PHASE IB EVALUATION OF IL-1 BETA

白细胞介素-1 β（IL-1 β）具有抗增殖， 免疫刺激、抗感染、骨髓保护和骨髓恢复 可能对癌症治疗有益的特性。 这项I期 在一项试验中，IL-1 β每天静脉注射15分钟，持续7天 晚期实体恶性肿瘤患者。 最大耐受剂量 单独IL-β的剂量为0.3 mcg/kg。 第二组患者接受 吲哚美辛加IL-1 β的临床前研究表明， 吲哚美辛可拮抗IL-1 β诱导的低血压。 的MTD IL-1 β +吲哚美辛为0.1 mcg/kg。 发烧发冷头痛 恶心、呕吐和肌痛是常见的， 剂量限制。观察到需要静脉输液和升压药的低血压 剂量为0.1 mcg/kg及以上。 剂量限制性毒性为IV级 低血压、支气管痉挛、心肌缺血、心房和 室性心律失常 IL-1 β治疗引起了显著的 总白色血细胞计数（主要为分段）的剂量相关性增加 嗜中性粒细胞和嗜中性条带）。 骨髓细胞构成为 治疗3天和7天后增加。 血小板计数 治疗期间下降，但显著高于基线 1-2治疗结束后的几周。 G-CSF显著增加， IL-6被注意到，并可能负责观察到的 造血作用 药代动力学研究表明，IL-1 β 半衰期很短，只有10-15分钟。 本研究证明 IL-1 β可以安全地用于人类， 生物学效应与IL-1 α观察到的生物学效应非常相似， 重要的，潜在的有益的，造血作用发生在 耐受良好的IL-1 β剂量。

Interleukin-1 beta (IL-1beta) possesses anti-proliferative, immunostimulatory, anti-infection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. In this phase I trial, IL-1beta was administered IV over 15 minutes daily for seven days to patients with advanced solid malignancies. The maximum tolerated dose of IL-beta alone was 0.3 mcg/kg. A second group of patients received indomethacin plus IL-1beta based on pre-clinical studies indicating that indomethacin could abrogate IL-1beta-induced hypotension. The MTD of IL-1beta plus indomethacin was 0.1 mcg/kg. Fever, chills, headache, nausea, vomiting, and myalgia were commonly observed, but were not dose-limiting. Hypotension requiring IV fluids and pressors was observed at doses of 0.1 mcg/kg and above. Dose-limiting toxicities were grade IV hypotension, bronchospasm, myocardial ischemia, and atrial and ventricular arrhythmias. IL-1beta treatment caused a significant dose-related increase in the total white blood count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity was increased after three days and seven days of treatment. Platelet counts declined during therapy, but were significantly elevated above baseline 1-2 weeks after the end of treatment. Significant increases in G-CSF and IL-6 were noted and may have been responsible for the observed hematopoietic effects. Pharmacokinetic studies indicated IL-1beta to have a short half-life of 10-15 minutes. This study demonstrates that IL-1beta can be safely administered to humans, that it produces biological effects very similar to those observed with IL-1alpha, and that important, potentially beneficial, hematopoietic effects occur at well-tolerated doses of IL-1beta.