重组人可溶性白细胞介素-1受体（rhu IL-1R）用于复发难治性急性髓系白血病患者的I期研究。

A phase I study of recombinant human soluble interleukin-1 receptor (rhu IL-1R) in patients with relapsed and refractory acute myeloid leukemia.

作者信息

Bernstein S H, Fay J, Frankel S, Christiansen N, Baer M R, Jacobs C, Blosch C, Hanna R, Herzig G

机构信息

Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

出版信息

Cancer Chemother Pharmacol. 1999;43(2):141-4. doi: 10.1007/s002800050874.

DOI:10.1007/s002800050874

PMID:9923819

Abstract

PURPOSE

The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML).

METHODS

The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels.

RESULTS

rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease.

CONCLUSIONS

rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.

摘要

目的

重组人白细胞介素-1受体（rhu IL-1R）是1型全长膜结合受体的可溶性截短形式，它与IL-1的结合亲和力与膜形式相同。因此，它可能具有临床潜力，通过隔离IL-1，从而防止其与膜结合受体结合并引发生物学效应。由于IL-1已被证明以自分泌方式调节白血病细胞增殖，因此对复发和难治性急性髓系白血病（AML）患者进行了rhu IL-1R的I期试验。

方法

研究组包括11名患者，他们依次接受三种剂量水平之一的治疗，在第1天接受单次静脉推注剂量，随后每天皮下注射13天，如果达到疾病稳定或更好的反应，则可选择额外治疗14天。剂量水平1：静脉推注500μg/m²，皮下剂量250μg/m²/天（5名患者）；剂量水平2：静脉推注1000μg/m²，皮下剂量500μg/m²/天（3名患者）；剂量水平3：静脉推注2000μg/m²，皮下剂量1000μg/m²/天（3名患者）。由于药物供应有限，该研究仅设计用于检查这三个剂量水平。

结果

rhu IL-1R耐受性良好。没有与研究药物相关的3级或4级非血液学毒性，并且未达到最大耐受剂量。在研究过程中未产生IL-1R阻断抗体。在rhu IL-1R给药前、给药期间和给药后均未检测到血清IL-1β、IL-6和TNF水平。静脉给药后的终末半衰期至少为7 - 12小时，皮下给药后为2 - 4天。静脉和皮下给药后，rhu IL-1R的血清水平分别达到预处理水平的360倍和25倍。没有患者对治疗有完全、部分或轻微反应；4例疾病稳定，7例疾病进展。