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

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因。在美国，每年有近20万男性和女性被诊断患有肺癌，其中约80%将死于这种疾病。需要更有效和更好耐受的治疗方案。在组织学上，大约85%的肺癌是非小细胞肺癌（NSCLC）。靶向表皮生长因子受体（EGFR）的新型疗法最近显示出对晚期NSCLC患者的显著生存获益，尽管只有相对较小比例的患者表现出客观缓解。基于回顾性分析，已经表明EGFR基因拷贝数和EGFR和ras突变可以有效区分对EGFR抑制有反应的患者。目前正在进行多项前瞻性试验，以验证这些预选因素。临床前，EGFR途径已被证明与胰岛素样生长因子-1受体（IGF-1 R）途径存在广泛的串扰，IGF-1 R可能在EGFR靶向药物（如厄洛替尼）的耐药机制中发挥重要作用。IMC-A12是一个完全人IgG 1/？针对IGF-1 R的单克隆抗体。该研究假设，IGF-1 R阻断剂与IMC-A12联合抗EGFR治疗与厄洛替尼联合使用，在NSCLC患者中的活性将高于单独使用任何一种药物，联合抑制可能逆转抗EGFR治疗的耐药机制。这项研究还假设，与EGFR和IGF-1 R通路相关的生物标志物（如基因拷贝数）可能预测最有可能从联合治疗中获益的患者。本基金的目的是完成厄洛替尼联合或不联合IMC-A12治疗晚期NSCLC患者的随机II期临床研究，以确认该联合用药在临床上可耐受，并评估该联合用药在目标人群中与厄洛替尼单药相比是否能显示出抗肿瘤效果改善的证据。将采集血液标本和存档肿瘤标本，用于分析临床获益/治疗耐药性的疑似生物标志物。将采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方面，以及对临床活性、毒性和厄洛替尼暴露相关结局的遗传生殖系效应。公共卫生相关性：肺癌是全世界癌症死亡的主要原因，并且自20世纪50年代中期以来在美国男性和自20世纪80年代中期以来在女性中，肺癌一直是恶性肿瘤死亡的最常见原因。尽管最近在靶向治疗可能导致肺癌的关键分子方面取得了进展，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。该项目是一项在患者中进行的临床试验，将测试两种新型靶向药物的合理组合，以克服肺癌中的一些治疗耐药性（新药靶向EGFR和IGF-1 R分子通路之间的通信），并着手探索可能预测未来将从这种组合中获得最大益处的因素。

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.