Abstract LB-407: Down-modulation of mRNA by EZN-2968, an hypoxia-inducible factor-1α (HIF-1α) mRNA antagonist, administered in adult patients with advanced solid tumors
Authors: Cohen Roger B. , Olszanski Anthony , Figueroa Jose , Hurwitz Herbert , Lokiec Francois M. , Rezaï Keyvan , Berkowitz Noah , Buchbinder Aby 
Published: August 2014

Abstract
Background: HIF-1 is a transcription factor that is a critical mediator of angiogenesis, cell proliferation, metabolism, survival, and adaptive responses to stress. Overexpression of HIF-1α is observed in many malignant tumors, and in some cases is associated with poor prognosis. Down-regulation of HIF-1α may impair tumor cell growth. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide that down-modulates HIF-1α mRNA and protein in vitro (IC50 &lt;1 nM and &lt;5 nM, respectively). Preclinically, EZN-2968 down-regulated endogenous HIF-1α in a dose-dependent manner.
Methods: The primary objective of this study was to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose of EZN-2968 when administered as a weekly 2-hour infusion. Secondary objectives were to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. Cohorts of 3–6 pts with advanced tumors received escalating doses of EZN-2968. Initial cohorts received EZN-2968 as a weekly 2-h infusion for 3 of 6 weeks. Later cohorts received EZN-2968 on a more intensive weekly schedule with shorter breaks (e.g., 4 weeks on, 2 weeks off, etc.).
Results: 49 pts (21 M/28 F; median age = 58 y [28–87 y]) received EZN-2968 doses of 1 (n=4), 1.5 (n=4), 2.3 (n=3), 3.5 (n=8), 5.3 (n=5), 8.0 (n=7), 12 (n=4), and 18 mg/kg (n=3), respectively, given weekly, for 3 of 6 weeks; 18 mg/kg (n=7) for 4 of 6 weeks; and 18 mg/kg (n=4) for 5 of 6 weeks. Pts received a median of 1 cycle (range: 1–10) of EZN-2968. Dose-limiting toxicities were intracerebral bleeding (n=1, 3.5 mg/kg), Grade 3 fatigue (n=2, 8 mg/kg, 18 mg/kg for 5 of 6 weeks), and Grade 3 increased AST (n=1, 18 mg/kg for 5 of 6 weeks). The MTD for EZN-2968 is 18 mg/kg given weekly for 4 of 6 weeks. Drug-related adverse events (AEs) reported for &gt;10% of pts were fatigue (29%) and headache (14%). Grade 3 drug-related AEs (fatigue [n=3], AST increase [n=3], ALT increase [n=2], and hyponatremia [n=1]) were reported for 7 patients (14%); no drug-related AE was Grade 4 or 5. PK data for all 49 patients will be presented. The current best response for EZN-2968 is stable disease (RECIST) in 16 pts; 7 pts were treated for &gt;90 days. Objective tumor shrinkage was observed in several pts, including a pt with renal cell cancer. HIF-1α expression was evaluated pretreatment and on-treatment in tumor (n=6) and skin (n=41) samples. Tumor biopsy HIF-1α mRNA decreased in 4 pts, increased in 1 pt, and did not change in 1 pt. Skin biopsy HIF-1α mRNA decreased in 63% (26/41) of pts, remained the same in 10% (4/41) of pts, and increased in 27% (11/41) of pts.
Conclusions: The MTD of EZN-2968 is 18 mg/kg given weekly for 4 of 6 weeks. EZN-2968 was generally well tolerated in previously treated pts with advanced tumors who received up to 10 cycles of EZN-2968. The best response was SD. Evidence for down-regulation of the HIF-1α target is supported by observations in tumor and skin biopsies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-407. doi:10.1158/1538-7445.AM2011-LB-407