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

这个子项目是众多研究子项目之一

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.