Horton Terzah M, Pati Debananda, Plon Sharon E, Thompson Patrick A, Bomgaars Lisa R, Adamson Peter C, Ingle Ashish M, Wright John, Brockman Adam H, Paton Martin, Blaney Susan M
Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Clin Cancer Res. 2007 Mar 1;13(5):1516-22. doi: 10.1158/1078-0432.CCR-06-2173.
A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia.
Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle.
Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses.
For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.
开展一项1期研究，以确定硼替佐米对复发/难治性白血病患儿的最大耐受剂量、剂量限制性毒性、药代动力学及生物学效应。
硼替佐米每周给药两次，连续给药2周，剂量为1.3或1.7mg/m²，随后休息1周。在第一个治疗周期中评估硼替佐米的药代动力学及核因子κB（NF-κB）结合活性。
2004年5月至2005年11月共纳入12例患者（9例急性淋巴细胞白血病，3例急性髓细胞白血病），中位年龄11岁（范围1-18岁），其中7例因疾病快速进展或感染未得到控制而无法对毒性进行全面评估。在1.7mg/m²剂量水平有2例患者出现剂量限制性毒性。1例患者出现3级意识模糊，另1例患者出现4级发热性中性粒细胞减少症，伴有4级低血压和3级肌酐升高。1.3mg/m²剂量的药代动力学分析显示清除率为11mL/h/m²，中央分布容积为6.7L/m²，终末半衰期为12.6小时。对5例患者检测了NF-κB活性，发现2例患者在硼替佐米给药后24小时NF-κB活性短暂升高，随后下降4至6倍。未观察到客观临床反应。
对于白血病患儿，硼替佐米的推荐2期剂量为每周给药两次，共2周，随后休息1周，剂量为1.3mg/m²/次。虽然硼替佐米治疗可抑制NF-κB活性，但作为单药在该人群中活性很小。
