Davis Ian D, Skrumsager Birte K, Cebon Jonathan, Nicholaou Theo, Barlow John W, Moller Niels Peter Hundahl, Skak Kresten, Lundsgaard Dorthe, Frederiksen Klaus Stensgaard, Thygesen Peter, McArthur Grant A
Austin Health, Melbourne, Victoria, Australia.
Clin Cancer Res. 2007 Jun 15;13(12):3630-6. doi: 10.1158/1078-0432.CCR-07-0410.
Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8(+) T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors.
Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 microg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9).
Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 microg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 microg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8(+) cells. One partial tumor response observed after treatment with IL-21 for 2 x 6 weeks (3/wk) became complete 3 months later.
IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 microg/kg in the 5+9 regimen.
人白细胞介素-21（IL-21）是一种具有多效性的I类细胞因子，可激活CD8(+)T细胞和自然杀伤细胞。我们报告了一项针对手术无法治愈的转移性黑色素瘤患者的重组人IL-21的1期研究。主要目的是通过确定剂量限制毒性（DLT）来研究安全性和耐受性。次要目的是确定外周血中各种生物标志物的剂量反应，估计最小生物学有效剂量，确定IL-21的药代动力学，确定治疗期间是否诱导产生抗IL-21抗体，并根据实体瘤疗效评价标准测量对肿瘤大小的影响。
采用开放标签、双臂、剂量递增试验，通过静脉推注给予IL-21，剂量水平为1至100μg/kg，使用两种平行治疗方案：每周三次，共6周（3/周）或三个周期，每天给药5天，随后休息9天（5+9）。
29名患者进入研究。IL-21总体耐受性良好，在1、3和10μg/kg剂量水平未观察到DLT。在3/周方案中，丙氨酸转氨酶升高、中性粒细胞减少以及伴有发热和寒战的头晕是DLT增加的表现。5+9方案中的DLT表现为天冬氨酸转氨酶和丙氨酸转氨酶升高、中性粒细胞减少、疲劳和血小板减少。两种方案的最大耐受剂量均定为30μg/kg。在所有剂量水平均观察到对生物标志物的影响，包括可溶性CD25水平升高以及CD8(+)细胞中穿孔素和颗粒酶B mRNA上调。在用IL-21治疗2×6周（3/周）后观察到1例部分肿瘤反应，3个月后变为完全缓解。
在所给予的所有剂量水平下，IL-21均具有生物活性且总体耐受性良好，2期研究已开始使用5+9方案中的30μg/kg剂量。
