Margolin Kim, Atkins Michael B, Dutcher Janice P, Ernstoff Marc S, Smith John W, Clark Joseph I, Baar Joseph, Sosman Jeffrey, Weber Jeffrey, Lathia Chetan, Brunetti Janice, Cihon Frank, Schwartz Brian
City of Hope National Medical Center, Duarte, California 91010-3000, USA.
Clin Cancer Res. 2007 Jun 1;13(11):3312-9. doi: 10.1158/1078-0432.CCR-06-1341.
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.
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.
The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 microg/kg, and the MTD was defined as 10.4 microg/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 microg/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 approximately 2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells.
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.
BAY 50 - 4798是白细胞介素-2的类似物，与自然杀伤细胞相比，它能选择性地激活T细胞。本I期研究旨在确定BAY 50 - 4798的最大耐受剂量（MTD）和安全性，筛查肿瘤反应，并评估其药代动力学。
招募了45例转移性黑色素瘤或肾癌患者，其中31例接受剂量递增治疗以确定MTD，20例肾细胞癌患者接受MTD治疗以检测抗肿瘤活性。BAY 50 - 4798在第1至5天和第15至19天每8小时静脉注射一次，如果肿瘤稳定或有反应，9周后可重复给药。
MTD根据接受的剂量来定义和报告。测试剂量范围为1.3至26.1微克/千克，基于与阿地白介素相似的毒性，MTD被定义为10.4微克/千克。两名患者实现部分缓解，一名是黑色素瘤患者，一名是肾细胞癌患者。在所有45例患者中，分别有53%和9%经历了3级和4级毒性。在接受10.4微克/千克MTD治疗的患者中，分别有71%和10%经历了3级和4级毒性。药代动力学显示出剂量依赖性的峰浓度（C(max)）和曲线下面积，半衰期约为2小时，且无蓄积迹象。淋巴细胞亚群分析证实，与自然杀伤细胞相比，T细胞亚群优先扩增。
BAY 50 - 4798在对高剂量白细胞介素-2有反应的恶性肿瘤中的抗肿瘤活性较低。在抗原特异性免疫治疗中，BAY 50 - 4798可能比阿地白介素具有优势。
