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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 这是一项IMC-A12（一种胰岛素样生长因子受体（IGFR）的重组单克隆抗体）与替西罗莫司（一种mTOR抑制剂）联合治疗儿童和青少年复发性或难治性实体瘤的I期联合研究。IMC-A12是一种完全重组的IgG 1单克隆抗体，以高亲和力特异性靶向人IGF-IR 1。它作为IGF-1和IGF-2配体结合和信号传导的拮抗剂，阻断配体与IGF-IR的结合，并抑制两种主要胰岛素样生长因子途径的下游信号传导：MAPK和PI 3 K/AKT。IMC-A12在多种细胞系和异种移植物中具有强效的体外和体内活性，且呈剂量依赖性。经处理的异种移植物的免疫组织化学分析表明，与未经处理的对照相比，IMC-A12导致IGF 1 R信号传导的抑制、肿瘤细胞表面受体的降解以及凋亡细胞数量的增加。 替西罗莫司是mTOR的小分子抑制剂。与雷帕霉素和依维莫司一样，替西罗莫司与FK 506结合蛋白（FKBP）12和mTOR形成复合物，抑制mTOR并产生抗增殖作用，包括G1期细胞周期阻滞和细胞凋亡。3 mTOR的主要下游靶点包括eIF 4 E结合蛋白（4 E-BP 1）4，5和p70 S6激酶，它们在参与G1期进展的mRNA编码蛋白的翻译调节中非常重要。Mtor抑制剂对许多人癌细胞系和异种移植模型具有有效的体外活性。此外，雷帕霉素类似物是高度亲脂性的，并且可以穿过血脑屏障。 mTOR信号传导的抑制通过IRS 1的稳定导致IGF-1 R信号传导的上调。这导致PIK 3/AKT/mT 0 R通路的激活。mTOR的抑制使IRS 1稳定，导致癌细胞系和用mTOR抑制剂（如雷帕霉素、坦罗莫司或RAD 001）治疗的患者中的AKT激活。IGF-1 R靶向抗体（CP 751871）和雷帕霉素的组合在6个儿童肉瘤异种移植模型中的5个中显示出协同活性。 在该I期试验中，将在患有实体瘤的患者中确定IMC-A12与替西罗莫司组合的最大耐受剂量。复发性或难治性实体瘤患者如果有足够的血液学、肝脏、肾脏和肺部状态，则符合资格。IMC-A12和替西罗莫司将每周施用。治疗周期被认为是28天。 I. 假设 我们提出了IMC-A12（抗IGF-1 R单克隆抗体）与CCI-779联合的I期试验 （替西罗莫司），一种用于实体瘤患者的mTOR抑制剂。如果患者有明显的疾病进展，她/他将从方案治疗中移除。如果有缓解或病情稳定，患者可以继续接受最多25个周期的治疗，总治疗时间为2年。 二. 具体目标 主要目标 1.估计IMC-A12（抗胰岛素生长因子-1受体单克隆抗体）每周一次静脉输注联合CCI- 779（替西罗莫司）每周一次静脉给药治疗难治性实体瘤儿童的最大耐受剂量（MTD）和推荐II期剂量。 2.定义和描述按照该方案给药的IMC-A12与替西罗莫司联合给药的毒性。 3.描述IMC-A12与替西罗莫司联合治疗儿童难治性癌症的药代动力学特征。 次要目的 1.在I期研究范围内初步确定IMC-A12和替西罗莫司联合用药的抗肿瘤活性。 2.通过评估：（a）外周血单核细胞（PBMNC）中IGFR表达和磷酸化的变化和（B）胰岛素受体表达和磷酸化来评估IMC-A12的生物活性。 3.通过测量PBMNC中磷酸化S6 Ser 235/236、磷酸化AKTSer 473和磷酸化eIF 4G ser 1108的水平来评估替西罗莫司的生物活性。

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.