盐酸洛拉曲克治疗恶性肿瘤的Ⅰ期临床试验  

Phase Ⅰ clinical trial of nolatrexed dihydrochloride in patients with solid tumors

作　　者：王兴元[1] 冯奉仪[1] 罗志国[1] 何静[1] 邢镨元[1] 

机构地区：[1]中国医学科学院中国协和医科大学肿瘤医院,北京100021

出　　处：《中国新药杂志》2005年第2期207-210,共4页Chinese Journal of New Drugs

摘　　要：目的:观察盐酸洛拉曲克治疗恶性肿瘤的安全性,不良反应与剂量的关系,确定推荐Ⅱ期临床研究的剂量。方法:共入选18例患者,盐酸洛拉曲克剂量分为6级,由初始剂量100mg·m^(-2)·d^(-1)开始逐级增加至200,340,570,740,920mg·m^(-2)·d^(-1),加入5d输液泵持续静脉点滴,21d为一周期,每剂量水平3例。观察药物对机体各系统的影响和毒性反应。结果:盐酸洛拉曲克主要毒性反应为骨髓抑制(白细胞、中性粒细胞和血小板降低)、消化道反应(恶心、呕吐、腹泻)和口腔黏膜炎,毒性反应恢复较快,无药物相关性死亡病例。毒性反应与剂量相关,740mg·m^(-2)·d^(-1)以下的剂量组主要是Ⅰ/Ⅱ度毒性反应,920mg·m^(-2)·d^(-1)剂量组均出现Ⅲ或Ⅳ度毒性反应。洛拉曲克的剂量限制性毒性(DLT)为骨髓抑制(白细胞、中性粒细胞和血小板降低)、腹泻、口腔黏膜炎。最大耐受剂量(MTD)为920mg·m^(-2)·d^(-1)。结论:盐酸洛拉曲克对消化道恶性肿瘤患者的耐受性良好,建议Ⅱ期临床研究推荐剂量为740mg·m^(-2)·d^(-1)×5d,21d为一周期。Objective: To evaluate the safety and maximum tolerated dose of nolatrexed dihydrochloride in patients with malignant tumors. Methods: 18 malignant cancer patients were recruited in the study. Cohorts of three patients were accrued to six dosing levels of nolatrexed dihydrochloride at 100, 200, 340, 570, 740, 920mg·m^(-2)·d^(-1) via a 5-day continuous infusion pump for a 21-day course of chemotherapy to establish the maximum tolerated dose (MTD). Results: The most dose-associated adverse reactions were myelosuppression (leucopenia, neutropenia, thromocytopenia), GI dysfunction (nausea, vomiting, diarrhea) and mucositis. No death report was associated with nolatrexed in the study. Grade Ⅰ/Ⅱ adverse reactions occurred in patients receiving the dosing of less than 740mg·m^(-2)·d^(-1), and grade Ⅲ/Ⅳ in patients receiving the dosing of 920mg·m^(-2)·d^(-1). Conclusion: Nolatrexed dihydrochloride was well tolerated in patients with GI solid tumors. The dosing regimen recommended in phase Ⅱ clinical trial was 740mg·m^(-2)·d^(-1).

关 键 词：盐酸洛拉曲克 恶性肿瘤Ⅰ期临床研究 剂量限制性毒性 最大耐受剂量 

分 类 号：R969.4[医药卫生—药理学] R979.1[医药卫生—药学]