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

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。 这是IMC-A12(免疫克隆系统)的I期研究，IMC-A12是一种重组人胰岛素样生长因子-I受体(IGF-IR)单抗，用于复发/难治性实体肿瘤的儿科患者。胰岛素样生长因子(IGF)系统在许多类型癌症的发生和发展中起着关键作用，包括许多儿科特有的癌症。IGF-I和IGF-II配体通过IGF-IR跨膜酪氨酸激酶信号通路促进癌细胞的增殖和存活。 在体外、动物模型和成人早期试验中，使用单抗干扰IGF-IR信号已在多种癌症中显示出抗肿瘤活性。在这项I期试验中，我们将评估毒性情况并确定IMC-A12每周一次静脉注射对患有复发或难治性实体肿瘤的儿童和青少年的最大耐受量(MTD)。1-21岁的难治性实体肿瘤患者将参加标准的I期剂量递增试验，起始剂量为6毫克/公斤。这项研究将包括将一剂疫苗增加到9剂 如果发现IMC-A12在6 mg/kg剂量下对儿童不能耐受，则可能会降低剂量。 由于临床证据表明IGF-1R抑制剂在尤文肉瘤/外周PNET患者中具有抗肿瘤活性，因此该试验纳入了一个包括该诊断患者的单独分层。尤文肉瘤/外周PNET层的患者将以实体肿瘤层中已被发现可耐受的剂量水平累积。 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IGF-IR和胰岛素受体(IR)在外周血单核细胞中的表达和激活。治疗前和治疗前将测定循环中的IGF-I、IGF-II、IGF-BP3、生长激素、胰岛素和C-肽水平。 用IMC-A12进行后处理。当肿瘤组织可用时，将被获取并储存起来，以供未来研究。 IMC-A12将对复发/难治性实体瘤的儿童具有抗肿瘤活性。 主要目标 1.采用有限剂量递增策略评估IMC-A12静脉滴注治疗儿童复发/难治性实体肿瘤的最大耐受量(MTD)或推荐剂量。

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.