Dynamic-contrast enhanced MRI as a BAY 43-9006 marker

描述(申请人提供)：索拉非尼(BAY 43-9006)是作为一种口服RAF-激酶抑制剂开发的，但更多的研究表明，它也是一种有效的VEGFR2和PDGFR抑制剂，其在体内的主要作用机制是抗血管生成。索拉非尼在转移性肾癌患者的II期随机停药研究中显示出活性。其他I期和II期数据显示，毒性随着剂量的增加而增加，但毒性和药代动力学都是高度可变的。因此，最终需要一种生物标记物来确定最佳剂量并预测索拉非尼治疗对患者的益处。对其他VEGFR和PDGFR抑制剂的研究表明，动态增强MRI(DCE-MRI)是一种有用的药效学标志，可以预测药物的益处。因此，DCE-MRI也可作为索拉非尼的药效学标志物。这一假设将在一项随机临床试验中得到验证，在该试验中，透明细胞肾癌患者被分配到安慰剂、低剂量或高剂量索拉非尼治疗。试验的主要终点是在治疗前和治疗4周后获得的DCE-MRI图像中K-Trans的变化。还将评估前60秒对比度浓度-时间曲线下的面积(AUC60)以及这两个参数在感兴趣区域的所有体素上的分布。最初被分配给安慰剂的患者随后将被随机分成第二次接受低剂量或高剂量索拉非尼治疗，并在4周的研究治疗后接受第三次DCE-MRI。然后，来自所有66名登记患者的数据将被用于二次分析，以确定K-反式或AUC60是否与索拉非尼或其代谢物的稳态浓度相关。如果拟议的初步试验证实DCE-MRI是索拉非尼的药效学标记物，将进行未来的临床试验，以确定DCE-MRI是否可以预测索拉非尼的益处。

DESCRIPTION (provided by applicant): Sorafenib (BAY 43-9006) was developed as an oral raf-kinase inhibitor, but additional studies have shown it to also be a potent inhibitor of VEGFR2 and PDGFR and that its principal mechanism of action in vivo is antiangiogenic. Sorafenib has shown activity in a phase II randomized discontinuation study in patients with metastatic renal cell cancer. Other phase I and phase II data show that toxicities increase with dose, but that toxicity as well as pharmacokinetics are all highly variable. There is thus an ultimate need for a biomarker to determine the best dose and to predict patient benefit with sorafenib treatment. Studies with other VEGFR and PDGFR inhibitors suggest that dynamic contrast enhanced MRI (DCE-MRI) is a useful pharmacodynamic marker and may be predictive of drug benefit. Therefore it is hypothesized that DCE-MRI is a pharmacodynamic marker for sorafenib as well. This hypothesis will be tested in a randomized clinical trial in which patients with clear cell renal cancer are assigned to therapy with placebo, low dose, or high dose sorafenib. The primary endpoint of the trial is the change in K-trans from DCE-MRI images obtained before and after 4 weeks of therapy. The area under the contrast concentration versus time curve for the first 60 seconds (AUC60) and the distribution of both parameters across all voxels of the region of interest will also be evaluated. Patients initially assigned to placebo will then be randomized a second time to low or high dose sorafenib therapy and will undergo a third DCE-MRI after 4 weeks of investigational therapy. Data from all 66 enrolled patients will then be used in secondary analyses to determine if K-trans or AUC60 correlates with steady state concentration of sorafenib or its metabolites. If the proposed preliminary trial confirms that DCE-MRI is a pharmacodynamic marker for sorafenib, future clinical trials determining whether DCE-MRI is predictive of sorafenib benefit will be undertaken.