Atkins M B, Redman B, Mier J, Gollob J, Weber J, Sosman J, MacPherson B L, Plasse T
Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Clin Cancer Res. 2001 Mar;7(3):486-92.
CNI-1493, an inhibitor of proinflammatory cytokines, was studied in a Phase I trial in melanoma and renal cancer patients receiving high-dose interleukin 2 (IL-2). Objectives of the study were to define the maximum tolerated dose (MTD) and toxicity of CNI-1493, to assess its pharmacological effects, and to define its pharmacokinetics. Twenty-four patients were treated in sequential cohorts with CNI-1493 doses from 2 through 32 mg/m2 daily. Patients first received only CNI-1493 daily for 5 days. After a 9-day rest, patients received two 5-day courses of IL-2 of 600,000 IU/kg every 8 h for up to 14 doses/course plus daily CNI-1493; courses were separated by a 9-day rest period. CNI-1493 administered alone was well tolerated at doses through 32 mg/m2; MTD was not reached. The only clinical toxicity attributed to CNI-1493 was occasional injection-site phlebitis. Grade 1 creatinine increases occurred in 1 of 7 patients at 4 mg/m2, in 1 of 1 patients at 25 mg/m2, and in 3 of 6 patients at 32 mg/m2 CNI-1493 alone. In combination with high-dose IL-2, CNI-1493 at > or = 25 mg/m2 seemed to exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m2, as compared with 1 of 16 patients at doses < or = 16 mg/m2. The MTD for CNI-1493 given with high-dose IL-2 was 16 mg/m2. The dose-limiting toxicity of IL-2 was hypotension in 63% of patients; overall tolerance to IL-2 was not improved by CNI-1493. However, relative to changes seen in a reference group receiving high-dose IL-2 alone, at doses > or = 4 mg/m2 CNI-1493 did show evidence of pharmacological activity as an inhibitor of tumor necrosis factor production.
CNI - 1493是一种促炎细胞因子抑制剂，在一项针对接受高剂量白细胞介素2（IL - 2）的黑色素瘤和肾癌患者的I期试验中进行了研究。该研究的目的是确定CNI - 1493的最大耐受剂量（MTD）和毒性，评估其药理作用，并确定其药代动力学。24名患者按顺序分组接受每日剂量为2至32 mg/m²的CNI - 1493治疗。患者首先仅接受5天的每日CNI - 1493治疗。在休息9天后，患者接受两个5天疗程的IL - 2治疗，剂量为600,000 IU/kg，每8小时一次，每个疗程最多14剂，同时每日服用CNI - 1493；两个疗程之间间隔9天休息期。单独给予CNI - 1493时，剂量高达32 mg/m²时耐受性良好；未达到MTD。归因于CNI - 1493的唯一临床毒性是偶尔出现的注射部位静脉炎。在单独使用32 mg/m²的CNI - 1493时，7名接受4 mg/m²治疗的患者中有1名出现1级肌酐升高，1名接受25 mg/m²治疗的患者中有1名出现1级肌酐升高，6名接受该剂量治疗的患者中有3名出现1级肌酐升高。与高剂量IL - 2联合使用时，≥25 mg/m²的CNI - 1493似乎会加重IL - 2诱导的肾毒性：在接受25或32 mg/m²治疗的6名患者中有3名出现3级或4级肌酐升高，而在剂量≤16 mg/m²的16名患者中有1名出现这种情况。与高剂量IL - 2联合使用时CNI - 1493的MTD为16 mg/m²。IL - 2的剂量限制性毒性是63%的患者出现低血压；CNI - 1493并未改善对IL - 2的总体耐受性。然而，相对于仅接受高剂量IL - 2的参考组中观察到的变化，在剂量≥4 mg/m²时CNI - 1493确实显示出作为肿瘤坏死因子产生抑制剂的药理活性证据。
