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Br J Cancer. 2013 Nov 12;109(10):2579-86. doi: 10.1038/bjc.2013.619. Epub 2013 Oct 29.

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.

Author information

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

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 <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.

PMID:
24169353
PMCID:
PMC3833213
DOI:
10.1038/bjc.2013.619
[Indexed for MEDLINE]
Free PMC Article

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