Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: A children's oncology group study (ADVL0015)
Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: A children's oncology group study (ADVL0015)
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DOI：
10.1200/jco.2004.12.185
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发表时间：
2004-12-01
影响因子：
45.3
通讯作者：
Adamson, PC
中科院分区：
文献类型：
--
作者：
Blaney, SM;Bernstein, M;Adamson, PC
目的研究蛋白酶体抑制剂波特佐米(原PS-341)对儿童复发性或难治性实体瘤的最大耐受量、剂量限制毒性(DLT)和药效学。结果2001年11月至2003年2月共入选15例患者，其中11例可评价。剂量限制性血小板减少，阻止了整个疗程(两周内四次剂量)的治疗，在五名以1.6 mg/m(2)剂量水平登记的可评估儿童中，有两名发生了。没有其他的DLT。对20S蛋白酶体活性的抑制似乎呈剂量依赖性。给药后1h，1.2 mg/m(2)/剂量组平均抑制率为67.2%+/-7.6%，1.6 mg/m(2)/剂量组为76.5%+/-3.3%。结论波特佐米对复发或难治性实体瘤患儿耐受性良好。对于实体瘤的儿童，推荐的II期剂量为1.2 mg/m(2)/剂量，每周两次静脉推注，连续两周，然后休息一周。(C)2004年，美国临床肿瘤学会
Purpose To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.Patients and Methods An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m(2)/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.Results Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m(2) dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% +/- 7.6% at the 1.2 mg/m(2)/dose and 76.5% +/- 3.3% at the 1.6 mg/m(2) /dose. There were no objective antitumor responses.Conclusion Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m(2)/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break. (C) 2004 by American Society of Clinical Oncology