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 “chemo‐switch” regimen as first‐line treatment in patients with mRCC. Methods. We assessed the maximum tolerated dose and antitumor activity of GCS in treatment‐naïve, 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/m2 per day plus capecitabine 650 mg/m2 per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000 mg/m2 per day plus capecitabine 850 mg/m2 per 12 hours plus sunitinib 37.5 mg/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 combination is recommended. 摘要 背景：吉西他滨联合卡培他滨和舒尼替尼（GCS）方案用于治疗转移性肾细胞癌（mRCC）显示出一定活性。在此我们对该多靶点“交替化疗”方案用于一线治疗mRCC 患者进行了检验。 方法：我们评估了GCS 方案用于晚期初治 mRCC 患者的最大耐受剂量和抗肿瘤活性。治疗方案包括静脉输注吉西他滨，第 1、8 天；口服卡培他滨，每日2次，第1 ∼ 14 天；口服舒尼替尼，每日1次，每 21天为一周期，共6个周期，随后由研究者判断是否继续舒尼替尼单药治疗。0级剂量水平（DL0）为吉西他滨每日1 000 mg/m2，卡培他滨每12 小时650 mg/m2，联合舒尼替尼37.5 mg/天；DL1为吉西他滨每日1 000 mg/m2，卡培他滨每12 小时850 mg/m2，联合舒尼替尼37.5 mg/天。 结果：共入组16例患者。DL1的 4 例患者中有2例发生剂量限制性毒性（DLT，3 级腹泻和4级血小板减少）。剂量下调至DL0时12例患者中只有1例发生DLT（3级腹泻、3级粘膜炎和3级血小板减少）。降低给药剂量很常见（58%的患者），仅7例患者能够接受这三种药物治疗达 3个周期以上。1例患者达到完全缓解，3例患者达到部分缓解，4 例患者获得的最佳疗效是疾病稳定。 结论：该联合方案的安全性在本试验患者人群中似乎不可控。不建议对该三联方案开展进一步研究。The Oncologist 2014;19:917–918