A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study.
A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study.
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enzastaurin 在难治性原发性中枢神经系统肿瘤儿科患者中的 1 期和药代动力学研究：一项儿科脑肿瘤联合研究。
DOI：
10.1093/neuonc/nou114
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发表时间：
2015
期刊：
影响因子：
15.9
通讯作者：
Blaney,SusanM
中科院分区：
文献类型：
--
作者：
Kilburn,LindsayB;Kocak,Mehmet;Decker,RodneyL;Wetmore,Cynthia;Chintagumpala,Murali;Su,Jack;Goldman,Stewart;Banerjee,Anuradha;Gilbertson,Richard;Fouladi,Maryam;Kun,Larry;Boyett,JamesM;Blaney,SusanM
BackgroundWe试图估计最大耐受或推荐的2期剂量，并描述enzaelatin，蛋白激酶Cβ的口服抑制剂，在儿童复发性中枢神经系统malignances. Methodsenzaelatin的药代动力学和毒性，连续给药，每天一次，3个剂量水平（260，340，和440 mg/m2），每天两次，440 mg/m2/day。在单次给药后和稳态时评价血浆药代动力学。抑制蛋白激酶C和Akt细胞信号在外周血单核细胞进行了评估。Akt通路活性测定在预处理肿瘤samples.ResultsThirty-three患者入组; 1是不合格的，3是不可评估的继发于早期进展性疾病。在剂量探索阶段没有剂量限制性毒性。接受440 mg/m2每日两次给药的2例受试者发生了3级血小板减少症的剂量限制性毒性，导致疗程2延迟开始，3级丙氨酸转氨酶升高，5天内未恢复。治疗期间未发生4级毒性反应。Enzalutamide的浓度随剂量增加和连续给药而增加;然而，Enzalutamide每日一次给药与每日两次给药在440 mg/m2剂量水平下无显著差异。没有客观的反应，但是，11名参与者有稳定的疾病>3个周期，7与神经胶质瘤，2室管膜瘤，和2脑干glioma. ConclusionEnzavin耐受性良好，在儿童复发性中枢神经系统恶性肿瘤，色素尿，疲劳，贫血，血小板减少，恶心是最常见的毒性。推荐的II期剂量为440 mg/m2/天，每日一次给药。
BackgroundWe sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.MethodsEnzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m2) and twice daily at 440 mg/m2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated.Akt pathway activity was measured in pretreatment tumor samples.ResultsThirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m2given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m2dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.ConclusionEnzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m2/day administered once daily.
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影响因子：
20.4
作者：
Chiappori, Alberto;Bepler, Gerold;von Pawel, Joachim
通讯作者：
von Pawel, Joachim
索拉非尼和舒尼替尼与 Enzastaurin（一种选择性蛋白激酶 C 抑制剂）在肾细胞癌细胞系中的协同作用。
影响因子：
9.7
作者：
U. Vogl;W. Berger;M. Micksche;C. Pirker;W. Lamm;Oskar Pichelmeyer;C. Zielinski;M. Schmidinger
通讯作者：
M. Schmidinger
影响因子：
50.5
作者：
Hanauske, A. -R.;Lahn, M.;Giaccone, G.
通讯作者：
Giaccone, G.
影响因子：
5.7
作者：
Jian, Weiguo;Yamashita, Hideyuki;Sonpavde, Guru
通讯作者：
Sonpavde, Guru
影响因子：
11.5
作者：
Rademaker-Lakhai, Jeany M.;Beerepoot, Laurens V.;Voest, Emile E.
通讯作者：
Voest, Emile E.