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.

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.

• Authors: D Bianchini, A Omlin, C Pezaro, D Lorente, R Ferraldeschi, D Mukherji, M Crespo, I Figueiredo, S Miranda, R Riisnaes, A Zivi, A Buchbinder, D E Rathkopf, G Attard, H I Scher, J de Bono, D C Danila
• Journal: British journal of cancer (Br J Cancer) Vol. 109 Issue 10 Pg. 2579-86 (Nov 12 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 24169353 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 5'-ACCaagtttcttcAGC-3'
• AR protein, human
• Androgen Antagonists
• Oligonucleotides
• Oligonucleotides, Antisense
• RNA, Messenger
• Receptors, Androgen
• locked nucleic acid
• DNA

Topics

• Adenocarcinoma (genetics, metabolism, pathology, therapy)
• Aged
• Aged, 80 and over
• Androgen Antagonists (adverse effects, pharmacokinetics, therapeutic use)
• DNA (adverse effects, pharmacokinetics, therapeutic use)
• Exons (genetics)
• Humans
• Male
• Middle Aged
• Oligonucleotides (adverse effects, pharmacokinetics, therapeutic use)
• Oligonucleotides, Antisense (adverse effects, pharmacokinetics, therapeutic use)
• Orchiectomy
• Prostatic Neoplasms (genetics, metabolism, pathology, therapy)
• RNA, Messenger (genetics)
• Receptors, Androgen (genetics)
• Treatment Failure