Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
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DOI：
10.1200/jco.2002.03.100
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发表时间：
2002-11-01
影响因子：
45.3
通讯作者：
Albanell, J
中科院分区：
文献类型：
--
作者：
Baselga, J;Rischin, D;Albanell, J
目的：确定选择性表皮生长因子受体(EGFR)酪氨酸激酶抑制剂ZD1839(易瑞沙)的安全性和耐受性，并探讨其在某些实体瘤患者中的药代动力学和药效学效应。研究对象包括晚期非小细胞肺癌、卵巢癌、头颈部癌、前列腺癌或结直肠癌。结果：88例患者接受ZD1839(150~1000 mg/d)治疗。1,000 mg/d时，12名患者中有5名出现剂量限制性毒性(3级腹泻[4名患者]和3级嗜睡[1名患者])。最常见的药物相关不良事件是痤疮样皮疹(%)和腹泻(47%)，一般较轻(1/2级)，停药后可逆转。延长给药时间后，ZD1839的安全性没有变化。药代动力学分析显示，98%的患者在第7天时稳定接触ZD1839。19名患者病情稳定，接受ZD1839治疗2：3个月；其中7名患者继续服用研究药物2：6个月。在治疗前和大约第28天进行的一系列皮肤活组织检查显示，EGFR信号通路受到抑制。结论：ZD1839的耐受性良好，剂量可达600 mg/d，剂量限制毒性为1000 mg/d。ZD1839治疗在一系列肿瘤类型和剂量上导致了有临床意义的疾病稳定。皮肤的药效学变化证实了EGFR信号的抑制，这是从ZD1839的作用模式预测的。(C)2002年，由美国临床肿瘤学会提供。
Purpose : To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types.Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited.Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for 2: 3 months; seven of these patients remained on study drug for 2: 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway.Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD 1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839. (C) 2002 by American Society of Clinical Oncology.