CLINICAL TRIAL: A PHASE I STUDY OF THE RAF KINASE AND RECEPTOR TYROSINE KINASE I

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。 索拉非尼的治疗将在患有难治性实体肿瘤的儿童中产生抗肿瘤活性。 主要的 1.确定难治性实体肿瘤患儿口服索拉非尼(索拉非尼)片剂的最大耐受量(MTD)和推荐的II期剂量，每12小时1次，共28天，周期间隔无间歇；确定难治性白血病患儿对实体瘤MTD的耐受性。 2.确定和描述索拉非尼口服Bid的毒性(大约每12小时一次)，周期为28天，周期之间没有休息期。 3.研究索拉非尼在儿童难治性实体瘤或白血病中的药代动力学。 次要 1.在一期研究范围内初步确定索拉非尼的抗肿瘤活性。 2.评价索拉非尼对循环内皮细胞(CEC)、外周血循环内皮细胞前体(CECP)、血管内皮生长因子(VEGF)和血管内皮生长因子受体-2(VEGFR-2)的生物学作用；b.难治性白血病患儿白血病细胞的基因表达、蛋白组学和ERK磷酸化 3.评价索拉非尼的药物遗传学。 4.应用动态增强磁共振成像(Demri)评价索拉非尼对可测量软组织肿瘤的实体瘤血管和肿瘤血流量的影响。 5.分析参加这项研究的患者的肿瘤样本和白血病原始细胞是否存在ras、raf或flt-3(白血病)突变。

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. Treatment with Sorafenib will result in anti-tumor activity in children with refractory solid tumors. PRIMARY 1. To determine the maximum tolerated dose (MTD) and recommended phase II dose of Sorafenib (sorafenib) administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors; and to determine whether children with refractory leukemia tolerate the solid tumor MTD. 2. To define and describe the toxicities of Sorafenib administered orally BID (approximately every 12 hours) for cycles of 28 days with no rest period between cycles. 3. To characterize the pharmacokinetics of Sorafenib in children with refractory solid tumors or leukemias. SECONDARY 1. To preliminarily define the antitumor activity of Sorafenib within the confines of a Phase 1 study. 2. To assess the biologic effect of Sorafenib on: a. Circulating endothelial cells (CEC), circulating endothelial cell percursors (CECP), VEGF, and VEGFR-2 inperipheral blood samples b. Gene expression and proteomic profile and ERK phosphorylation in leukemic blasts from children with refractory leukemias 3. To assess the pharmacogenetics of Sorafenib. 4. To assess the effect of Sorafenib on solid tumor vascularity and tumor blood flow using dynamic contrast enhanced MRI (DEMRI) in patients with measurable soft tissue tumors. 5. To analyze tumor samples and leukemic blasts from patients entered on this study for the presence of ras,raf, or flt-3 (leukemias) mutations.