CLINICAL TRIAL: PH I PK STUDY OF TEMSIROLIMUS (CCI-779) IN PTS WITH IMPAIRED LIV

临床试验：替西罗莫司 (CCI-779) 在 LIV 受损的 PTS 中的 PH I PK 研究

• 批准号: 7718722
• 负责人: John Sarantopoulos
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718722
• 关键词: Adult; Binding; CCI-779; Caring; Cell Cycle; Cells; Child; Classification; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Cytoplasmic Protein; Dose; Dose-Limiting; Drug Kinetics; Enrollment; Esters; Female; Functional disorder; Funding; Grant; Hepatic; Human; Immunosuppressive Agents; Institution; Malignant Neoplasms; Measures; Mediating; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylation; Phosphotransferases; Population; Predictive Value; Property; Propionic Acids; Propionic acid; Recommendation; Research; Research Personnel; Resources; Safety; Signal Pathway; Sirolimus; Source; Toxic effect; United States National Institutes of Health; clinically relevant; cohort; inhibitor/antagonist; liver function; male; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES: Primary: To evalute the safety, tolerability, and to establish the maximum tolerated recommended dose (RD) for CCI-779 (temsirolimus) in cohorts of patients with varying degrees of hepatic dysfunction (mild, moderate, and severe) in order to provide appropriate dosing recommendations for CCI-779 (temsirolimus) in this population. Secondary: 1. To characterize the pharmacokinetic (PK) profile of CCI-779 (temsirolimus) in patients with varying degrees of hepatic function. 2. To determine if the pharmacodynamic (PD) profile of CCI-779 (temsirolimus) as measured by drug effects on p70s6 kinase and p4EBPI phosphorylation and other markers of mTOR inhibition in peripheral blood mononuclear cells (PBMC) is altered in patients with varying degrees of hepatic function. 3. To document the non-dose limiting toxicities and any anti-tumor efficacy associated with administration of CCI-779 (temsirolimus) in this patient population. 4. To compare the NCI ODWG criteria and the Child-Pugh classification of hepatic dysfunction in terms of their predictive value in reducing interpatient variability in the PK and PD of CCI-779 (temsirolimus). RESEARCH PLAN: Adult male and female patients with advanced malignancies and normal and impaired liver function are expected to participate in the study. METHODS: Potential patients eligible for care at the VA will be treated with CCI-779. Enrollment of about 10 patients is anticipated. CLINICAL RELEVANCE: CCI-779 (temsirolimus) is a noncytotoxic cell-cycle inhibitor with immunosuppressive and anti-tumor properties. Temsirolimus is the 2,2-bis(hydroxymethyl)-propionic acid ester of the macrocyclic immunosuppressive agent, sirolimus. Mechanically, temisirolimus binds to the intracellular cytoplasmic protein (FKBP)12, which blocks the activity of mammalian target of rapamycin (mTOR), a human kinase that mediates key signaling pathways in the cell.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目标： 主要目的：评估安全性、耐受性，并确定 CCI-779（替西罗莫司）在不同程度肝功能障碍（轻度、中度和重度）患者队列中的最大耐受推荐剂量（RD），以便为该人群中的 CCI-779（替西罗莫司）提供适当的剂量建议。 次要： 1. 表征 CCI-779（替西罗莫司）在不同程度肝功能患者中的药代动力学 (PK) 特征。 2. 确定 CCI-779（替西罗莫司）的药效学 (PD) 特征（通过药物对 p70s6 激酶和 p4EBPI 磷酸化以及外周血单核细胞 (PBMC) 中 mTOR 抑制的其他标志物的影响）在不同程度肝功能的患者中是否发生改变。 3.记录与在该患者群体中施用CCI-779（替西罗莫司）相关的非剂量限制性毒性和任何抗肿瘤功效。 4. 比较 NCI ODWG 标准和肝功能障碍的 Child-Pugh 分类在减少 CCI-779（替西罗莫司）的 PK 和 PD 患者间差异方面的预测价值。 研究计划：患有晚期恶性肿瘤且肝功能正常和受损的成年男性和女性患者预计将参加该研究。 方法：符合 VA 护理资格的潜在患者将接受 CCI-779 治疗。 预计约有 10 名患者入组。 临床相关性：CCI-779（替西罗莫司）是一种非细胞毒性细胞周期抑制剂，具有免疫抑制和抗肿瘤特性。 替西罗莫司是大环免疫抑制剂西罗莫司的 2,2-双（羟甲基）丙酸酯。 从机械角度而言，替米西罗莫司与细胞内细胞质蛋白 (FKBP)12 结合，从而阻断哺乳动物雷帕霉素靶点 (mTOR) 的活性，雷帕霉素靶点是一种介导细胞内关键信号通路的人类激酶。