NABTT 0401 - BAY 43-9006 FOR PATIENTS WITH GLIOMA

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。 这项研究有四个主要目标。第一个目标是确定在接受或不接受已知由P450肝酶复合体代谢的抗惊厥药物的情况下，Bay 43-9006在接受或不接受抗惊厥治疗时的最大耐受量(MTD)。第二个目标是评估和估计与剂量相关的毒性。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和不服用酶诱导剂的患者之间的药代动力学差异。最后，估计总体存活率。恶性胶质瘤的特征是 有丝分裂信号通路的改变，如EGFR(表皮生长因子受体)和PDGFR(血小板衍生生长因子受体)。RAS/RAF信号通路是细胞对生长信号和血管生成因子反应的重要中介。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，这一通路经常被异常激活。BAY 43-9006在体外对c-raf、野生型和突变型b-raf均有很强的抑制作用。此外，Bay 43-9006对甲苯磺酸盐的进一步鉴定表明，该药物抑制了几种与肿瘤进展有关的受体酪氨酸激酶和MAPK家族成员P38A。BAY 43-9006已经在多种肿瘤类型的多个I期和II期研究中进行了评估。到目前为止，已有500多名患者接受了单一药物BAY 43-9006的治疗。BAY 43-9006将连续4周口服申办。28天的周期将代表一个治疗周期。起始剂量为200毫克，每日2次。在这项研究中，患者将根据细胞色素P450诱导的抗惊厥药物的使用情况进行分层。在这项研究的每个队列中，每组3名患者(A组3名，B组3名)将接受200 mg的起始剂量，2次/d×4周，直到肿瘤进展。剂量将会增加 以循序渐进的方式，扩展到推定MTD的总共6名患者。

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. 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.