Abstract
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 included colorectal cancer (7 pts); renal cancer (4 pts); soft-tissue sarcoma (STS; 2 pts); angiosarcoma (1 pt); melanoma (1 pt); and breast, ovarian, pancreatic, and prostate cancers (1 pt each). No dose-limiting toxicities were observed. The most common adverse events (Aes) were vomiting (32%); fatigue (26%); and anemia, diarrhea, nausea, and tumor pain (each 21%). Most Aes were Grade 1 or 2. Plasma PK for Day 1 is tabulated below. Stable disease was observed for 1 pt with angiosarcoma (28 wks) and 1 pt with renal cancer (12 wks). Conclusions: EZN-2968 was well tolerated in previously treated pts with advanced malignancies. PK data do not show accumulation of EZN-2968. Dose escalation is ongoing; final results will be presented at the meeting. Durable stable disease has been observed. [Table: see text] [Table: see text]
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