Division of Cancer Medicine, Department of Investigational Therapeutics (Phase 1 Program), Unit 455, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Clin Cancer Res. 2009 Nov 15;15(22):7061-8. doi: 10.1158/1078-0432.CCR-09-1241. Epub 2009 Nov 10.
We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.
A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).
Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had > or =50% reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (> or =6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months).
Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.
我们评估了 Raf-1、RET、KIT、血小板衍生生长因子受体和血管内皮生长因子受体 2 激酶抑制剂索拉非尼与法尼基转移酶抑制剂替匹法尼联合应用的安全性、最大耐受剂量、药代动力学和生物学效应。
采用标准的 3+3 期剂量递增设计，28 天为一个周期（索拉非尼每天一次，替匹法尼连续 21 天，口服）。
共治疗了 50 例患者，43 例患者在第 2 周期后达到了重新分期评估。最常见的不良反应是 1 至 2 级皮疹、高血糖和腹泻。剂量限制毒性是皮疹，推荐的 II 期剂量是索拉非尼 400mg 口服 qam/200mg 口服 qpm 和替匹法尼口服 100mg 每日 2 次。尽管替匹法尼的剂量较低，但四分之一的患者法尼基转移酶水平下降了>或=50%。有趣的是，8 例甲状腺髓样癌患者中有 6 例（n=3）获得持久的稳定疾病或部分缓解（n=3），持续时间为 12 至 26+个月。其中 5 例有可获得的组织，在他们中发现了 RET 基因突变。9 例患者也出现了长时间（>或=6 个月）的稳定疾病，具体情况如下：甲状腺乳头状癌（n=4；18+至 27+个月）、肾上腺皮质癌（n=2；7 个月和 11 个月）、黑色素瘤（血小板衍生生长因子受体突变阳性；14 个月）、肾癌（6 个月）和胰腺癌（6 个月）各 1 例。
我们的研究表明，替匹法尼与索拉非尼联合应用具有良好的耐受性。该联合方案具有活性，特别是在甲状腺髓样癌患者中，这种肿瘤的特征是 RET 基因突变。
