Abstract A216: Results of a phase 1, open-label, dose-escalation study evaluating the safety and tolerability of EZN-3042, a survivin mRNA antagonist, administered with docetaxel (D) in adult patients (Pts) with advanced solid tumors.
Authors: Tolcher Anthony W. , Patnaik Amita , Papadopoulos Kyriakos P. , Agnew James , Lokiec Francois M. , Rezai Keyvan , Kalambakas Stacey , Buchbinder Aby 
Published: June 2012

Abstract
Background: Survivin, the smallest member of the inhibitors of apoptosis protein gene family, functions as a key regulator of mitosis and apoptosis. Overexpression of survivin in many cancers is correlated with an increased rate of recurrence and reduced survival, and over expression of survivin has been associated with taxane resistance. EZN-3042 is a potent locked nucleic acid antisense oligonucleotide that down-modulates survivin mRNA and consequently protein in vitro. Preclinically, EZN-3042 enhances apoptotic and antitumor effects of taxanes.
Methods: This study was designed to determine the safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary evidence of antitumor activity of EZN-3042 as a single agent (SA) and in combination (EZN-3042 + D). The maximum tolerated dose (MTD) of SA EZN-3042 is 6.5 mg/kg. (Reported at AACR 2011, abstract LB-409). Patients with advanced tumors received EZN-3042 (qwk) + D (75 mg/m2 q3wk), either after disease progression following SA therapy (during dose escalation of SA EZN-3042), or directly (after MTD of SA EZN-3042 was determined).
Results: 16 pts (7 M / 9 F; median age = 66 y [44–75 y]) received EZN-3042 + D. 10 pts received EZN-3042 +D doses of 2.5 mg/kg (n=7) and 5 mg/kg (n=3) after progression on SA EZN-3042; 6 pts received 6.5 mg/kg of EZN-3042 + D doses directly. Tumor types included prostate cancer (n=6); breast cancer (n=3); pancreas cancer (n=2); and non-small cell lung cancer, leiomyosarcoma, gastric, tongue, and unknown primary cancer (n=1 each). Dose-limiting toxicity was observed in 1 pt at 2.5 mg/kg of EZN-3042 (Grade 3 neutropenic fever) and 1 pt at 6.5 mg/kg of EZN-3042 (Grade 3 AST & ALT). Doses higher than 6.5 mg/kg were not evaluated for EZN-3042 +D since they were found to exceed the MTD for SA EZN-3042. Drug-related AEs (in &gt;20% pts) for EZN-3042 + D were fatigue (56%), alopecia (38%), neutropenia (31%), anorexia, nausea and peripheral sensory neuropathy (25% each). Most AEs were Grade 1 or 2. Preliminary assessment of antitumor activity indicates that the best response for EZN-3042 + D was confirmed PR in 1 pt with prostate cancer (2.5 mg/kg, 27 weeks).
Conclusions: EZN-3042 + docetaxel was well tolerated in previously treated pts with advanced tumors. The MTD of EZN-3042 + D is 6.5 mg/kg. EZN-3042 is being evaluated in a window of opportunity study in combination with chemotherapy in pediatric patients with relapsed acute lymphoblastic leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A216.