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%).
  
  
  CONCLUSIONS
  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.affiliation: 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.
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authors.lastname: Bianchini
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mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004247:DNA / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005091:Exons / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D017211:Treatment Failure
chemical_list: C571998:5'-ACCaagtttcttcAGC-3'; C410798:AR protein, human; D000726:Androgen Antagonists; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011944:Receptors, Androgen; C477371:locked nucleic acid; D004247:DNA