Phase I trial of intravenous IL-4 Pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor
Phase I trial of intravenous IL-4 Pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor
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DOI：
10.1097/01.cji.0000162782.86008.ml
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发表时间：
2005-07-01
影响因子：
3.9
通讯作者：
Figlin, R
中科院分区：
文献类型：
--
作者：
Garland, L;Gitlitz, B;Figlin, R
NBI-3001是一种新型的减毒假单胞菌外毒素与循环排列的IL-4融合的免疫毒素，通过瘤内给药在多形性胶质母细胞瘤中显示出一定的抗肿瘤作用。作者评估了以剂量递增设计静脉注射 NBI-3001 给肿瘤显示至少 10% IL-4 受体表达的肾细胞癌和非小细胞肺癌患者的安全性和耐受性。 3 至 6 名患者组成的队列接受 0.008、0.016 和 0.027 mg/m(2) 每日 X 5 天的剂量水平治疗，每 28 天一次。连续监测中和抗体 (NAB) 滴度、NBI-3001 血浆水平和患者耐受性。14 名患者接受了总共 36 个周期的 NBI-3001（范围 1-6）。在剂量水平 0.008 和 0.016 mg/m(2) 下未发现剂量限制性毒性。在 0.027 mg/m(2) 剂量下，两名患者在第 1 周期期间出现自限性 3 级或 4 级转氨酶升高。在接受至少两个周期治疗的 7 名患者中，有 5 名检测到 NAB 滴度超过 1: 100；第一周期后的中位效价和后续周期中的中位最大效价分别为 1:50 和约 1:1,710。没有发现客观的肿瘤反应。 12 名可评估的肾细胞癌患者中有 8 名病情稳定； 4 名患者出现疾病进展。高 NAB 滴度导致四名患者退出研究。静脉注射 NBI-3001 的剂量限制性毒性是转氨酶升高至 0.027 mg/m(2)。 0.016 mg/m(2) 的 NBI-3001 耐受性良好。 NBI-3001 的循环水平较低，加上 NAB 滴度上升，可能导致表达 IL-4R 的肿瘤缺乏反应。
NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m(2) daily X 5 days every 28 days. Neutralizing antibody (NAB)titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m(2). At 0.027 mg/m(2), two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1: 100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle I and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m(2). NBI-3001 at 0.016 mg/m(2) was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.