Furman Wayne L, Navid Fariba, Daw Najat C, McCarville M Beth, McGregor Lisa M, Spunt Sheri L, Rodriguez-Galindo Carlos, Panetta John C, Crews Kristine R, Wu Jianrong, Gajjar Amar J, Houghton Peter J, Santana Victor M, Stewart Clinton F
Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-3678, USA.
J Clin Oncol. 2009 Sep 20;27(27):4599-604. doi: 10.1200/JCO.2008.19.6642. Epub 2009 Aug 17.
To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan.
IV irinotecan (15 or 20 mg/m(2)) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m(2)) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis.
The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m(2)/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m(2)/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma.
IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.
评估表皮生长因子受体抑制剂吉非替尼与静脉注射伊立替康联合应用于难治性实体瘤患儿时的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。评估吉非替尼对静脉注射伊立替康药代动力学及单次口服伊立替康生物利用度的影响。
静脉注射伊立替康（15或20mg/m²），连续2周，每日1次，共5天。口服吉非替尼（150或112.5mg/m²），每日1次，共12或21天。在第2疗程的第9天给予单次口服伊立替康，以便进行药代动力学分析。
该研究纳入了29例复发性实体瘤患者。吉非替尼与伊立替康联合应用的21天方案不耐受。腹泻是最常见的DLT。联合方案的MTD为连续2周、每日1次静脉注射伊立替康15mg/m²共5天，以及口服吉非替尼112.5mg/m²共12天。与历史对照相比，吉非替尼使口服伊立替康的生物利用度提高了4倍（中位数，0.09对0.42；P<.000001），使伊立替康和SN-38的表观清除率（暴露的反向指标）分别降低了37%和38%（P<.0001）。1例难治性尤因肉瘤患者出现部分缓解。
静脉注射伊立替康与口服吉非替尼联合应用12天在儿童中耐受性良好。我们观察到1例部分缓解。吉非替尼显著提高了口服伊立替康的生物利用度。该联合方案值得进一步研究，特别是与口服伊立替康联合应用时。
