Pharmacogenomics of Neoadjuvant Gemcitabine-Pemetrexed *

描述(申请人提供)：美国、欧洲和日本的多家机构正在研究在确诊后尽早实施化疗(新辅助化疗或诱导化疗)，以努力降低非小细胞肺癌(NSCLC)患者的疾病复发风险。在IB-IIIA期铂联合吉西他滨、紫杉醇或多西紫杉醇治疗2-3周期的IB-IIIA患者中，放射学有效率为56-70%，完全缓解率为1-8%，部分缓解率为55-%。在化疗前经病理证实的N2病患者中，50%的病例切除时N2结节为阴性。6-16%的患者(95%的CL，0-23%)有完全病理缓解的记录。在治疗过程中观察到2-10%的患者病情进展，70%-92%的患者实现了完全手术切除。重要的是设计出毒性较小但有效的方案，这些方案耐受性好，可以迅速给药，以便及时进行手术。新辅助治疗允许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、失活和疗效相关的基因的表达将预测治疗反应和预后。我们进一步假设，这些基因的表达在化疗期间会发生变化。我们建议在可切除的NSCLC患者中使用吉西他滨和培美曲塞进行新辅助化疗的II期研究，特别是将分子参数与主要临床研究终点疾病反应(放射学CR+PR)和次要终点手术时完全病理反应、无瘤生存期和总生存期相关联。

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.