A randomized phase II study of erlotinib with or without the anti-IGF-1R monoclon

厄洛替尼联合或不联合抗 IGF-1R 单克隆抗体的随机 II 期研究

基本信息

批准号：
7683939
负责人：
David Ross Camidge
金额：
$ 34.84万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683939
关键词：
Adenosine Triphosphate Adult Adverse event Aftercare Archives Binding Biological Biological Markers Blood specimen Cancer Etiology Cancer Patient Cause of Death Cell surface Cessation of life Chemotherapy-Oncologic Procedure Clinical Clinical Research Clinical Trials Code Communication Cross-Over Studies Data Dependence Diagnosis Digit structure Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Ensure Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Equilibrium Erlotinib Failure Family Fluorescent in Situ Hybridization Formalin Funding Future Gene Dosage Gene Mutation Genes Genetic Genetic Crossing Over Genetic Polymorphism Goals Grant Histologic Homo Human Human Resources IGF Type 2 Receptor IGF1R gene IgG1 Immunohistochemistry In Vitro Inherited Insulin Receptor Insulin-Like Growth Factor I Insulin-Like Growth Factor II Insulin-Like Growth-Factor Binding Protein 1 Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Integration Host Factors Letters Licensing Ligands Liver MET gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Molecular Monoclonal Antibodies Muscle Mutation Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Outcome Paraffin Embedding Pathway interactions Patients Pemetrexed Pharmaceutical Preparations Phase Phase II Clinical Trials Phase III Clinical Trials Phosphorylation Platinum Play Population Progression-Free Survivals Protein Tyrosine Kinase Proteins Protocols documentation Randomized Receptor Inhibition Receptor Signaling Recurrence Resistance Role Safety Serum Signal Transduction Site Skin Somatropin Specimen Staging Survival Rate Symptoms System Target Populations Testing Therapeutic Time Tissues Toxic effect Treatment Protocols Treatment outcome Tumor Tissue Tumor-Derived Tyrosine Kinase Inhibitor United States Upper arm Woman advanced disease base bone c-erbB-1 Proto-Oncogenes cell type chemotherapy dimer docetaxel improved in vivo member men novel palliation prevent prospective public health relevance receptor expression resistance mechanism response standard of care tumor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death worldwide. In the USA, nearly 200,000 men and women are diagnosed with lung cancer every year and approximately 80% of them will die from the disease. More effective, and better tolerated, treatment regimens are needed. Histologically, approximately 85% of lung cancers are non-small cell lung cancer (NSCLC). Novel therapies targeting the epidermal growth factor receptor (EGFR) have recently shown a significant survival benefit in patients with advanced NSCLC, although only a relatively small percentage of patients manifest objective responses. Based on retrospective analyses it has already been shown that EGFR gene copy number and EGFR and ras mutations can usefully differentiate patients that are more/less likely to respond to EGFR inhibition. Multiple prospective trials are now in progress to verify these as pre-selection factors. Pre-clinically, the EGFR pathway has been shown to have extensive crosstalk with the insulin-like growth factor-1 receptor (IGF-1R) pathway and IGF-1R may play an important role in resistance mechanisms to EGFR-targeted agents, such as erlotinib. IMC-A12 is a fully human IgG1/? monoclonal antibody directed against the IGF-1R. This grant hypothesizes that the combination of IGF-1R blockade with IMC-A12 and anti-EGFR therapy with erlotinib will demonstrate greater activity in NSCLC patients than either agent alone and that combined inhibition may reverse mechanisms of resistance to anti-EGFR therapy. This grant also hypothesizes that biomarkers, such as gene copy number, that relate to both the EGFR and IGF-1R pathways may predict those most likely to benefit from the combination. The goal of this grant is to complete a randomized phase II clinical study of erlotinib with or without IMC-A12 in patients with advanced NSCLC, to confirm that the combination will be clinically tolerable and to assess whether the combination will demonstrate evidence of improved anti-tumor effects compared to erlotinib alone in the target population. Blood specimens and archived tumor specimens will be collected for analysis of suspected biomarkers of clinical benefit/treatment resistance. Additional blood specimens from the patients will be collected to explore aspects of drug-drug pharmacokinetic interactions between IMC-A12 and erlotinib, and inherited germline effects on outcomes relating to clinical activity, toxicity and erlotinib exposures. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death worldwide, and it has been the most common cause of death from malignancy in the USA in men since the mid-1950s and in women since the mid-1980s. Although recent advances in targeting treatment to key molecules that may drive lung cancer have improved the outlook for some patients, treatment resistance remains a major problem. This project is a clinical trial in patients and will test a rational combination of two novel targeted agents to overcome some of this treatment resistance in lung cancer (the new drugs target the communication that goes on between the EGFR and IGF-1R molecular pathways) and sets out to explore the factors that may predict those who will gain the most benefit from this combination in the future.

描述（由申请人提供）：肺癌是全世界癌症死亡的主要原因。在美国，每年有近 200,000 名男性和女性被诊断患有肺癌，其中约 80% 将死于该疾病。需要更有效、更好耐受的治疗方案。从组织学角度来看，大约 85% 的肺癌是非小细胞肺癌 (NSCLC)。最近，针对表皮生长因子受体 (EGFR) 的新疗法显示出晚期 NSCLC 患者显着的生存获益，尽管只有相对较小比例的患者表现出客观反应。基于回顾性分析，已经表明 EGFR 基因拷贝数以及 EGFR 和 ras 突变可以有效地区分对 EGFR 抑制更有反应/不太可能反应的患者。目前正在进行多项前瞻性试验，以验证这些作为预选因素。临床前，EGFR 通路已被证明与胰岛素样生长因子 1 受体 (IGF-1R) 通路有广泛的串扰，IGF-1R 可能在 EGFR 靶向药物的耐药机制中发挥重要作用，例如厄洛替尼。 IMC-A12 是完全人源 IgG1/?针对 IGF-1R 的单克隆抗体。这项拨款假设，IGF-1R 阻断与 IMC-A12 联合抗 EGFR 治疗与厄洛替尼在 NSCLC 患者中将表现出比单独使用任一药物更大的活性，并且联合抑制可能逆转抗 EGFR 治疗的耐药机制。该资助还假设与 EGFR 和 IGF-1R 通路相关的生物标志物（例如基因拷贝数）可以预测那些最有可能从该组合中受益的人。这笔拨款的目标是完成一项厄洛替尼联合或不联合 IMC-A12 在晚期 NSCLC 患者中的随机 II 期临床研究，以确认该组合具有临床耐受性，并评估该组合是否能证明该组合能改善抗肿瘤效果。与单独使用厄洛替尼相比，在目标人群中的肿瘤效果。将收集血液样本和存档的肿瘤样本，用于分析临床获益/治疗耐药性的可疑生物标志物。将收集患者的额外血液样本，以探索 IMC-A12 和厄洛替尼之间的药物-药物药代动力学相互作用的各个方面，以及遗传种系对与临床活性、毒性和厄洛替尼暴露相关的结果的影响。公共卫生相关性：肺癌是全球癌症死亡的主要原因，自 20 世纪 50 年代中期以来，肺癌一直是美国男性和 20 世纪 80 年代中期以来女性最常见的恶性肿瘤死亡原因。尽管针对可能导致肺癌的关键分子的靶向治疗的最新进展改善了一些患者的前景，但治疗耐药性仍然是一个主要问题。该项目是一项针对患者的临床试验，将测试两种新型靶向药物的合理组合，以克服肺癌的一些治疗耐药性（新药针对 EGFR 和 IGF-1R 分子途径之间的通讯），以及着手探索可能预测哪些人未来将从这种组合中获得最大利益的因素。