Phase I and pharmacokientic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours
Phase I and pharmacokientic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours
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DOI：
10.1093/annonc/mdg174
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发表时间：
2003-04-01
影响因子：
50.5
通讯作者：
Marty, A
中科院分区：
文献类型：
--
作者：
Bennouna, J;Fumoleau, P;Marty, A
背景：长春氟宁是一种新型长春花生物碱，采用超酸性化学半合成方法在长春瑞滨的20'位选择性引入两个氟原子而获得。在人类肿瘤异种移植物中，长春氟宁在测试的 11 个肿瘤中的 7 个中显示出明确的抗肿瘤活性，而长春瑞滨在 11 个肿瘤中的 3 个中显示出明确的抗肿瘤活性。 患者和方法：在这项 I 期研究中，长春氟宁以 10 分钟静脉注射的方式给予 31 名晚期恶性肿瘤患者。每 3 周输注一次，剂量在 30 至 400 mg/m2 之间递增。结果：对药代动力学参数和毒性进行了评估，在 400 mg/m2 剂量下，五分之三的患者出现了剂量限制性毒性。在最大耐受剂量（MTD），即400 mg/m(2)下，长春氟宁的毒性特征主要包括粘膜炎。便秘和短期中性粒细胞减少症。长春氟宁曲线下面积随着给药剂量的增加而增加，但没有观察到消除饱和。结论：长春氟宁的 MTD 在每 3 周 400 mg/m2 时达到。根据方案规则，推荐剂量确定为 350 mg/m2。对早期 II 期试验中纳入的第一批患者进行初步评估后，将推荐剂量降低至每 3 周 320 mg/m2，以进一步开发长春氟宁。三种部分反应（两种在乳腺癌中，一种在肾细胞癌中）表明，在预处理程度较低的患者群体中可能会看到活性。
Background: Vinflunine is a novel vinca alkaloid obtained by semi-synthesis using super-acidic chemistry to selectively introduce two fluorine atoms at the 20' position of vinorelbine. In human tumour xenografts, vinflunine showed definite antitumour activity in seven out of 11 tumours tested compared with three out of 11 for vinorelbine.Patients and methods: In this phase I study, vinflunine was administered to 31 patients with advanced malignancies as a 10-min i.v. infusion every 3 weeks according to an escalating schedule of doses between 30 and 400 mg/m(2).Results: Pharmacokinetic parameters and toxicities were assessed and, at 400 mg/m2, three out of five patients experienced dose-limiting toxicity. At the maximum tolerated dose (MTD), i.e. 400 mg/m(2), the toxicity profile of vinflunine consisted mainly of mucositis. constipation and neutropenia of short duration. Vinflunine area under the curve increased as a proportion of the administered dose whereas no saturation of elimination was observed.Conclusion: The MTD of vinflunine was achieved at 400 mg/m2 every 3 weeks. According to protocol rules, the recommended dose was established at 350 mg/m(2), A preliminary assessment of first patients included in early phase II trials led to reduction of the recommended dose to 320 mg/m2 every 3 weeks for further development of vinflunine. Three partial responses (two in breast carcinoma. one in renal cell carcinoma) suggest that activity is likely to be seen in less heavily pretreated patient populations.