First-in-human Phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer.
First-in-human Phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer.
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DOI：
10.1038/bjc.2013.619
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发表时间：
2013-11-12
影响因子：
8.8
通讯作者：
Danila, D. C.
中科院分区：
文献类型：
--
作者：
Bianchini, D.;Omlin, A.;Pezaro, C.;Lorente, D.;Ferraldeschi, R.;Mukherji, D.;Crespo, M.;Figueiredo, I.;Miranda, S.;Riisnaes, R.;Zivi, A.;Buchbinder, A.;Rathkopf, D. E.;Attard, G.;Scher, H. I.;de Bono, J.;Danila, D. C.
前列腺癌仍然依赖于雄激素受体（AR）信号，即使在出现去势抵抗后。EZN-4176是第三代反义寡核苷酸，与AR mRNA的铰链区（外显子4）结合，导致全长AR mRNA降解和AR蛋白表达降低。这项I期研究旨在评估EZN-4176在去势抵抗性前列腺癌（CRPC）男性中的作用。进展性CRPC患者符合条件;允许既往接受阿比特龙和Enzalutamide治疗。EZN-4176每周（QW）1小时静脉输注给药。起始剂量为0.5 mg kg−1，4周剂量限制性毒性（DLT）期和3+3改良Fibonacci剂量递增设计。在确定每周给药的DLT后，开始每2周一次的方案。共有22例患者接受了EZN-4176治疗。在10 mg kg−1 QW剂量下，由于3-4级ALT或AST升高，观察到2例DLT。未观察到确认的生化或软组织反应。在基线时循环肿瘤细胞<5的8名患者中，在3名（38%）患者中观察到转化为<5。最常见的EZN-4176相关毒性（所有等级）为疲乏（59%）、肝功能检查ALT（41%）和AST（41%）的可逆性异常以及输注相关反应，包括寒战（36%）和发热（14%）。EZN-4176在探索的剂量和时间表下的活性极小。最高剂量10 mg kg−1 QW与显著但可逆的转氨酶升高相关。
Prostate cancer remains dependent of androgen receptor (AR) signalling, even after emergence of castration resistance. EZN-4176 is a third-generation antisense oligonucleotide that binds to the hinge region (exon 4) of AR mRNA resulting in full-length AR mRNA degradation and decreased AR protein expression. This Phase I study aimed to evaluate EZN-4176 in men with castration-resistant prostate cancer (CRPC). Patients with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) 1-h intravenous infusion. The starting dose was 0.5 mg kg−1 with a 4-week dose-limiting toxicity (DLT) period and a 3+3 modified Fibonacci dose escalation design. After determination of the DLT for weekly administration, an every 2 weeks schedule was initiated. A total of 22 patients were treated with EZN-4176. At 10 mg kg−1 QW, two DLTs were observed due to grade 3–4 ALT or AST elevation. No confirmed biochemical or soft tissue responses were observed. Of eight patients with ⩾5 circulating tumour cells at baseline, a conversion to <5 was observed in three (38%) patients. The most common EZN-4176-related toxicities (all grades) were fatigue (59%), reversible abnormalities in liver function tests ALT (41%) and AST (41%) and infusion-related reactions including chills (36%) and pyrexia (14%). Activity of EZN-4176 at the doses and schedules explored was minimal. The highest dose of 10 mg kg−1 QW was associated with significant but reversible transaminase elevation.
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影响因子：
14.9
作者：
Swayze EE;Siwkowski AM;Wancewicz EV;Migawa MT;Wyrzykiewicz TK;Hung G;Monia BP;Bennett CF
通讯作者：
Bennett CF
影响因子：
11.2
作者：
Richards J;Lim AC;Hay CW;Taylor AE;Wingate A;Nowakowska K;Pezaro C;Carreira S;Goodall J;Arlt W;McEwan IJ;de Bono JS;Attard G
通讯作者：
Attard G
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
通讯作者：
de Bono, Johann S.