The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.

中文翻译：

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普拉曲沙联合奥沙利铂治疗晚期食管胃癌：具有预测性分子相关性的 II 期试验

我们研究的目的是评估普拉曲沙联合奥沙利铂治疗晚期食管胃癌 (EGC) 的疗效，分析叶酸代谢途径基因多态性对普拉曲沙毒性和疗效的影响，并评估肿瘤上皮的 microRNA 谱。作为预测性生物标志物。这是一项两阶段试验，队列安全性领先，主要终点为总体反应率 (ORR)。患者每两周接受一次静脉注射奥沙利铂 (85 mg/m2) 和普拉曲沙（剂量水平 1 [D1]，120 mg/m2；剂量水平 1 [D-1] 100 mg/m2）。在种系 DNA 中评估了编码参与普拉曲沙代谢的蛋白质的基因中的单核苷酸多态性 (SNP)。对肿瘤上皮进行微RNA分析。ORR 为 26%。在 D1 时在 4 名患者中的 2 名中观察到剂量限制性毒性，在 D-1 时未观察到。DHFR rs11951910 中的 T>C 多态性与较低的无进展生存期显着相关（PFS；P ≤ 0.01），而 SLC19A1 rs2838957 G>A 多态性的存在与改善的 PFS 相关（P = 0.02）。GGH rs3780130 A>T 和 SLC19A1 rs1051266 G>A 多态性的存在与更好的总生存率显着相关（OS；P = 0.01），而 GGH rs7010484 T>C 多态性与 OS 降低显着相关（P = 0.04）。上皮微RNA表达谱与疾病进展或反应之间没有相关性。我们得出结论，奥沙利铂和普拉曲沙的组合是安全的，耐受性良好，并且在晚期 EGC 中具有中等疗效。