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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