A first-in-human, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ARN-509 in patients with progressive advanced castration-resistant prostate cancer (CRPC).

Abstract

TPS190 Background: The results of molecular profiling studies show that androgen receptor (AR) overexpression is associated with resistance to conventional anti-androgens such as bicalutamide (Nat Med 10:33-39, 2004). ARN-509 is a novel small molecule AR antagonist that lacks the partial agonist activity seen with bicalutamide in the context of AR overexpression, an in vitro mimic of castration resistance. In addition, ARN-509 reduces the efficiency of nuclear translocation, and impairs AR binding to DNA and AR target gene modulation, thereby inhibiting tumor growth and promoting apoptosis. A phase I/II clinical trial of continuous oral ARN-509 in patients with progressive CRPC with and without prior chemotherapy began in July 2010. Methods: The study is designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor effects of ARN-509 in patients with progressive CRPC. In the dose escalation phase, patients are assigned using standard 3x3 dose escalation criteria to receive oral ARN509 at the following dose levels: 30, 60, 90, 120, 180, 240, and 300 mg. The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of ARN-509 that leads to a DLT in a maximum of 30% of patients. Pharmacokinetic (PK) analysis is performed after a single dose of ARN509 in week-1. Correlative studies include circulating tumor cells, optional FDG and FDHT PET imaging, and optional tumor biopsies. Following completion of the dose escalation phase, three expansion cohorts will be enrolled at the RP2D to provide an initial signal of anti-tumor activity with a time to PSA progression endpoint. The three expansion cohorts include: 1) non-metastatic CRPC docetaxel (doc) and abiraterone (abi)-naive (50 patients); 2) mCRPC doc and abi-naive (20 patients); and 3) mCRPC abi pre-treated (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will be evaluated in the expansion phase. The escalation phase is ongoing; enrollment to cohort 4 (120 mg) began in January 2011.DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.