NABTT 0401 - BAY 43-9006 FOR PATIENTS WITH GLIOMA

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来源获得了主要资金， 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。 本研究有四个主要目标。第一个目的是确定BAY 43-9006在复发性恶性胶质瘤成人患者中给药时的最大耐受剂量（MTD），接受或不接受已知由P450肝酶复合物代谢的抗惊厥药。第二个目的是评估和估计剂量相关毒性。第三，描述这种给药途径的药代动力学，测量BAY 43-9906，并评估服用酶诱导剂的患者与未服用酶诱导剂的患者之间的药代动力学差异。最后，评估总体生存率。恶性神经胶质瘤的特征在于： 促有丝分裂信号通路如EGFR（表皮生长因子受体）和PDGFR（血小板衍生生长因子受体）的改变。RAS/raf信号通路是对生长信号和血管生成因子反应的重要介质。在人类肿瘤中，由于存在激活的ras、突变的b-raf或生长因子受体的过度表达，该途径经常被异常激活。BAY 43-9006是体外c-raf、野生型和突变型b-raf的有效抑制剂。此外，BAY 43-9006甲苯磺酸盐的进一步表征显示，该药剂抑制参与肿瘤进展的几种受体酪氨酸激酶和MAPK家族成员p38 a。Bay 43-9006已在多种肿瘤类型的多项I期和II期研究中进行了评价。迄今为止，已有超过500名患者接受了BAY 43-9006单药治疗。BAY 43-9006将口服给药，BID，连续4周。28天周期将代表一个治疗周期。起始剂量为200 mg BID。将根据本研究中细胞色素P450诱导抗惊厥药的使用对患者进行分层。研究的每个组中每个队列的3名患者（来自A组的3名和来自B组的3名）将以200 mg BID x 4周的起始剂量治疗，直至肿瘤进展。剂量将递增 以逐步的方式扩展到总共6名患者的假定MTD。

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. There are four primary objectives to this study. The first objective is to determine the maximum tolerated dose (MTD) of BAY 43-9006 when administered to adults with recurrent malignant glioma, receiving or not receiving anti-convulsants known to be metabolized by the P450 hepatic enzyme complex. The second objective is to assess and estimate the dose-related toxicities. Thirdly, to describe the pharmacokinetics of this route of administration, measuring BAY 43-9906, and to assess the pharmacokinetic difference between patients taking enzyme-inducing agents and those who are not. And lastly, to estimate overall survival. Malignant gliomas are characterized by alterations in mitogenic signaling pathways such as the EGFR (epidermal growth factor receptor) and the PDGFR (platelet derived growth factor receptor). The RAS/raf signaling pathway is an important mediator of responses to growth signals and angiogenic factors. This pathway is often aberrantly activated in human tumors due to presence of activated ras, mutant b-raf, or over expression of growth factor receptors. BAY 43-9006 is a potent inhibitor of c-raf, and wild-type and mutant b-raf in vitro. Additionally, further characterization of BAY 43-9006 tosylate revealed that this agent inhibits several receptor tyrosine kinases that are involved in tumor progression and p38a, a member of the MAPK family. Bay 43-9006 has been evaluated in multiple Phase I and Phase II studies in a variety of tumor types. To date, over 500 patients have been treated with single agent BAY 43-9006. BAY 43-9006 will be administered orally BID for 4 consecutive weeks. The 28-day period will represent one treatment cycle. The starting dose will be 200 mg BID. Patients will be stratified according to the use of cytochrome P450-inducing anticonvulsants in this study. Three patients per cohort in each arm of the study (3 from Group A and 3 from Group B) will be treated at the starting dose of 200 mg BID x 4 weeks until tumor progression. The dose will be escalated in a stepwise fashion with an expansion to a total of 6 patients at the putative MTD.