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-1Beta）具有抗增殖性， 免疫刺激性，抗感染，脊髓保护和骨髓遗传 可能对癌症治疗有益的特性。 在这个阶段第一 试验，IL-1Beta每天在15分钟内施用IV，持续7天 给晚期固体恶性肿瘤的患者。 最大耐受剂量 仅IL-BETA的时间为0.3 mcg/kg。 第二组患者接受 基于临床前研究表明，放射状甲霉素和IL-1Beta 吲哚美辛可以消除IL-1Beta诱导的低血压。 MTD IL-1Beta加吲哚美辛为0.1 mcg/kg。 发烧，发冷，头痛， 通常观察到恶心，呕吐和肌痛，但不是 剂量限制。观察到需要静脉输液和压力的低血压 剂量为0.1 mcg/kg及以上。 剂量限制毒性是IV级 低血压，支气管痉挛，心肌缺血和心房， 心室心律不齐。 IL-1BETA治疗引起了重要的 总白血计数与剂量有关的增加（主要分段 中性粒细胞和中性粒细胞带）。 骨髓细胞是 三天和七天的治疗后增加。 血小板计数 治疗期间下降，但显着升高了基线 治疗结束后1-2周。 G-CSF和 注意到IL-6，可能是对观察到的 造血作用。 药代动力学研究表明IL-1Beta 半衰期为10-15分钟。 这项研究表明 IL-1Beta可以安全地管理给人类，它会产生 生物学效应与IL-1Alpha观察到的生物效应非常相似，并且 这种重要的，潜在的有益的造血作用发生在 耐受剂量的IL-1Beta。