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

Publication

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

Journal Paper/Review - Oct 29, 2013

Bianchini D, de Bono J, Scher H I, Attard G, Rathkopf D E, Buchbinder A, Zivi A, Riisnaes R, Miranda S, Figueiredo I, Crespo M, Mukherji D, Ferraldeschi R, Lorente D, Pezaro C, Omlin Aurelius, Danila D C

Citation

Bianchini D, de Bono J, Scher H, Attard G, Rathkopf D, Buchbinder A, Zivi A, Riisnaes R, Miranda S, Figueiredo I, Crespo M, Mukherji D, Ferraldeschi R, Lorente D, Pezaro C, Omlin A, Danila D. 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. Br J Cancer 2013; 109:2579-86.

Type

Journal Paper/Review (English)

Journal

Br J Cancer 2013; 109

Publication Date

Oct 29, 2013

Issn Electronic

1532-1827

Pages

2579-86

Brief description/objective

BACKGROUND
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).

METHODS
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.

RESULTS
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%).

CONCLUSION
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.