PHASE IB EVALUATION OF IL-1 BETA

白介素1β(IL-1Beta)具有抗增殖、 免疫刺激、抗感染、骨髓保护和骨髓保存 可能有益于癌症治疗的特性。在这个阶段 I试验，IL-1Beta每天静脉注射超过15分钟，共7次 给晚期实体恶性肿瘤患者的天数。最大值 IL-1β单独耐受量为0.3微克/公斤。第二组 患者在临床前基础上接受吲哚美辛联合IL-1β治疗 研究表明吲哚美辛可阻断IL-1β诱导的 低血压。IL-1β联合吲哚美辛的MTD尚未得到证实 已确定，尽管有一名患者的剂量限制毒性为0.3 微克/公斤加消炎痛。发烧，发冷，头痛，恶心，呕吐， 和肌痛是常见的观察，但没有剂量限制。 观察到需要静脉输液和加压的低血压。 0.1微克/公斤及以上。剂量限制毒性为IV级 低血压、支气管痉挛、心肌缺血和房颤 室性心律失常。IL-1β治疗引起显著的 总白细胞计数与剂量相关的增加(主要是分段的 中性粒细胞和中性粒细胞带)。骨髓细胞数 在治疗三天和七天后增加。血小板计数 在治疗期间有所下降，但显著高于基线 治疗结束后1~2周。粒细胞集落刺激因子显著升高 和IL-6被注意到，并可能是导致观察到的 有造血作用。药代动力学研究表明IL-1β可 有10-15分钟的短暂半衰期。这项研究表明 IL-1β可以安全地应用于人类，它产生的 与IL-1α非常相似的生物效应，以及 重要的，潜在有益的，造血作用发生在 耐受性良好的IL-1β剂量。

Interleukin-1 beta (IL-1Beta) possesses antiproliferative, 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-1beta 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 has not been determined, although one patient has had dose-limiting toxicity at 0.3 mcg/kg plus indomethacin. 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.