Androgen Receptor Expression In Tissue Research Articles

776P - A Phase 1/2 Study of At13387, a Heat Shock Protein 90 (Hsp90) Inhibitor in Combination with Abiraterone Acetate (Aa) and Prednisone (P) in Patients (Pts) with Castration-Resistant Prostate Cancer (Mcrpc) No Longer Responding to Aa

ABSTRACT Aim: Hsp90 is a molecular chaperone required for the proper folding and function of multiple client proteins including the androgen receptor (AR). AT13387 (AT), a synthetic Hsp90 inhibitor displays activity against multiple prostate cancer models. A 2-part, Phase 1/2, randomized study was initiated to investigate the combination of AT + AA/P in mCRPC pts progressing on AA. Methods: The primary objectives were the safety and tolerability of AT/AA/P and to select the treatment regimen for the Ph2, based on assessment of safety and antitumor activity. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and progression-free survival (PFS). Part 1 used a rolling six design to determine the maximum tolerated dose (MTD) of the AT/AA/P combination. All pts continued to receive oral AA/P (1000 mg Qd/5 mg BID) at progression, being randomized to receive 1 of 2 AT dosing regimens: AT at the starting dose of 220 mg/m2 IV once weekly for 3 weeks (R1), or 120 mg/m2 on Days 1 & 2 weekly for 3 weeks (R2) in a 4-week cycle. PD studies evaluated AR expression in tissue and circulating tumor cells (CTC) pre and post AT treatment. Results: Overall 48 patients were treated (R1: AT at 220-260 mg/m2; R2: AT at 120-160 mg/m2). The most frequent AT- treatment related ≥ Grade 3 toxicities were diarrhea (21%) and fatigue (13%). Diarrhea was dose-limiting for both regimens (AT at 260 mg/m2 and 160 mg/m2 for R1 and R2, respectively). PK analysis showed that AT exposures were similar to what was observed in previous studies while AA exposures appeared to be ∼30% lower when co-administered with AT. PD analyses indicated limited target knockdown. Multiple subjects showed transient decreases in PSA but no PCWG2 PSA responses or objective RECIST tumor responses were observed and the study did not proceed to Ph2. Conclusions: Our study represents the first clinical trial of an Hsp90 inhibitor in combination with AA/P. MTDs were reached for once-weekly (220 mg/m2) and twice-weekly (120 mg/m2) regimens; however AT + AA/P did not demonstrate adequate antitumor activity at these doses for the study to proceed to Part 2. Disclosure: J. Garcia: grants/research Support & consultant/independent contractor for JJ N.J. Vogelzang: Research funding from Astex; A. Oganesian, L. Manlapaz-Espiritu, Y. Hao and H. Keer: Astex employee. All other authors have declared no conflicts of interest.

First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC).

5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]