Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors
Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors
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DOI：
10.1093/annonc/mdi247
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发表时间：
2005-08-01
影响因子：
50.5
通讯作者：
Hurwitz, HI
中科院分区：
文献类型：
--
作者：
Holden, SN;Eckhardt, SG;Hurwitz, HI
背景资料：ZD 6474选择性抑制血管内皮生长因子受体和表皮生长因子受体的酪氨酸激酶活性。在晚期实体瘤患者的I期剂量递增研究中评估了ZD 6474的安全性、耐受性和药代动力学。（50-600 mg），28天为一个周期，直至观察到疾病进展或不可接受的毒性。结果：77例患者接受了50 mg（n = 9）、100 mg（n = 19）、200 mg（n = 8）、300 mg（n = 25）、500 mg（n = 8）和600 mg（n = 8）剂量治疗。不良事件通常为轻度，最常见的剂量限制性毒性（DLT）为腹泻（n = 4）、高血压（n = 4）和皮疹（n = 3）。大多数不良事件的发生率似乎呈剂量依赖性。在500 mg/天队列中，3/8例患者发生DLT，因此认为该剂量超过最大耐受剂量。药代动力学分析证实，ZD 6474是适合于每日一次口服dose.Conclusions：每日一次口服给药的ZD 6474在300 mg/天一般是晚期实体瘤患者的耐受性良好，该剂量正在研究的11期试验。
Background: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors.Patients and methods: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.Results: Seventy-seven patients were treated at doses of 50 mg (n = 9), 100 mg (n = 19), 200 mg (n = 8) 300 mg (n = 25), 500 mg (n = 8), and 600 mg (n = 8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n = 4), hypertension (n = 4), and rash (n = 3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing.Conclusions: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase 11 trials.