Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies
Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies
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DOI：
10.1200/jco.2001.19.13.3267
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发表时间：
2001-07-01
影响因子：
45.3
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Hidalgo, M;Siu, LL;Rowinsky, EK
目的：为了评估OSI-774给药的可行性，推荐长期连续每日方案的cc剂量，表征其药代动力学行为，并获得抗癌活性的初步证据，患者和方法：在三个研究部分（A至C）中，用递增剂量的OSI-774治疗晚期实体恶性肿瘤患者，以评估逐渐延长的治疗间隔。A部分患者接受OSI-774 25至100 mg，每日一次，每周3天，每4周一次，持续3周。部分B患者接受范围为50至200 mg的OSI-774剂量，每天一次，每4周一次，持续3周，以确定最大耐受剂量（MTD）。在C部分，患者按连续、不间断的时间表接受该MTD。OSI-774及其O-去甲基代谢产物OSI-420的药代动力学进行了characterized.Results：40例患者共接受了123个28天的OSI-774疗程。在A部分中，没有严重毒性妨碍OSI-774从25 mg/d递增至100 mg/d。在部分B中，当OSI-774剂量超过150 mg/d时，重度腹泻和/或皮肤毒性的发生率高得不可接受。OSI-774 150 mg/d每日不间断给药代表了延长每日给药方案的MTD。OSI-774的药代动力学与剂量无关：每日重复治疗不会导致药物蓄积（150 mg/d [平均值]：最小稳态血浆浓度，1.20 +/- 0.62 mug/mL;清除率，6.33 +/- 6.41 L/h;消除半衰期，24.4 +/- 14.6小时;分布容积，136. 4 +/- 93.1 L; OSI-420相对于OSI-774的血药浓度-时间曲线下面积为0.12 +/- 0.12 μ g/h/mL）。结论：OSI-774每日连续不间断口服给药的疾病导向研究的推荐剂量为150 mg/d。OSI-774耐受性良好，几例表皮样恶性肿瘤患者表现出抗肿瘤活性或相对较长的疾病稳定期。OSI-774对这些影响的确切作用尚不清楚。(C)2001年，美国临床肿瘤学会。
Purpose: To assess the feasibility of administering OSI-774, to recommend cc dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity,Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterised.Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent: repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 mug/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 mug/h/mL).Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known. (C) 2001 by American Society of Clinical Oncology.