Phase II randomized trial of CPT-11 and Mitomycin C

描述（由申请人提供）：晚期胃癌和食管癌患者的预后不良表明明显需要更有效的治疗。基于单机构试验中接近50%的缓解率，基于伊立替康-（CPT-11）顺铂的治疗获得了支持。然而，反应是短暂的，并且与该方案相关的显著毒性的高发生率。基于其他人的临床前发现，记录了丝裂霉素C（MMC）给药后CPT-11的靶酶拓扑异构酶I（Topo I）活性的上调，以及我们观察到CPT-11降低DT-心肌黄酶（NQ 0 R）水平，我们最近完成了一项联合用药的临床设计I期研究。低剂量MMC用于调节Topo I和CPT-11活性。我们证明了MMC给药后外周血单核细胞（PBMC）中Topo I基因的表达上调，在难治性实体恶性肿瘤患者（包括食管癌和胃癌患者）中具有良好的耐受性和令人鼓舞的抗肿瘤活性。在这个建议中，我们计划研究晚期和既往未经治疗的食管和胃食管交界处腺癌患者。一项两组、随机、II期试验将比较MMC和CPT-11序贯治疗的两种方案，以选择两种方案中最好的方案进行III期评价。作为NQ 01突变、拓扑异构酶I和羧酸酯酶基因表达作为MMC和CPT-11化疗耐药性预测因子的重要性的潜在人类概念验证，我们将获得肿瘤组织和PBMC样本，以评价这些基因、预后和抗肿瘤活性之间的可能关联。

DESCRIPTION (provided by applicant): The poor prognosis of patients with advanced gastric and esophageal cancer indicates an obvious need for more effective treatments. Based on a response rate approaching 50% in single institution trials, irinotecan- (CPT-11) cisplatin based therapy has been gaining support. However, responses are short lived and a high incidence of significant toxicity has been associated with this regimen. Based on the preclinical findings of others, documenting upregulation of topoisomerase I (Topo I) activity, the target enzyme for CPT-11, after administration of mitomycin C (MMC) and our observation that CPT-11 decreases the levels of DT-Diaphorase (NQ0R), we recently completed a pharmacologically designed phase I study of the combination. Low doses of MMC were used to modulate Topo I and CPT-11 activity. We demonstrated upregulation of expression of the Topo I gene in peripheral blood mononuclear cells (PBMC) after MMC administration, good tolerability and encouraging antitumor activity in patients with refractory solid malignancies that included patients with esophageal and stomach cancer. In this proposal, we plan to study advanced- and previously-untreated patients with esophageal and GE junction adenocarcinomas. A two arm, randomized, phase II trial will compare two schedules of sequential MMC and CPT-11 to pick the best of the two schedules for phase III evaluation. As a potential proof-of-concept in humans of the importance of NQ01 mutations, topoisomerase I and carboxylesterase gene expression, as predictors of chemoresistance to MMC and CPT-11, we will obtain tumor tissue and PBMC samples in order to evaluate possible associations between these genes, prognosis and antitumor activity.