Pharmacogenomics of Neoadjuvant Gemcitabine-Pemetrexed

新辅助吉西他滨-培美曲塞的药物基因组学

• 批准号: 6938729
• 负责人: GEROLD BEPLER
• 金额: $ 29.38万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938729
• 关键词: antineoplastics; biopsy; clinical research; clinical trial phase II; combination chemotherapy; dihydrofolate reductase; drug metabolism; enzyme induction /repression; gemcitabine; gene expression; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; nonsmall cell lung cancer; patient oriented research; pharmacogenetics; prognosis; ribonucleotide reductase; tumor suppressor proteins

DESCRIPTION (provided by applicant): The administration of chemotherapy at the earliest time (neoadjuvant or induction chemotherapy) following diagnosis in an effort to reduce the risk of disease recurrence in patients with non-small cell lung cancer (NSCLC) is under investigation at multiple institutions in the U.S., Europe, and Japan. This approach has resulted in radiographic response rates of 56-70% with complete remission rates of 1-8% and partial remission rates of 55-64% in patients with stage IB-IIIA with 2-3 cycles of platinum plus gemcitabine, paclitaxel, or docetaxel. Patients with pathologically proven N2 disease prior to chemotherapy had negative N2 nodes on resection in 50% of cases. A complete pathologic remission has been documented in 6-16% of patients (95% Cl, 0-23%). Disease progression during treatment has been observed in 2-10% of patients, and a complete surgical resection was achieved in 70-92% of patients. It is important to devise less toxic, yet efficacious regimens that are well tolerated and can be given expeditiously so as to allow surgery to be done in a timely fashion. Neoadjuvant therapy allows for investigations of molecular parameters that may affect response to chemotherapy and patients' survival. It is our hypothesis that the expression of genes associated with activation, inactivation, and efficacy of the drugs gemcitabine and pemetrexed will predict response to therapy and prognosis. We further hypothesize that the expression of these genes will be altered during chemotherapy. We propose a phase II study of neoadjuvant chemotherapy with gemcitabine and pemetrexed in patients with resectable NSCLC, specifically correlating molecular parameters to the primary clinical study endpoint disease response (radiographic CR+PR) and the secondary endpoints complete pathological response at surgery, disease-free survival, and overall survival.

描述（由申请人提供）：美国、欧洲和日本的多个机构正在研究诊断后尽早给予化疗（新辅助或诱导化疗），以降低非小细胞肺癌 (NSCLC) 患者疾病复发的风险。这种方法使 IB-IIIA 期患者接受 2-3 个周期的铂加吉西他滨、紫杉醇或多西他赛治疗后，放射学缓解率为 56-70%，完全缓解率为 1-8%，部分缓解率为 55-64%。化疗前经病理证实患有 N2 疾病的患者中，50% 的病例在切除时 N2 淋巴结呈阴性。据记录，6-16% 的患者出现完全病理缓解（95% Cl，0-23%）。 2-10% 的患者在治疗期间观察到疾病进展，70-92% 的患者实现了完全手术切除。重要的是要设计出毒性较小、有效、耐受性良好且可以迅速给予的治疗方案，以便及时进行手术。新辅助治疗可以研究可能影响化疗反应和患者生存的分子参数。我们的假设是，与药物吉西他滨和培美曲塞的激活、失活和功效相关的基因的表达将预测对治疗的反应和预后。我们进一步假设这些基因的表达在化疗过程中会发生改变。我们提出了一项针对可切除 NSCLC 患者使用吉西他滨和培美曲塞进行新辅助化疗的 II 期研究，特别将分子参数与主要临床研究终点疾病反应（放射学 CR+PR）以及次要终点手术时的完整病理反应、无病生存期和总生存期相关联。