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 Article


Authors: 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.
Article Title: 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. © 2013 Cancer Research UK. All rights reserved.
Journal Title: British Journal of Cancer
Volume: 109
Issue: 10
ISSN: 0007-0920
Publisher: Nature Publishing Group  
Date Published: 2013-11-12
Start Page: 2579
End Page: 2586
Language: English
DOI: 10.1038/bjc.2013.619
PROVIDER: scopus
PMCID: PMC3833213
PUBMED: 24169353
DOI/URL:
Notes: --- - "Export Date: 2 December 2013" - "CODEN: BJCAA" - "Source: Scopus"
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  1. Dana Elizabeth Rathkopf
    273 Rathkopf
  2. Howard Scher
    1130 Scher
  3. Daniel C Danila
    155 Danila