Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma.
Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma.
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DOI：
10.1007/s11060-010-0143-7
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发表时间：
2010-10
影响因子：
3.9
通讯作者：
Olson JJ
中科院分区：
文献类型：
--
作者：
Phuphanich S;Supko JG;Carson KA;Grossman SA;Burt Nabors L;Mikkelsen T;Lesser G;Rosenfeld S;Desideri S;Olson JJ
硼替佐米选择性结合并抑制20S蛋白酶体的活性位点。本研究旨在确定复发性恶性胶质瘤患者硼替佐米的副作用和最大耐受剂量（MTD）。在服用或未服用酶促抗癫痫药物（+/−EIASD）的患者中分别进行剂量递增。两组的起始剂量为0.9 mg/m2，静脉滴注，每周两次，每4周周期的前3次。影像学评价疗效，血浆20S蛋白酶体活性抑制及影像学监测疗效。纳入的66例患者中位年龄为51岁，中位KPS为90%，77%患有多形性胶质母细胞瘤。−EIASD组基于3级血小板减少、感觉神经病变和疲劳的MTD为1.70 mg/m2。在+EIASD组中，在未达到MTD标准的情况下，升高至2.5 mg/m2终止。然而，当剂量超过1.90 mg/m2时，该组的蛋白酶体抑制没有变化，这表明进一步的剂量增加不太可能增加生物效应。接受2.1 mg/m2硼替佐米治疗的+EIASD患者的平均蛋白酶体抑制率为77±12%，接受1.7 mg/m2硼替佐米治疗的−EIASD患者的平均蛋白酶体抑制率为79±6%。观察到两个部分反应。本研究确定EIASDs影响硼替佐米的MTD和全血20S蛋白酶体最大抑制所需的剂量。在复发性高级别胶质瘤患者的I期研究中注意到一些临床活性证据。
Bortezomib selectively binds and inhibits the 20S proteasome enzyme’s active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/−EIASD). The starting dose in both groups was 0.9 mg/m2 intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the −EIASD group was 1.70 mg/m2 based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m2 without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m2 suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m2 of bortezomib at 77 ± 12% and in −EIASD patients treated with a dose of 1.7 mg/m2 at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.
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影响因子：
45.3
作者：
Fetell, MR;Grossman, SA;Piantadosi, S
通讯作者：
Piantadosi, S
影响因子：
4.7
作者：
Giles, Francis J
通讯作者：
Giles, Francis J
影响因子：
45.3
作者：
Carson, Kathryn A.;Grossman, Stuart A.;Shaw, Edward G.
通讯作者：
Shaw, Edward G.
影响因子：
3.9
作者：
Faucette, SR;Wang, HB;LeCluyse, EL
通讯作者：
LeCluyse, EL
影响因子：
2.2
作者：
Bold, RJ;Virudachalam, S;McConkey, DJ
通讯作者：
McConkey, DJ