EZN-2968, a novel hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies

2564 Background: HIF-1 is a transcription factor that regulates expression of many key genes, notably those switching cell metabolism to anaerobic glycolysis and inducing neovascularization in response to hypoxia. Increased HIF-1α levels are associated with poor prognosis in several neoplasms. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide suppressing HIF-1α mRNA translation in vitro (IC50 ∼1–5 nM). Methods: This study was designed to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2968. Pts with advanced malignancies were treated with EZN-2968 administered as a daily 2-hr IV infusion x 5 days every 4 weeks using a 3+3 dose-escalating design. Dose escalation was based on toxicities observed during Cycle 1. Results: 19 pts (11 men; median age = 60 y [47–79 y]) were treated with EZN-2968 doses of 0.5 (3 pts), 0.8 (3 pts), 1.2 (3 pts), 1.8 (4 pts), 2.7 (3 pts), and 4.1 (3 pts) mg/kg/day. Tumor types in...