Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas.
Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas.
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COL-3 在复发性高级别胶质瘤患者中的 I 期和药代动力学研究。
DOI：
10.1007/s11060-011-0602-9
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发表时间：
2011
影响因子：
3.9
通讯作者：
Grossman,StuartA
中科院分区：
文献类型：
--
作者：
Rudek,MichelleA;New,Pamela;Mikkelsen,Tom;Phuphanich,Surasak;Alavi,JaneB;Nabors,LouisB;Piantadosi,Steven;Fisher,JoyD;Grossman,StuartA
COL-3是一种化学修饰的四环素，靶向基质金属蛋白酶调控的多个方面。本I期临床试验旨在确定COL-3在复发性高级别胶质瘤成人中的最大耐受剂量（MTD），描述酶诱导抗癫痫药物（EIAD）对其药代动力学的影响，并获得活性的初步证据。复发性高级别胶质瘤的成人患者根据EIAD的使用进行分层。COL-3每天口服给药，不间断，直到疾病进展或治疗相关的剂量限制性毒性（DLT）。每个EIAD组中的3例患者在每个剂量水平下进行评价，从25 mg/m2/天开始，递增至25 mg/m2/天。评估了毒性、反应和药代动力学。对33名患者进行了评价。−EIAD患者的MTD为75 mg/m2/天，而+EIAD患者的MTD未确定。观察到的常见毒性为贫血、共济失调、腹泻、低钾血症、CNS出血和肌痛。观察到1例部分缓解。−EIAD患者的稳态谷浓度往往更高，仅在100 mg/m2/d剂量水平下才明显（P= 0.01）。这项研究表明：（a）EIAD的使用确实影响了COL-3在较高剂量下的药代动力学;和（B）没有足够的证据表明单药活性需要在复发性高级别胶质瘤中进行进一步研究。
COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m2/day and escalated by 25 mg/m2/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m2/day in the −EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. −EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m2/day dose level (P= 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.