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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目标： 主要：评价CCI-779（替西罗莫司）在不同程度肝功能障碍（轻度、中度和重度）患者队列中的安全性、耐受性，并确定最大耐受推荐剂量（RD），以便为该人群提供CCI-779（替西罗莫司）的适当给药建议。 次要： 1. 描述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（通过药物对外周血单核细胞（PBMC）中p70 s6激酶和p4 EBPI磷酸化以及其他mTOR抑制标志物的影响进行测量）是否在不同程度肝功能患者中发生改变。 3. 记录该患者人群中与CCI-779（替西罗莫司）给药相关的非剂量限制性毒性和任何抗肿瘤疗效。 4. 比较NCI ODWG标准和肝功能障碍Child-Pugh分类在降低CCI-779（替西罗莫司）PK和PD患者间变异性方面的预测值。 研究报告：预计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将参加本研究。 方法：有资格在VA接受治疗的潜在患者将接受CCI-779治疗。 预计入组约10例患者。 临床相关性：CCI-779（替西罗莫司）是一种具有免疫抑制和抗肿瘤特性的非细胞毒性细胞周期抑制剂。 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。 在机械上，替西罗莫司结合细胞内胞质蛋白（FKBP）12，其阻断哺乳动物雷帕霉素靶蛋白（mTOR）的活性，mTOR是一种介导细胞中关键信号传导途径的人激酶。

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.