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

临床试验：H-22658 - ADVL0712 - IMC-A12 抗 IGF-I 的 I 期研究

• 批准号: 7950665
• 负责人: PATRICK THOMPSON
• 金额: $ 1.84万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950665
• 关键词: Adolescent; Adult; Aftercare; Animal Model; Biological Markers; Biology; C-Peptide; Cell Proliferation; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diagnosis; Dose; Dose-Limiting; Drug Kinetics; Enrollment; Evaluation; Ewings sarcoma; Ewings sarcoma-primitive neuroectodermal tumor; Funding; Future; Grant; Growth; In Vitro; Institution; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Intravenous infusion procedures; Ligands; Lymphocyte; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Monoclonal Antibodies; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Play; Protein Tyrosine Kinase; Proteins; Receptor Activation; Receptor Signaling; Recombinants; Recurrence; Refractory; Relapse; Research; Research Personnel; Resources; Role; Schedule; Signal Transduction; Solid Neoplasm; Somatomedins; Somatotropin; Source; Specificity; System; Toxic effect; Tumor Tissue; United States National Institutes of Health; aged; blood glucose regulation; cancer cell; cancer type; human monoclonal antibodies; inhibitor/antagonist; receptor expression; tumor

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. I. HYPOTHESIS IMC-A12 will have anti-tumor activity in children with relapsed/refractory solid tumors. II. SPECIFIC AIMS 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. 2. To define and describe the toxicities of IMC-A12 in children with relapsed/refractory solid tumors. 3. To characterize the pharmacokinetics of IMC-A12 in children with relapsed/refractory solid tumors. Secondary Aims 1. To preliminarily define the antitumor activity of IMC-A12 in children with relapsed/refractory solid tumors within the confines of a Phase 1 study. 2. To obtain initial Phase 2 efficacy data on the antitumor activity of IMC-A12 in children with Ewing sarcoma/peripheral PNET. 3. To examine change in IGF-IR and insulin receptor (IR) levels and IGF-IR and IR activation in lymphocytes as biomarkers of IMC-A12 action and specificity. 4. To evaluate the effect of IMC-A12 on circulating levels of proteins involved in linear growth and glucose homeostasis, including IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide. 5. To develop exploratory data concerning biomarkers of activity.

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一项IMC-A12（Imclone Systems）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）的单克隆抗体，在儿科复发性/难治性实体瘤患者。胰岛素样生长因子（IGF）系统在许多类型的癌症（包括许多儿科特异性癌症）的发展和进展中起着关键作用。通过IGF-IR跨膜酪氨酸激酶的IGF-I和IGF-II配体信号传导促进癌细胞增殖和存活。 使用单克隆抗体来破坏IGF-IR信号传导已经在体外、动物模型和早期成人试验中显示出在多种癌症中的抗肿瘤活性。在这项I期试验中，我们将评估毒性特征，并确定每周一次在患有复发性或难治性实体瘤的儿童和青少年中静脉内施用IMC-A12的最大耐受剂量（MTD）。1-21岁的难治性实体瘤患者将入组标准I期剂量递增研究 试验的起始剂量为6 mg/kg。该研究将包括一次剂量递增至9 mg/kg，如果发现IMC-A12在6 mg/kg剂量下在儿童中不可耐受，则可能降低剂量。 由于IGF-1 R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，本试验中纳入了包括该诊断患者的单独分层。尤文肉瘤/外周PNET分层中的患者将在实体瘤分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）的表达和活化。将在IMC-A12治疗前后测量IGF-I、IGF-II、IGF-BP 3、生长激素、胰岛素和C肽的循环水平。将获得肿瘤组织（如可用）并储存用于未来研究。 I.假设 IMC-A12将在患有复发性/难治性实体瘤的儿童中具有抗肿瘤活性。 二.具体目标 主要目标 1.采用有限剂量递增策略，估计IMC-A12每周一次IV输注治疗复发性/难治性实体瘤儿童的2期评价的最大耐受剂量（MTD）或推荐剂量。 2.定义和描述IMC-A12在儿童复发/难治性实体瘤中的毒性。 3.描述IMC-A12在复发性/难治性实体瘤儿童中的药代动力学特征。 次要目的 1.初步确定IMC-A12在儿童肿瘤中的抗肿瘤活性， 复发性/难治性实体瘤，在1期研究范围内。 2.获得IMC-A12在尤文肉瘤/外周PNET儿童中抗肿瘤活性的初始II期疗效数据。 3.检查淋巴细胞中IGF-IR和胰岛素受体（IR）水平的变化以及IGF-IR和IR活化作为IMC-A12作用和特异性的生物标志物。 4.评价IMC-A12对参与线性生长和葡萄糖稳态的蛋白质（包括IGF-I、IGF-II、IGF-BP 3、生长激素、胰岛素和C肽）循环水平的影响。 5.开发关于活性生物标志物的探索性数据。