A phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma
A phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma
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DOI：
10.1093/jjco/hyi229
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发表时间：
2006-02-01
影响因子：
2.4
通讯作者：
Abbruzzese, JL
中科院分区：
文献类型：
--
作者：
Hoff, PM;Wolff, RA;Abbruzzese, JL
背景资料：血管内皮生长因子（VEGF）是参与结直肠癌发展的最常研究的促血管生成因子之一。小分子酪氨酸激酶抑制剂semaxanib（SU 5416）是靶向VEGF信号通路的几种药物之一，其开发主要集中在治疗结直肠癌。我们设计并进行了一项由美国国家癌症研究所赞助的试验，以确定最大耐受剂量（MTD）和剂量限制性毒性（DLT）。semaxanib每周两次与伊立替康每周一次联合治疗至少一次治疗失败的晚期结直肠癌患者。伊立替康剂量固定为125 mg/m2，每周给药一次，持续4周，随后停药2周。既往接受盆腔放疗的患者接受100 mg/m2的减量治疗。semaxanib剂量逐渐增加，从85到110 mg/m2，最后到145 mg/m2。结果：在我们的研究中，10例患者接受了治疗，所有患者的毒性均可评价。没有药物相关的4级毒性。发生了1起3级头痛和1起3级呕吐。最常见的1级和2级毒性包括腹泻、腹部绞痛、贫血和恶心。9例患者完成了至少一个6周周期的治疗，并被认为可评价缓解。在这九个，两个有部分反应，三个稳定的疾病和四个进行性疾病后的第一个cycles.Conclusions：伊立替康和semaxanib可以在其完整的单药推荐剂量没有显着的毒性，并结合显示出临床活动的迹象。然而，由于III期试验的结果令人沮丧，因此不太可能进一步探索这种组合。
Background: One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer.Methods: We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m(2) given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100 mg/m(2). The semaxanib dose was escalated, going from 85 to 110 mg/m(2) and finally to 145 mg/m(2).Results: Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle.Conclusions: Both irinotecan and semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.