of GC and gefitinib is active in advanced TCC, although the relative contribution of gefitinib cannot be determined. However, this regimen was associated with excessive toxicity, possibly due to the fixed dose rate infusion of G. Accrual has therefore continued employing a standard G dosing schedule. No significant financial relationships to disclose.

Duke Scholars

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics