Phase II randomized trial of CPT-11 and Mitomycin C

描述(申请人提供)：进展期胃癌和食道癌患者预后较差，表明明显需要更有效的治疗。基于单机构试验中接近50%的有效率，伊立替康(CPT-11)顺铂治疗已获得支持。然而，这种方案的反应是短暂的，而且严重毒性的发生率很高。根据其他人的临床前发现，在给予丝裂霉素C(MMC)后，CPT-11的靶酶拓扑异构酶I(Topo I)活性上调，以及我们观察到CPT-11降低了DT-黄递酶(NQ0R)的水平，我们最近完成了该组合的药物设计的I期研究。用小剂量MMC调节Topo I和CPT-11活性。我们证明了MMC给药后，外周血单个核细胞(PBMC)Topo I基因表达上调，耐受性良好，对包括食道癌和胃癌在内的难治性实体肿瘤患者具有良好的抗肿瘤活性。在这项提案中，我们计划研究晚期和以前未经治疗的食管腺癌和GE交界腺癌患者。一项双臂随机II期试验将比较MMC和CPT-11的两个序贯方案，以选择两个方案中最好的一个进行III期评估。作为NQ01突变、拓扑异构酶I和羧酸酯酶基因表达作为预测MMC和CPT-11化疗耐药性的预测因子在人类中的潜在概念验证，我们将获得肿瘤组织和PBMC样本，以评估这些基因、预后和抗肿瘤活性之间的可能联系。

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.