A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer
A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer
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DOI：
10.1007/s00280-007-0509-5
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发表时间：
2008-04-01
影响因子：
3
通讯作者：
Jayson, G. C.
中科院分区：
文献类型：
--
作者：
Clamp, A. R.;Schoeffski, P.;Jayson, G. C.
用途 OSI-7904L 是一种有效的胸苷酸合酶 (TS) 抑制剂的脂质体制剂。这项 I 期研究评估了晚期结直肠癌患者每 21 天与奥沙利铂联合给药的 OSI-7904L 的安全性、耐受性和药代动力学 (PK)。方法 在预定剂量水平下采用 3+3 研究设计。研究了 TS 增强子区域和 XPD 酶的多态性作为疗效和毒性的潜在预测因子。结果 14 名患者接受了 76 个周期的治疗。在研究的最高剂量水平（OSI-7904L 9 mg/m(2)，奥沙利铂 130 mg/m(2)）下，九名患者中的一名在第 1 周期出现了 3 级口腔粘膜炎的剂量限制性毒性，另外 5 名患者需要减少剂量。口腔炎、腹泻、恶心、疲劳、感觉神经病变和皮疹的毒性特征与 TS 抑制剂/奥沙利铂联合方案的预期一致。 PK 分析显示患者间差异较大，OSI-7904L 和奥沙利铂之间未检测到相互作用。两名患者记录了部分放射学反应。结论 进一步研究的推荐方案是 OSI-7904L 9 mg/m(2) 和奥沙利铂 130 mg/m(2)。
Purpose OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK)of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.Method A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of effcacy and toxicity.Results Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.Conclusions The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).