Phase 1 Study of Oxaliplatin and Irinotecan in Pediatric Patients With Refractory Solid Tumors
Phase 1 Study of Oxaliplatin and Irinotecan in Pediatric Patients With Refractory Solid Tumors
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DOI：
10.1002/cncr.24175
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发表时间：
2009-04-15
期刊：
影响因子：
6.2
通讯作者：
Blaney, Susan M.
中科院分区：
文献类型：
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作者：
McGregor, Lisa M.;Spunt, Sheri L.;Blaney, Susan M.
背景：在这份报告中，作者估计了奥沙利铂联合伊立替康治疗儿童难治性实体肿瘤的最大耐受量(MTD)，并调查了其毒性。方法：奥沙利铂与伊立替康联合应用于第1、8天，第1~5天，第8~12天，共21天。每天口服头孢菌素以缓解伊立替康相关性腹泻。对奥沙利铂和尿苷二磷酸葡萄糖醛酸基转移酶1家族多肽A1(UGT1A1)基因分型进行了药代动力学研究。结果：13例患者入选。首剂(奥沙利铂60 mg/m(2)，伊立替康20 mg/m(2))出现限量性腹泻3例，血清脂肪酶升高3例，血清淀粉酶升高2例，结肠炎、腹痛、头痛各1例。接受两种药物减量治疗(40 mg/m(2)/剂量奥沙利铂；15 mg/m(2)/剂量伊立替康)的7名患者中只有1名出现剂量限制性毒性(DLT)：腹泻。奥沙利铂剂量为60 mg/m(2)，伊立替康剂量为15 mg/m(2)时，3例患者中有2例出现DLT(1例腹泻，1例低钾血症)。骨髓抑制程度很小。1例完全缓解，1例病情稳定，治疗6个周期。奥沙利铂药时曲线下的中位数面积(AUC(O>；infinity))为5.9微克。小时/毫升(范围为1.87-7.6微克小时/毫升)。UGT1A1基因启动子区6/6、6/7和7/7型频率分别为5/10、4/10和1/10。结论：奥沙利铂联合伊立替康的MTD为40 mg/m(2)，联用伊立替康15 mg/m(2)，第1~5天和8~12天。有一些抗肿瘤活性的证据；然而，观察到了严重的毒性，既有预料中的(腹泻)，也有意想不到的(胰酶升高)。癌症杂志2009；115：1765-75。(C)2009年美国癌症协会。
BACKGROUND: For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors. METHODS: Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan-associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed. RESULTS: Thirteen patients were enrolled. Dose-limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m(2); irinotecan at a dose of 20 mg/m(2)). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m(2)/dose oxaliplatin; 15 mg/m(2)/dose irinotecan) experienced a dose-limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re-escalated (60 mg/m(2)) with irinotecan at a dose of 15 mg/m(2), 2 of 3 patients had a DLT (1 episode of diarrhea, I episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC(O ->infinity),) was 5.9 mu g . hour/mL (range, 1.87-7.6 mu g . hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and I of 10, respectively. CONCLUSIONS: The oxaliplatin MTD was 40 mg/m(2) per dose on Days I and 8 in combination with irinotecan 15 mg/m(2) per dose on Days 1-5 and Days 8-12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009;115:1765-75. (C) 2009 American Cancer Society.