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: 7121257
• 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 2007-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121257
• 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）：尽管最近在治疗方面取得了进展，但结直肠癌是美国癌症死亡率的第三大原因，并且晚期疾病的生存率仍然极低。该项目的长期目标是研究口服表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）在结直肠癌中的临床活性和生物学效应，并开发经过验证的定量药效学测定的特定专业知识，以帮助细胞信号抑制剂的临床开发。尽管使用 EGFR 抑制剂和化疗的联合试验在其他癌症类型中呈阴性，但 EGFR 是结直肠癌的有效靶点，并且吉非替尼与 FOLFOX 联合的 II 期试验显示出令人印象深刻的 80% 缓解率。在肺癌等其他肿瘤类型中观察到的 EGFR 突变尚未在结直肠癌中观察到。这类药物显然对这种疾病有效，但最佳患者选择、对结直肠肿瘤的确切效果以及反应预测因素都是重要的未知数。 该应用程序围绕两个 IRB 批准的协议构建。具体目标 #1 是一项 I 期研究，将口服 EGFR TKI 厄洛替尼与 FOLFOX/贝伐珠单抗结合用于晚期疾病。该候选人是该试验的主要研究者，负责开发和协调生物学研究，其中包括对一部分患者治疗前和治疗后活检中的 EGFR 信号传导进行定量分析。具体目标 #2 是一项完全由候选人（联合首席研究员）撰写的 II 期试验，将吉非替尼添加到基于 5-FU 的新辅助放化疗中，用于可切除直肠癌。所有受试者将在治疗前和治疗后进行肿瘤和正常结肠活检，以评估药物的生物学效应。在这两项研究中，活检均在 EGFR 抑制剂单一疗法的“导入”期后进行，以剖析其在不进行其他治疗的情况下的效果。这两项试验的中心主题都是将EGFR抑制剂合理纳入结直肠癌的治疗中，并增加我们对EGFR抑制剂药理作用的了解。