A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer
A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer
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DOI：
10.1158/1078-0432.ccr-07-4740
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发表时间：
2008-06-01
影响因子：
11.5
通讯作者：
Dar, Mohammed M.
中科院分区：
文献类型：
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作者：
Robertson, Michael J.;Kirkwood, John M.;Dar, Mohammed M.
目的：白细胞介素18（IL-18）是一种免疫刺激性细胞因子，在临床前模型中具有抗肿瘤活性。进行了重组人IL-18（rhIL-18）的I期研究，以确定在两种不同时间表中以不同剂量给予晚期癌症患者的rhIL-18的毒性、药代动力学和生物活性。3 - 4名患者的队列给予递增剂量的rh IL-18，作为2小时静脉输注，连续5天，每28天重复一次，A组）或每周一次（B组），持续6个月。使用标准标准对毒性进行分级。结果：19例患者（10例黑色素瘤和9例肾细胞癌）分别给予rhIL-18 100，500或1,000 μ g/kg（A组）或100，1,000或2,000 μ g/kg（B组）。常见的副作用包括寒战、发热、头痛、疲劳和恶心。常见的实验室检查异常包括一过性、无症状的1 - 3级淋巴细胞减少症、1 - 4级高血糖症、1 - 2级贫血、中性粒细胞减少症、低白蛋白血症、肝酶升高和血清肌酐升高。未观察到剂量限制性毒性。rhIL-18的生物学效应包括一过性淋巴细胞减少和淋巴细胞活化抗原表达增加。IFN-γ，粒细胞-巨噬细胞集落刺激因子，IL-18结合蛋白的血清浓度增加观察后dosing.Conclusions：rhIL-18可以给予生物活性剂量的每周输注或每天输注5天，每28天重复的晚期癌症患者。毒性通常为轻度至中度，并且未确定任一方案的rhIL-18的最大耐受剂量。
Purpose: Interleukin-18 (IL-18) is an immuncistimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer.Experimental Design: Cohorts of three to four patients were given escalating doses of rh IL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements.Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 mu g/kg (group A) or 100, 1,000, or 2,000 mu g/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing.Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.