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.

Figure 1

Pharmacokinetics of ENZ-4176. Each colour line represents mean plasma EZN-4176 levels (linear scale) along the initial (A) 25 and (B) 168 h after the first infusion for the different dose-escalation levels. Dose (mg) vs (C) C_max (ng ml⁻¹) and (D) AUC_0–∞ (ng h ml⁻¹) (log–log scale). Both C_max and AUC_0–∞ increased with dose.

Figure 2

(A) Waterfall plot showing percentage PSA change from baseline at 12 weeks (N=11 evaluable patients). Coloured bars represent individual patients and colours correspond to the dose of EZN-4176. Increases in PSA were capped at 100%. (B) Waterfall plot showing percentage PSA change from baseline at any time on study (N=22). Coloured bars represent individual patients and colours correspond to the dose of EZN-4176. Increases in PSA were capped at 100%.

Figure 3

Waterfall plot showing percentage CTC count change from baseline at any time on study in patients with a baseline CTC count of ⩾5 (N=8). The absolute CTC count at baseline and best response are indicated for each patient in the table. Coloured bars represent individual patients and colours correspond to the dose of EZN-4176 (see Figure 2). Increases in CTC counts were capped at 50%.

Figure 4

Expression of AR in tumour before EZN-4176 (top) treatment and 24 h after dosing on cycle 1 day 16 (bottom). No significant AR depletion was observed. AR antibody targeting the amino terminus (A) and carboxy terminus domain (B) of AR.