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

该子项目是利用 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 VEGF Trap是以高亲和力结合VEGF的人源化重组融合蛋白，并且已显示阻断VEGF信号传导途径。动物模型已经揭示了针对几种不同肿瘤类型的显着抗肿瘤活性，促进了成功的成人I期临床试验和正在进行的II期试验。我们提出了一项VEGF Trap在>1岁和<21岁复发性或难治性实体瘤儿童中的I期剂量递增试验。在研究的A部分，我们将确定VEGF Trap的最大耐受剂量和VEGF Trap的推荐II期剂量（每14天给药一次）。起始剂量为2 mg/kg/剂，静脉给药一次 每14天。最大耐受剂量将根据前2个周期（每个周期持续14天）的毒性确定，最大剂量递增为5 mg/kg/剂IV，每14天一次。在确定14天方案的推荐II期剂量后，研究的B部分将确定与每21天静脉给予VEGF Trap（A部分推荐儿科II期剂量的150%）相关的毒性。我们还将报告VEGF Trap在所有患者中的毒性。 将在第1周期和第2周期进行药代动力学研究，以确定结合和游离VEGF Trap的谷水平。将监测抗VEGF Trap抗体。将完成相关研究，包括测定循环内皮细胞、胎盘生长因子、可溶性VEGFR 1、可溶性VEGFR 2以及外周血单核细胞中VEGFR 1和VEGFR 2的RNA水平。我们还将使用DCEMRI探索肿瘤血管通透性的变化对VEGF Trap的反应。最后，在第一阶段研究的范围内，我们计划报告 儿童实体瘤中的VEGF陷阱。 I.假设 VEGF Trap在儿童难治性实体瘤中具有抗肿瘤活性。 二.具体目标 主要目标 1.估计最大耐受剂量（MTD）或推荐的II期剂量， 每14天静脉注射一次VEGF Trap治疗难治性实体瘤儿童。 2.估计最大耐受剂量（MTD）或推荐的II期剂量， 每21天静脉注射一次VEGF Trap治疗难治性实体瘤儿童。 3.定义和描述分别按14天和21天方案静脉注射VEGF Trap的毒性。 4.描述静脉注射VEGF Trap在难治性癌症儿童中的药代动力学特征。 次要目的 1.在I期研究范围内，初步确定静脉注射VEGF Trap治疗儿童难治性实体瘤的抗肿瘤活性。 2.描述VEGF Trap治疗期间循环内皮细胞（CEC）和血浆血管生成因子的变化。 3.确定获得早期MRI的可行性，并在接受VEGF Trap的患者中使用动态对比增强MRI（DCE-MRI）探索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.