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

• Published in: British journal of cancer Vol. 109; no. 10; pp. 2579 - 2586
• Main Authors: BIANCHINI, D, OMLIN, A, ZIVI, A, BUCHBINDER, A, RATHKOPF, D. E, ATTARD, G, SCHER, H. I, DE BONO, J, DANILA, D. C, PEZARO, C, LORENTE, D, FERRALDESCHI, R, MUKHERJI, D, CRESPO, M, FIGUEIREDO, I, MIRANDA, S, RIISNAES, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 12.11.2013
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - therapy; Aged; Aged, 80 and over; Androgen Antagonists - adverse effects; Androgen Antagonists - pharmacokinetics; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Biological and medical sciences; Bisphosphonates; Cancer research; Cancer therapies; Clinical Study; DNA - adverse effects; DNA - pharmacokinetics; DNA - therapeutic use; Exons - genetics; Humans; Male; Medical research; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Neutropenia; Oligonucleotides - adverse effects; Oligonucleotides - pharmacokinetics; Oligonucleotides - therapeutic use; Oligonucleotides, Antisense - adverse effects; Oligonucleotides, Antisense - pharmacokinetics; Oligonucleotides, Antisense - therapeutic use; Orchiectomy; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Protein expression; Receptors, Androgen - genetics; RNA, Messenger - genetics; Thrombocytopenia; Toxicity; Treatment Failure; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United Kingdom > UK; New York; United States > US; Human; Urinary system disease; Prostate disease; Malignant tumor; castration-resistant prostate cancer; Antisense oligonucleotide; Resistance; Cancerology; Exon; Messenger RNA; Treatment; Castration; Androgen receptor; Phase I trial; Locked nucleic acid; Male genital diseases; Prostate cancer; EZN-4176; Cancer; Hormonal receptor; phase I clinical trial
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.619

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). 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. 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%). 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.