CLINICAL TRIAL: H-22658 - ADVL0712 - A PHASE I STUDY OF IMC-A12 (ANTI-IGF-I

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这是 IMC-A12 (Imclone Systems) 的一项 I 期研究，IMC-A12 是一种针对胰岛素样生长因子-I 受体 (IGF-IR) 的重组人单克隆抗体，用于患有复发/难治性实体瘤的儿科患者。胰岛素样生长因子 (IGF) 系统在多种癌症（包括许多儿科特有癌症）的发生和进展中发挥着关键作用。 IGF-I 和 IGF-II 配体信号通过 IGF-IR 跨膜酪氨酸激酶促进癌细胞增殖和存活。 使用单克隆抗体破坏 IGF-IR 信号传导已在体外、动物模型和早期成人试验中显示出对多种癌症的抗肿瘤活性。在这项 I 期试验中，我们将评估毒性特征并确定每周一次静脉注射 IMC-A12 对患有复发或难治性实体瘤的儿童和青少年的最大耐受剂量 (MTD)。年龄为 1-21 岁的难治性实体瘤患者将参加标准 I 期剂量递增试验，起始剂量为 6 mg/kg。该研究将包括一次剂量递增至 9 如果儿童在 6 mg/kg 剂量下未发现 IMC-A12 耐受，则应降低 6 mg/kg 剂量，并可能降低剂量。 由于 IGF-1R 抑制剂在尤文肉瘤/外周 PNET 患者中具有抗肿瘤活性的临床证据，因此本试验已纳入包含该诊断患者的单独分层。尤文肉瘤/外周 PNET 层中的患者将在已发现实体瘤层中可耐受的剂量水平下累积。 本研究还将评估 IMC-A12 在儿童中的药代动力学。相关生物学研究将包括评估外周血单核细胞中 IGF-IR 和胰岛素受体 (IR) 的表达和激活。将在治疗前和治疗前测量 IGF-I、IGF-II、IGF-BP3、生长激素、胰岛素和 C 肽的循环水平。 IMC-A12 后处理。如果有肿瘤组织，将获得并储存以供未来研究。 IMC-A12 对患有复发/难治性实体瘤的儿童具有抗肿瘤活性。 主要目标 1. 使用有限剂量递增策略，估计复发/难治性实体瘤儿童每周一次静脉输注 IMC-A12 的最大耐受剂量 (MTD) 或 2 期评估的推荐剂量。

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. This is a Phase I study of IMC-A12 (Imclone Systems), a recombinant human monoclonal antibody to the insulin-like growth factor-I receptor (IGF-IR), in pediatric patients with recurrent/refractory solid tumors. The insulin-like growth factor (IGF)system plays a critical role in the development and progression of many types of cancer,including many pediatric-specific cancers. IGF-I and IGF-II ligand signaling through the IGF-IR transmembrane tyrosine kinase promotes cancer cell proliferation and survival. Use of monoclonal antibodies to disrupt IGF-IR signaling has shown anti-tumor activity in a variety of cancers in vitro, in animal models, and in early-phase adult trials. In this Phase I trial, we will evaluate the toxicity profile and determine the maximum tolerated dose (MTD) of IMC-A12 administered intravenously on a once a week schedule in children and adolescents with relapsed or refractory solid tumors. Patients aged 1-21 years with refractory solid tumors will be enrolled in a standard Phase I dose escalation trial at a starting dose of 6 mg/kg. The study will include one dose escalation up to 9 mg/kg and potential dose de-escalation if IMC-A12 is not found to be tolerable in children at the 6 mg/kg dose. Due to clinical evidence of anti-tumor activity for IGF-1R inhibitors in patients with Ewing sarcoma/peripheral PNET, a separate stratum that includes patients with this diagnosis has been incorporated in this trial. Patients in the Ewing sarcoma/peripheral PNET stratum will accrue at a dose level that has been found to be tolerable in the solid tumor stratum. The pharmacokinetics of IMC-A12 in children will also be evaluated in this study. Correlative biology studies will include assessment of IGF-IR and insulin receptor (IR) expression and activation in peripheral blood mononuclear cells. Circulating levels of IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide will be measured preand post-treatment with IMC-A12. Tumor tissue, when available, will be obtained and banked for future studies. IMC-A12 will have anti-tumor activity in children with relapsed/refractory solid tumors. Primary Aims 1. To estimate the maximum tolerated dose (MTD) or recommended dose for Phase 2 evaluation of IMC-A12 administered as an IV infusion once weekly in children with relapsed/refractory solid tumors using a limited dose escalation strategy.