Evaluation of Oral EGFR Inhibitors in Colorectal Cancer

口服 EGFR 抑制剂治疗结直肠癌的评价

• 批准号: 6955416
• 负责人: WELLS A Messersmith
• 金额: $ 14.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955416
• 关键词: antineoplastics; biopsy; clinical research; clinical trial phase I; clinical trial phase II; colorectal neoplasms; combination cancer therapy; cytochrome P450; drug screening /evaluation; epidermal growth factor; fluorouracil; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; kinase inhibitor; leucovorin; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplasm /cancer radiation therapy; oral administration; patient oriented research; pharmacokinetics; phosphatidylinositol 3 kinase; positron emission tomography; receptor expression

DESCRIPTION (provided by applicant): Despite recent advances in treatment, colorectal cancer is the third leading cause of cancer mortality in the US, and survival for advanced disease remains extremely low. The long-term objectives of this project are to investigate the clinical activity and biologic effects of oral Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKI) in colorectal cancer, and to develop a specific expertise in validated, quantitative pharmacodynamic assays to aid in the clinical development of cell signaling inhibitors. Although combination trials using EGFR inhibitors and chemotherapy were negative in other cancer types, EGFR is validated target in colorectal cancer, and a phase II trial combining gefitinib with FOLFOX has shown an impressive 80% response rate. EGFR mutations seen in other tumor types such as lung cancer have not been seen in colorectal cancer. This class of agents is clearly active in this disease, but optimal patient selection, the exact effects on colorectal tumors, and predictors of response are all significant unknowns. This application is structured around two IRB-approved protocols. Specific Aim #1 is a phase I study combining the oral EGFR TKI erlotinib with FOLFOX/bevacizumab in the advanced disease setting. The candidate is the principal investigator of the trial, and developed and coordinated biologic studies which include quantitative analysis of EGFR signaling in pre- and post-treatment biopsies in a subset of patients. Specific Aim #2 is a phase II trial written entirely by candidate (co-Principal Investigator) adding gefitinib to neoadjuvant 5-FU based chemoradiation for resectable rectal cancer. All subjects will have pre- and post-treatment tumor and normal colon biopsies to evaluate the biologic effects of the drugs. In both studies, biopsies occur after a "lead-in" period of monotherapy with the EGFR inhibitors to dissect their effects without other treatment. The central theme of both trials is to rationally incorporate EGFR inhibitors into the treatment of colorectal cancer as well as to increase our understanding of EGFR inhibitor pharmacological actions.

描述（由申请人提供）：尽管治疗最近进展，但结直肠癌是美国癌症死亡率的第三主要原因，而晚期疾病的生存仍然极低。该项目的长期目标是研究结直肠癌中口服表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的临床活性和生物学作用，并在经过验证的，定量的药物学测定方面开发了特定的专业知识，以帮助有助于细胞信号抑制剂的临床发育。尽管使用EGFR抑制剂和化学疗法的联合试验在其他癌症类型中为阴性，但EGFR在结直肠癌中得到了验证，并且将Gefitinib与FOLFOX相结合的II期试验显示出令人印象深刻的80％反应率。在大肠癌中尚未看到其他肿瘤类型（例如肺癌）中看到的EGFR突变。这种类药物在该疾病中显然是活跃的，但是最佳的患者选择，对结直肠肿瘤的确切影响以及反应的预测因素都是重要的未知因素。 该应用程序围绕两个IRB批准的协议进行结构。具体目的＃1是一项I期研究，将口服EGFR TKI Erlotinib与FOLFOX/BEVACIZUMAB结合在晚期疾病环境中。候选人是该试验的主要研究者，并开发和协调的生物学研究包括对EGFR信号的定量分析，其中一部分患者的治疗前和治疗后活检中的EGFR信号传导。具体目标＃2是一项完全由候选人（联合主管研究者）撰写的II期试验，将吉非替尼添加到新辅助5-FU的基于5-FU的化学放疗中，用于可切除的直肠癌。所有受试者将具有治疗前和治疗后的肿瘤和正常结肠活检，以评估药物的生物学作用。在这两项研究中，活检在与EGFR抑制剂单一疗法的“铅中”期间发生后，在没有其他治疗的情况下剖析其作用。两种试验的中心主题是合理地将EGFR抑制剂纳入结直肠癌的治疗中，并增强我们对EGFR抑制剂药理作用的理解。