Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors
Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors
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DOI：
10.1200/jco.2005.01.8960
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发表时间：
2006-05-20
影响因子：
45.3
通讯作者：
Rowinsky, Eric K.
中科院分区：
文献类型：
--
作者：
Erlichman, Charles;Hidalgo, Manuel;Rowinsky, Eric K.
目的研究EKB-569对晚期实体肿瘤患者的最大耐受量(MTD)和剂量限制毒性。EKB-569是一种选择性的、不可逆转的表皮生长因子受体(EGFR)抑制剂，在间歇给药方案(28天周期中的14天)或连续给药方案(28天周期中的每一天)中每天口服一次。结果30名患者在间歇剂量队列中的中位数为2个周期(1至10个周期)；29名患者在连续剂量队列中的中位数为3个周期(1至8个周期)。剂量限制毒性为3级腹泻，两组的MTD均为75 mg EKB-569/d。其他常见的毒性包括皮疹、恶心和虚弱。暴露于EKB-569呈剂量比例关系。在MTD，平均标准差终末半衰期为21.7+/-4.2小时，峰值浓度从第1天到第14/15天增加1.2倍。未观察到主要的抗肿瘤反应。1例非小细胞肺癌和1例皮肤鳞状细胞癌患者病情稳定时间分别为33周和24周。结论EKB-569每日1次口服的MTD为75 mg。这种不可逆转的EGFR抑制剂的耐受性毒性和较长的半衰期需要作为单一药物和与其他药物联合使用进行进一步评估。
PurposeThe maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors.Patients and MethodsPlanned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days I and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort.ResultsThirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean standard deviation terminal half-life was 21.7 +/- 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non-small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively.ConclusionThe MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.