A locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer

British Journal of Cancer (2013) 109, 2579–2586. doi:10.1038/bjc.2013.619 www.bjcancer.com
Published online 29 October 2013
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

D Bianchini1,2, A Omlin1,2, C Pezaro1,2, D Lorente1,2, R Ferraldeschi1,2, D Mukherji1,2, M Crespo1,2, I Figueiredo1,2, S Miranda1,2, R Riisnaes1,2, A Zivi1,2, A Buchbinder1,2, D E Rathkopf1,2, G Attard1,2, H I Scher1,2, J de Bono1,2,3,4 and D C Danila1,2,3,4

1Prostate Cancer Targeted Therapy Group and Drug Development Unit, Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK
2Memorial Sloan-Kettering Cancer Center (MSKCC) and Weill Cornell Medical College, Center for Prostate and Urologic Cancers, New York, NY, USA
3ENZON Pharmaceuticals Inc.; Bridgewater, NJ, USA

Correspondence: Professor J de Bono, E-mail: johann.de-bono@icr.ac.uk

Abstract
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 greater than or equal to5 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.

Keywords:

castration-resistant prostate cancer; EZN-4176; antisense oligonucleotide; phase I clinical trial