Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer
Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer
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DOI：
10.1158/1078-0432.ccr-06-1341
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Schwartz, Brian
中科院分区：
文献类型：
--
作者：
Margolin, Kim;Atkins, Michael B.;Schwartz, Brian
目的：BAY 50-4798是一种白细胞介素2的类似物，它选择性地激活T细胞而不是自然杀伤细胞。这项I期研究旨在确定BAY 50-4798的最大耐受量(MTD)和安全性，筛选肿瘤反应，并评估药代动力学。实验设计：45例转移性黑色素瘤或肾癌患者，31例递增剂量以确定MTD，20例肾癌患者经MTD治疗以检测抗肿瘤活性。BAY 50-4798静脉注射。每隔8h，第1~5天和15~19天，如果肿瘤稳定或有反应，9周后可重复。结果：MTD由接收的剂量定义并报告。试验剂量范围为1.3至26.1微克/公斤，MTD定义为10.4微克/公斤，其毒性与白血球相似。两名患者部分缓解，一名患者患有黑色素瘤，一名患者患有肾癌。在所有45例患者中，分别有53%和9%的患者出现了3级和4级毒性，在MTD为10.4微克/公斤的患者中，分别有71%和10%的患者出现了3级和4级毒性。药动学显示药物浓度(C-max)和曲线下面积呈剂量依赖性，半衰期接近2 h，无蓄积迹象。淋巴细胞亚群分析证实T细胞亚群优先于自然杀伤细胞的扩增。结论：BAY50-4798对大剂量白介素2有较低的抗肿瘤活性。在抗原特异性免疫治疗中，BAY 50-4798可能比ALDIL更具优势。
Purpose: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics.Experimental Design: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding.Results: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 mu g/kg, and the MTD was defined as 10.4 mu g/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively, Among the patients treated at the MTD of 10.4 mu g/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (C-max) and area under the curve with a half-life of similar to 2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells.Conclusions: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.