Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma.

BACKGROUND: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma.

PATIENTS AND METHODS: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 22-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete).

RESULTS: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths.

CONCLUSION: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.