Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.
Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.
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DOI：
10.1007/s00280-015-2709-8
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发表时间：
2015-04
影响因子：
3
通讯作者：
Zanna, Claudio
中科院分区：
文献类型：
--
作者：
Hurwitz, Herbert I.;Smith, David C.;Pitot, Henry C.;Brill, Jeffrey M.;Chugh, Rashmi;Rouits, Elisabeth;Rubin, Joseph;Strickler, John;Vuagniaux, Gregoire;Sorensen, J. Mel;Zanna, Claudio
评价细胞凋亡抑制蛋白拮抗剂DEBIO1143的安全性/耐受性、药代动力学(PK)、药效学(PD)和抗肿瘤活性。这项在晚期癌症患者中进行的首次人体研究采用了加速剂量滴定设计。DEBIO1143每天口服一次，第1-5天，每2或3周一次，直到疾病进展或患者退出。在单个患者中，5 mg的起始剂量增加了100%，直到出现相关的2级毒性。这导致扩大到3名患者和随后的6名患者的队列，并将剂量增量减少到50%。当同一队列中的任何两名患者经历剂量限制性毒性(DLT)时，超过最大耐受剂量(MTD)。分别于第1、5天取PK、PD标本。31名患者接受了5至900 mg的剂量。只有一种DLT被报道为180毫克。未发现MTD。最常见的不良反应是乏力(26%)、恶心(23%)和呕吐(13%)。平均tmax约为1小时，T1/2约为6小时。随着剂量从80 mg增加到900 mg，暴露成比例增加，5天内没有累积。血浆CCL2在给药后3~6h升高，上皮细胞凋亡标记物M30在给药后第5天升高；PBMCs中CIAP-1水平在各剂量组均降低。5例(17.1%)以病情稳定为最佳治疗反应。DEBIO1143在剂量高达900微克时耐受性良好，在剂量大于80微克时引起帕金森病效应。有限的抗肿瘤活性可能意味着发展，而不是辅助治疗。本文的在线版本(doi：10.1007/s00280-015-2709-8)包含补充材料，授权用户可以使用。
To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1–5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100 % in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50 %. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26 %), nausea (23 %), and vomiting (13 %). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3–6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17 %) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment. The online version of this article (doi:10.1007/s00280-015-2709-8) contains supplementary material, which is available to authorized users.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
2.1
作者：
Zhang T;Li Y;Zou P;Yu JY;McEachern D;Wang S;Sun D
通讯作者：
Sun D
影响因子：
4
作者：
Dubrez L;Berthelet J;Glorian V
通讯作者：
Glorian V
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
3.6
作者：
Brunckhorst, Melissa K.;Lerner, Dimitry;Yu, Qin
通讯作者：
Yu, Qin