CLINICAL TRIAL: ADVL0714, A PHASE I STUDY OF VEGF TRAP

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。 血管内皮生长因子陷阱是一种人源化的重组融合蛋白，能与血管内皮生长因子高亲和力结合，并能阻断血管内皮生长因子信号转导通路。动物模型显示了对几种不同肿瘤类型的显着抗肿瘤活性，促使成功的成人I期临床试验和正在进行的II期试验。我们建议在1岁和21岁复发或难治性实体肿瘤的儿童中进行血管内皮生长因子陷阱的I期剂量升级试验。在研究的A部分，我们将确定每14天给药一次的最大耐受剂量和推荐的第二阶段剂量。起始剂量为2毫克/公斤/次静脉注射。 每隔14天。最大耐受剂量将根据前两个周期(每个周期持续14天)的毒性确定，最大剂量每14天递增5 mg/kg/剂量IV。在确定了14天计划的推荐第二阶段剂量后，B部分将确定每21天静脉注射一次的毒性，剂量是A部分推荐的儿科第二阶段剂量的150%。我们还将报告所有患者使用VEGF Trap的毒性。 药代动力学研究将在周期1和周期2进行，以确定结合和游离的VEGFTrap的谷值。将进行抗血管内皮生长因子陷阱抗体的监测。相关研究将完成，包括循环内皮细胞、胎盘生长因子、可溶性VEGFR1、可溶性VEGFR2的测定，以及外周血单个核细胞VEGFR1和VEGFR2的RNA水平。我们还将使用DCEMRI探讨血管内皮生长因子陷阱对肿瘤血管通透性的影响。最后，在第一阶段研究的范围内，我们计划报告 血管内皮生长因子陷阱在儿童实体瘤中的应用 一、假说 VEGF Trap对患有难治性实体瘤的儿童具有抗肿瘤活性。 二、具体目标 主要目标 1.估计最大耐受剂量(MTD)或建议的第二阶段剂量 难治性实体瘤患儿每14天静脉注射一次血管内皮生长因子陷阱。 2.估计最大耐受剂量(MTD)或建议的第二阶段剂量 难治性实体瘤患儿每21天静脉注射一次血管内皮生长因子陷阱。 3.确定和描述静脉注射血管内皮细胞生长因子陷阱的毒性，分别按14天和21天的方案进行。 4.研究难治性肿瘤患儿静脉注射血管内皮细胞生长因子诱导剂的药代动力学。 次要目标 1.在一期研究范围内初步确定静脉注射血管内皮细胞生长因子陷阱治疗儿童难治性实体瘤的抗肿瘤活性。 2.描述血管内皮生长因子诱导剂治疗过程中循环内皮细胞和血浆血管生成因子的变化。 3.探讨应用动态增强磁共振成像(DCE-MRI)对接受血管内皮细胞生长因子诱导剂治疗的患者进行早期MRI检查的可行性及肿瘤血管通透性的变化。

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. VEGF Trap is a humanized recombinant fusion protein that binds VEGF with high affinity and has been shown to block VEGF signaling pathways. Animal models have revealed significant anti-tumor activity against several different tumor types prompting successful adult Phase I clinical trials and ongoing Phase II trials. We propose a Phase I dose escalation trial of VEGF Trap in children >1 year and <21 years old with relapsed or refractory solid tumors. In Part A of the study, we will determine the maximum tolerated dose of VEGF Trap and recommended Phase II dose of VEGF Trap when administered once every 14 days. The starting dose will be 2 mg/kg/dose given intravenously once every 14 days. The maximum tolerated dose will be determined based on toxicity during the first 2 cycles (each lasting 14 days), with a maximum dose escalation of 5mg/kg/dose IV every 14 days. After the recommended Phase II dose has been determined for the 14 day schedule, Part B of the study will determine the toxicities associated with administration of VEGF Trap given intravenously every 21 days at 150% of the recommended pediatric Phase II dose of Part A. We will also report the toxicities of VEGF Trap in all patients. Pharmacokinetic studies will be performed during cycle 1 and cycle 2 to determine the trough levels of bound and free VEGF Trap. Monitoring for anti-VEGF Trap antibodies will be performed. Correlative studies will be completed including assay of circulating endothelial cells, placental growth factor, soluble VEGFR1, soluble VEGFR2, and RNA levels of VEGFR1 and VEGFR2 in peripheral blood mononuclear cells. We will also explore changes in tumor vascular permeability in response to VEGF Trap using DCEMRI. Finally, within the confines of a Phase I study, we plan to report the activity profile of VEGF Trap in pediatric solid tumors. I. HYPOTHESIS VEGF Trap will have anti-tumor activity in children with refractory solid tumors. II. SPECIFIC AIMS Primary Aims 1. To estimate the maximum tolerated dose (MTD) or recommended Phase 2 dose of VEGF Trap administered intravenously every 14 days to children with refractory solid tumors. 2. To estimate the maximum tolerated dose (MTD) or recommended Phase 2 dose of VEGF Trap administered intravenously every 21 days to children with refractory solid tumors. 3. To define and describe the toxicities of intravenous VEGF Trap administered on a 14 day and 21 day schedule, respectively. 4. To characterize the pharmacokinetics of intravenous VEGF Trap in children with refractory cancer. Secondary Aims 1. To preliminarily define the antitumor activity of intravenous VEGF Trap in children with refractory solid tumors within the confines of a Phase 1 study. 2. To describe changes in circulating endothelial cells (CECs) and plasma angiogenic factors during treatment with VEGF Trap. 3. To determine the feasibility of obtaining an early MRI and to explore changes in tumor vascular permeability using dynamic contrast-enhanced MRI (DCE-MRI) in patients receiving VEGF Trap.