Department of Medical Oncology 452, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen, 6500 HB, The Netherlands.
Br J Cancer. 2010 Nov 23;103(11):1637-43. doi: 10.1038/sj.bjc.6605777. Epub 2010 Nov 2.
The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically.
A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination.
Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d.
The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination.
索拉非尼（血管内皮生长因子受体 2 抑制剂）与西罗莫司（雷帕霉素靶蛋白抑制剂）联合应用可能具有协同作用。
进行了一项索拉非尼每日两次（b.i.d.）和西罗莫司每日一次（q.d.）的 I 期剂量递增研究，以确定该联合方案在实体瘤患者中的推荐剂量。次要目的是确定安全性概况和最大耐受剂量（MTD），并评估该联合方案的药代动力学（PK）。
剂量限制性毒性为肝转氨酶升高和皮肤毒性。报告的最常见不良事件为肝转氨酶升高、低磷血症、乏力、厌食、腹泻、恶心、皮疹和掌跖感觉迟钝。西罗莫司未改变索拉非尼的 PK；相反，索拉非尼降低了西罗莫司的 AUC（0-96）和 C（max）。未观察到客观缓解；8 例患者的疾病稳定中位数为 16.3 周（范围 8-24）。联合用药的 MTD 为索拉非尼 200mg b.i.d.联合西罗莫司 1mg q.d.
索拉非尼和西罗莫司联合应用具有增强的毒性，这不能用两种药物的 PK 来解释。MTD 时的相对低剂量，结合 PK 结果，不支持进一步开发该联合方案。
