Journal
BRITISH JOURNAL OF CANCER
Volume 109, Issue 10, Pages 2579-2586Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.619
Keywords
castration-resistant prostate cancer; EZN-4176; antisense oligonucleotide; phase I clinical trial
Categories
Funding
- Enzon pharmaceuticals
- Cancer Research UK
- Experimental Cancer Medical Centre (ECMC)
- Department of Health [C51/A7401]
- Prostate Cancer Foundation (PCF)
- Experimental Cancer Medicine Centre initiative ECMC
- NIHR Biomedical Research Centre (BRC)
- Cancer Research UK Clinician Scientist Fellowship
- Royal Marsden NIHR Biomedical Research Centre
- Swiss Cancer League [BIL KLS-02592-02-2010]
- Cancer Research UK [13239] Funding Source: researchfish
- National Institute for Health Research [CL-2008-22-001] Funding Source: researchfish
Ask authors/readers for more resources
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 0.5mgkg(-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 10mgkg(-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 10mgkg(-1) QW was associated with significant but reversible transaminase elevation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available