Phase I Study of Sunitinib in Combination With Gemcitabine and Capecitabine for First-Line Treatment of Metastatic or Unresectable Renal Cell Carcinoma

Background. The combination of gemcitabine plus capecitabine and sunitinib (GCS) shows activity in metastatic renal cell carcinoma (mRCC). We tested the multitargeted "chemoswitch" regimen as first-line treatment in patients with mRCC. Methods. We assessed the maximum tolerated dose and antitumor activity of GCS in treatment-naive, advanced mRCC patients. Treatment consisted of intravenous gemcitabine on days 1 and 8, oral capecitabine twice daily on days 1-14, and oral sunitinib daily for six 21-day cycles, followed by sunitinib monotherapy at the investigator's discretion. Dose level 0 (DL0) was gemcitabine 1,000 mg/m(2) per day plus capecitabine 650 mg/m2 per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000mg/m(2) per day plus capecitabine 850mg/m(2) per 12 hours plus sunitinib 37.5mg/day. Results. Sixteen patients were enrolled. At DL1, two of four patients had dose-limiting toxicity (DLT; grade 3 diarrhea and grade 4 thrombocytopenia). The dose was reduced to DL0 when only 1 of 12 patients experienced DLT (grade 3 diarrhea, grade 3 mucositis, and grade 3 thrombocytopenia). Dose reductions were frequent (58% of patients), and only seven patients were able to receive the three drugs for more than three cycles. One patient achieved a complete response, three had partial responses, and the best response for four was stable disease. Conclusion. The safety profile of the combination does not seem manageable in this patient population. No further development of the combinationis recommended.