CLINICAL TRIAL: ADVL0813 A PHASE I STUDY OF IMC-A12 (ANTI-INSULIN-LIKE GROWTH F

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 这是一项IMC-A12的I期联合研究，IMC-A12是一种针对胰岛素样生长因子受体(IGFR)的重组单抗，它与替西罗莫司(一种mTOR抑制剂)联合用于治疗复发或难治性实体肿瘤的儿童和青少年。IMC-A12是一种完全重组的针对人IGF-IR1的高亲和力的IgG1单抗。它作为IGF-1和IGF-2配体结合和信号传递的拮抗剂，阻断配体与IGF-IR的结合，并抑制两个主要的胰岛素样生长因子途径：MAPK和PI3K/AKT的下游信号转导。IMC-A12在多种细胞株和异种移植瘤中具有较强的体外和体内活性，且呈剂量依赖关系。免疫组织化学分析显示，与未经处理的对照相比，IMC-A12导致IGFIR信号的抑制，肿瘤细胞表面受体的降解，并增加了凋亡细胞的数量。 替西罗莫司是一种mTOR的小分子抑制剂。与雷帕霉素和伊维莫司一样，替西罗莫司与FK506结合蛋白(FKBP)12和mTOR形成复合体，抑制mTOR并导致抗增殖作用，包括G1期细胞周期停滞和细胞凋亡。3 mTOR的主要下游靶点包括eIF4E结合蛋白(4E-BP1)4，5和p70S6激酶，这些蛋白在编码参与G1期进展的蛋白的翻译调控中起重要作用。MTOR抑制剂在体外对许多人类癌细胞和异种移植模型具有很强的活性。此外，雷帕霉素类似物具有高度的亲脂性，可以穿过血脑屏障。 抑制mTOR信号通过稳定IRS1导致IGF-1R信号上调。这导致PIK3/AKT/mTOR通路的激活。抑制mTOR可以稳定IRS1，导致癌细胞株和mTOR抑制剂治疗的患者的AKT激活，如雷帕霉素、替西罗莫司或RAD001。IGF-1R靶向抗体(CP751871)和雷帕霉素的组合在6个儿童肉瘤异种移植模型中显示出5个协同活性。 在这项I期试验中，IMC-A12联合替西罗莫司的最大耐受量将在实体瘤患者中确定。复发或难治性实体肿瘤的患者，如果他们有足够的血液学、肝脏、肾脏和肺状况，就符合条件。IMC-A12和替西罗莫司每周给药一次。治疗周期被认为是28天。 一、假说 我们提出了IMC-A12(抗IGF-1R单抗)联合CCI-779的I期试验 (替西罗莫司)，一种mTOR抑制剂，用于实体肿瘤患者。如果患者有明显的进展性疾病，S将被排除在常规治疗之外。如果有反应或病情稳定，患者可以继续接受最多25个周期的治疗，总疗程为2年。 二、具体目标 主要目标 1.评估难治性实体瘤患儿每周1次静脉滴注抗胰岛素生长因子-1受体单抗(IMC-A12)联合CCI-779(替西罗莫司)治疗难治性实体瘤的最大耐受量(MTD)和推荐的II期剂量。 2.定义和描述按本附表实施的IMC-A12与替西罗莫司联合应用的毒性。 3.研究IMC-A12联合替西罗莫司在儿童难治性肿瘤中的药代动力学特征。 次要目标 1.在一期研究范围内初步确定IMC-A12与替西罗莫司的联合抗肿瘤活性。 2.评价IMC-A12的生物学活性：(A)外周血单个核细胞(PBMNC)中IGFR表达和磷酸化的变化；(B)胰岛素受体表达和磷酸化的变化。 3.通过检测PBMNC中磷酸化S6Ser235/236、磷酸化AKTSer473和磷酸化eIF4G Ser1108的水平，评价替西罗莫司的生物学活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT This is a Phase I combination study of IMC-A12, a recombinant monoclonal antibody to the insulin-like growth factor receptor (IGFR) in combination with temsirolimus, an mTOR inhibitor in children and adolescents with recurrent or refractory solid tumors. IMC-A12 is a fully recombinant IgG1 monoclonal antibody that specifically targets the human IGF-IR1 with high affinity. It acts as an antagonist of IGF-1 and IGF-2 ligand binding and signaling and blocks ligand binding to IGF-IR and inhibits downstream signaling of the two major insulin-like growth factor pathways: MAPK and PI3K/AKT. IMC-A12 has potent in vitro and in vivo activity in a variety of cell-lines and xenografts, in a dose dependent manner. Immunohistochemical analysis of treated xenografts demonstrated that the IMC-A12 led to suppression of IGFIR signaling, degradation of the surface receptor on tumor cells, and increased the number of apoptotic cells relative to untreated controls. Temsirolimus is a small molecule inhibitor of mTOR. Like rapamycin and everolimus, temsirolimus forms a complex with FK506-binding protein (FKBP)12 and mTOR, inhibiting mTOR and leading to antiproliferative effects, including G1 phase cell cycle arrest and apoptosis.3 The primary downstream targets of mTOR include eIF4E binding protein (4E-BP1)4,5 and p70S6 kinase important in the translation regulation of mRNA encoding proteins involved in G1 phase progression. The Mtor inhibitors have potent in vitro activity against many human cancer cell lines and xenograft models. Furthermore, rapamycin analogues are highly lipophilic and can cross the blood brain barrier. Inhibition of mTOR signaling leads to upregulation of IGF-1R signaling through stabilization of IRS1. This leads to activation of the PIK3/AKT/mTOR pathway.Inhibition of mTOR stabilizes IRS1 resulting in AKT activation in cancer cell lines and in patients treated with mTOR inhibitors, such as rapamycin, temsirolimus or RAD001. The combination of an IGF-1R targeted antibody (CP751871) and rapamycin demonstrated synergistic activity in 5 of 6 childhood sarcoma xenograft models.24 In this Phase I trial the maximum tolerated dose of IMC-A12 in combination with temsirolimus will be determined in patients with solid tumors. Patients with recurrent or refractory solid tumors will be eligible if they have adequate hematologic, hepatic, renal, and pulmonary status. IMC-A12 and temsirolimus will be administered weekly. A cycle of therapy is considered to be 28 days. I. HYPOTHESIS We propose a Phase I trial of IMC-A12 (anti-IGF-1R monoclonal antibody) in combination with CCI-779 (temsirolimus), an mTOR inhibitor in patients with solid tumors. If a patient has clearly progressive disease, s/he will be removed from protocol therapy. If there is a response or stable disease, the patient can continue to receive up to 25 cycles of therapy, for a total duration of therapy of 2 years. II. SPECIFIC AIMS Primary Aims 1. To estimate the maximum tolerated dose (MTD) and recommended Phase II dose of IMC-A12 (anti-insulin growth factor-1 receptor monoclonal antibody) administered as an intravenous infusion once weekly in combination with CCI- 779 (temsirolimus) administered intravenously once weekly to children with refractory solid tumors. 2. To define and describe the toxicities of IMC-A12 in combination with temsirolimus administered on this schedule. 3. To characterize the pharmacokinetics of IMC-A12 in combination with temsirolimus in children with refractory cancer. Secondary Aims 1. To preliminarily define the antitumor activity of the combination of IMC-A12 and temsirolimus within the confines of a Phase I study. 2. To assess the biologic activity of IMC-A12 by assessing: (a) changes in IGFR expression and phosphorylation and (b) insulin receptor expression and phosphorylation in peripheral blood mononuclear cells (PBMNC). 3. To assess the biological activity of temsirolimus by measuring levels of phosphor-S6Ser235/236, phosphor-AKTSer473, and phosphor-eIF4G ser1108 in PBMNC.