A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours.
A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours.
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DOI：
10.1038/sj.bjc.6604300
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发表时间：
2008-04-22
影响因子：
8.8
通讯作者：
Schellens, J. H. M.
中科院分区：
文献类型：
--
作者：
Siegel-Lakhai, W. S.;Zandvliet, A. S.;Huitema, A. D. R.;Tibben, M. M.;Milano, G.;Girre, V.;Dieras, V.;King, A.;Richmond, E.;Wanders, J.;Beijnen, J. H.;Schellens, J. H. M.
这项剂量递增研究旨在确定多靶点细胞周期抑制剂 indisulam 与卡培他滨联合治疗实体瘤患者的推荐剂量，并评估联合用药的药代动力学。 35 名患者在每个 21 天周期的第一天接受胰岛素治疗。卡培他滨在第 1-14 天每天给药两次 (BID)。测定印地磺草胺、卡培他滨及其三种代谢物的血浆浓度以进行药代动力学分析。主要的剂量限制性毒性是骨髓抑制。手足综合征和口腔炎是主要的非血液学毒性。推荐剂量最初确定为吲地舒仑 700mgm−2 和卡培他滨 1250mgm−2 BID。然而，在第 2 周期期间，三名患者对推荐剂量的耐受性较差。在另外 9 名患者中，在第 1 和第 2 周期中，服用 500 mg m−2 的印地舒仑和 1250 mg m−2 卡培他滨 BID 的剂量被证明是安全的。第 1 周期期间的 Indisulam 药代动力学与 I 期单药治疗研究的药代动力学数据一致。然而，由于卡培他滨和印地磺草之间的药物相互作用，第 2 周期时印地磺拉姆的暴露量显着增加。两名患者得到部分缓解，一名患有结肠癌，另一名患有胰腺癌。十七名患者病情稳定。 Indisulam (700mgm−2) 与卡培他滨 (1250mgm−2 BID) 联合使用在第一个周期中具有良好的耐受性。在多个治疗周期中，吲地磺草胺 500mgm−2 和卡培他滨 1250mgm−2 BID 的剂量被认为是安全的。第 2 周期期间观察到的较高毒性发生率可以通过时间依赖性药代动力学药物相互作用来解释。
This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m−2 and capecitabine 1250 mg m−2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m−2) in combination with capecitabine (1250 mg m−2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction.
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