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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目标： 主要目的：评估CCI-779(替西罗莫斯)的安全性、耐受性，并建立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量(RD)，以便在该人群中为CCI-779(替西罗莫斯)提供适当的剂量建议。 次要： 1.研究CCI-779(替西罗莫司)在不同程度肝功能患者体内的药代动力学特征。 2.探讨CCI-779(替西罗莫司)对不同程度肝功能患者外周血单个核细胞(PBMC)中p70s6和p4EBPI磷酸化及其他mTOR抑制标志物的药效学(PD)谱是否发生改变。 3.记录CCI-779(替西罗莫斯)在该患者群体中的非剂量限制性毒性和任何抗肿瘤疗效。 4.比较NCI ODWG标准和Child-Pugh肝功能分级对降低CCI-779(替西罗莫司)PK和PD的患者间变异性的预测价值。 研究计划：预计成年男性和女性晚期恶性肿瘤患者以及肝功能正常和受损的患者将参与这项研究。 方法：有资格在退伍军人管理局接受治疗的潜在患者将接受CCI-779治疗。预计将有大约10名患者参加。 临床意义：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2，2-二(羟甲基)-丙酸酯。机械上，泰米西莫司与细胞内胞浆蛋白(FKBP)12结合，后者阻断哺乳动物雷帕霉素靶标(MTOR)的活性，mTOR是一种人类激酶，介导细胞中的关键信号通路。

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.