Abstract OT3-2-07: Phase I study of ARN-810, a novel selective estrogen receptor degrader, in post-menopausal women with locally advanced or metastatic estrogen receptor positive breast cancer
Authors: Mayer IA , Bardia A , Dickler MN , Manning HC , Mahmood U , Ulaner GA , Hager JH , Rix P , Zack N , Maneval EC , Chen I , Baselga J , Arteaga CL 
Published: August 2014

Abstract
Background: Modulation of estrogen synthesis or its receptor activity represents the treatment of choice for postmenopausal women with estrogen receptor-positive (ER+) breast cancer (BC). However, despite initial response to hormonal manipulation, most tumors ultimately develop endocrine resistance. The emerging evidence that ERα can signal in both ligand-dependent and independent manner supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. ARN-810 is a novel, non-steroidal ERα antagonist that induces proteasomal-mediated degradation of ERα in breast cancer cell lines at picomolar concentrations. This unique biological profile coupled with good oral pharmacokinetics (PK) produced tumor regression in both tamoxifen-sensitive and resistant BC models. Importantly, in the tamoxifen-resistant model, response to ER modulators like fulvestrant and tamoxifen was limited to tumor growth arrest.
Trial Design: This is a safety and PK study of ARN-810 administered orally on a continuous daily dosing regimen with a PK lead-in. The incidence of dose limiting toxicity (DLT) will be assessed in the first cycle of treatment (28 days). Patients will be assigned to escalating doses of ARN-810 in cohorts of 3-6 patients per dose until determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 Dose (RP2D) using standard 3+3 criteria. The MTD and/or RP2D will be defined as the dose with ≤1 out of 6 patients with DLT. Key eligibility criteria include postmenopausal women with locally advanced or metastatic ER+ (HER2-) BC, ECOG PS 0/1, and adequate organ function. Untreated or symptomatic brain metastases and endometrial disorders are exclusionary. At the MTD and/or RP2D, expansion cohorts of patients with disease progression after ≤2 prior hormonal therapies (≤1 in the metastatic setting) or prior therapy with fulvestrant will be enrolled. Plasma PK after first dose and at steady-state will be analyzed using non-compartmental methods. Pre- and post-treatment functional imaging with [18F]-fluoroestradiol (FES)-PET to assess tumor ER binding and paired tumor biopsies to assess for ER target modulation by IHC and gene expression will be performed.
Objectives: The primary objective is to determine the MTD and/or RP2D of ARN-810. In addition to safety and PK, evaluation of biomarkers of pharmacodynamic (PD) response with FES-PET and ER target gene expression will be explored along with preliminary antitumor activity.
Statistical Methods: Descriptive statistics will be used to summarize patient characteristics, treatment administration/compliance, safety and PK parameters, antitumor activity endpoints, and exploratory biomarkers.
Status: To date, 3 patients have been enrolled in the first cohort at 100 mg/day. The target accrual for the dose escalation will depend upon the observed safety and PK/PD profile, which will determine the number of escalations. During dose expansion, 30 patients will be enrolled. More information about this study can be found at http://clinicaltrials.gov/ct2/show/NCT01823835?term = ARN-810.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-07.