EPOTHILONE B ANALOGUE BMS-247550 IN PTS WITH MALIGNANCIES & LIVER DYSFUNCTION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。BMS-247550是天然产物epothilone B的半合成类似物，专门设计用于克服天然产物的代谢不稳定性。与紫杉醇类似，BMS-247550在细胞分裂周期的有丝分裂期阻断细胞，是一种高效的细胞毒性药物，能够在低纳摩尔浓度下杀死癌细胞。BMS-247550在许多临床前人类肿瘤模型中显示出令人印象深刻的抗肿瘤活性。这是一项多中心I期临床试验，旨在确定需要调整BMS-247550剂量的肝功能损害水平。该研究将有四组不同程度肝功能障碍（正常、轻度、中度和重度）的患者，并按照方案中详细的剂量递增。所有受试者将接受预用药以减少过敏反应。受试者将在每21天周期的第一天通过静脉输注3小时以上接受研究药物。受试者可重复循环，直至疾病进展或出现不可接受的副作用。受试者将在GCRC进行首次输注，并留宿过夜以观察药代动力学。受试者还将返回GCRC进行3次门诊，以进行药代动力学检查。所有站点将招收84名受试者，本站点预计招收8名受试者。

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. BMS-247550 is a semi-synthetic analog of the natural product epothilone B, specifically designed to overcome the metabolic instability of the natural product. Similar to paclitaxel, BMS-247550 blocks cells in the mitotic phase of the cell division cycle and is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentration. BMS-247550 has demonstrated impressive antitumor activity in a number of preclinical human tumor models. This is a multi-center Phase I trial to define the levels of hepatic impairment at which dose modifications of BMS-247550 are required. The study will have four parallel groups of patients with different degrees of liver dysfunction (normal, mild, moderate and severe) and follow dose-escalation as detailed in the protocol. All subjects will receive premedication to minimize hypersensitivity reactions. Subjects will receive the study drug by intravenous infusion over three hours on the first day of every 21-day cycle. Subjects may repeat cycles until disease progression or unacceptable side effects. Subjects will have first infusion at the GCRC and stay overnight for pharmacokinetics. Subjects will return to the GCRC for 3 outpatient visits for pharmacokinetics as well. 84 subjects will be enrolled at all sites and 8 subjects are expected at this site.