PHASE IB EVALUATION OF IL-1 BETA

IL-1 Beta 的 IB 期评估

• 批准号: 3838220
• 负责人: J W SMITH
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838220
• 关键词: arrhythmia; biological response modifiers; blood cell count; bone marrow exam; bronchospasm; clinical trials; colony stimulating factor; combination chemotherapy; dosage; drug administration rate /duration; drug adverse effect; human subject; human therapy evaluation; human tissue; hypotension; immunomodulators; indomethacin; interleukin 1; interleukin 6; intravenous administration; leukocyte count; myocardial ischemia /hypoxia; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; pharmacokinetics; platelets

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.

白介素1β(IL-1β)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。在此阶段I 试验中，IL-1β每天静脉注射超过15分钟，持续7天 给晚期实体恶性肿瘤患者。最大耐受量 单用IL-β为0.3微克/公斤。第二组患者接受了 吲哚美辛联合IL-1β的临床前研究表明 吲哚美辛可对抗IL-1β诱导的低血压。的MTD IL-1β+吲哚美辛为0.1微克/公斤。发烧，发冷，头痛， 恶心、呕吐和肌痛是常见的症状，但并不常见。 剂量限制。观察到需要静脉输液和加压的低血压 剂量为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治疗引起了显著的 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。