Clamp A R, Schöffski P, Valle J W, Wilson R H, Marreaud S, Govaerts A-S, Debois M, Lacombe D, Twelves C, Chick J, Jayson G C
Cancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK.
Cancer Chemother Pharmacol. 2008 Apr;61(4):579-85. doi: 10.1007/s00280-007-0509-5. Epub 2007 May 23.
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.
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 efficacy and toxicity.
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.
The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).
OSI-7904L是一种强效胸苷酸合成酶（TS）抑制剂的脂质体制剂。这项I期研究评估了在晚期结直肠癌患者中每21天联合使用奥沙利铂给予OSI-7904L的安全性、耐受性和药代动力学（PK）。
在预定义的剂量水平采用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指标。
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/m²，奥沙利铂130 mg/m²）下，9名患者中有1名在第1周期出现3级口腔黏膜炎的剂量限制性毒性，另有5名患者需要降低剂量。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/奥沙利铂联合方案预期的一致。PK分析显示患者间变异性高，OSI-7904L与奥沙利铂之间未检测到相互作用。两名患者记录到部分影像学反应。
进一步研究的推荐方案是OSI-7904L 9 mg/m²和奥沙利铂130 mg/m²。
