Abstract LB-409: Results of a phase 1, open-label, dose-escalation study evaluating the safety and tolerability of EZN-3042, a survivin mRNA antagonist, administered with or without docetaxel in adult patients with advanced solid tumors or lymphoma
Authors: Tolcher Anthony W. , Patnaik Amita , Papadopoulos Kyriakos P. , Agnew James , Lokiec François M. , Rezai Keyvan , Kalambakas Stacey , Buchbinder Aby 
Published: August 2014

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. EZN-3042 is a potent locked nucleic acid antisense oligonucleotide that down-modulates survivin mRNA and consequently protein in vitro (IC50 &lt;5 nM). 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 with docetaxel (EZN-3042 + D). Using a novel dose-escalation design, pts with advanced tumors first received SA EZN-3042 as a 2-h IV infusion qwk. After disease progression following SA therapy, pts could receive EZN-3042 (qwk) + D (75 mg/m2 q3wk). Dose escalation (3+3) for SA and EZN-3042 + D was independently based on toxicities observed during Cycle 1 of SA EZN-3042 or EZN-3042 + D, respectively (modified Fibonacci dose-escalation design).
Results: 25 pts (14 M/11 F; median age = 61 y [44–75 y]) enrolled in the study. 24 pts received SA EZN-3042 doses of 2.5 (n=3), 5 (n=9), 6.5 (n=6), and 8 mg/kg (n=6); 1 pt did not receive SA EZN-3042 but was treated directly with EZN-3042 (6.5 mg/kg) + D. Tumor types included prostate cancer (PC) (n=9); colorectal cancer (CRC) (n=5); breast cancer (n=3); non-small cell lung cancer (n=2); and pancreatic cancer, lymphoma, mesothelioma, leiomyosarcoma, thymic carcinoma, and unknown primary cancer (n=1 each). 11 pts received EZN-3042 (2.5 mg/kg: n=7, 5 mg/kg: n=3, 6.5 mg/kg: n=1) + D. Dose-limiting toxicity was observed in 3 pts at 8 mg/kg of SA EZN-3042 (Grade 3 increased aspartate or alanine aminotransferase [AST or ALT]) and in 1 pt who had received EZN-3042 (2.5 mg/kg) + D (Grade 3 neutropenic fever).The MTD for SA EZN-3042 is 6.5 mg/kg. Drug-related adverse events (AEs) (in &gt;15% pts) for SA EZN-3042 were AST increase (42%), ALT increase (38%), fatigue (33%), and diarrhea (17%). Drug-related AEs (in &gt;20% pts) for EZN-3042 + D were fatigue (64%), neutropenia (55%), alopecia (46%), anorexia (36%), and leukopenia and nausea (27% each). Most AEs were Grade 1 or 2. PK data for all 24 patients will be presented. Preliminary assessment of antitumor activity indicates that the best response for SA EZN-3042 was stable disease in 5 pts, including 1 pt with thymic carcinoma (5 mg/kg, 16 weeks); the best response for EZN-3042 (2.5 mg/kg) + D was a confirmed partial response in 1 pt with PC (27 weeks).
Conclusions: EZN-3042 was well tolerated in previously treated pts with advanced tumors. The MTD of SA EZN-3042 is 6.5 mg/kg.
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-409. doi:10.1158/1538-7445.AM2011-LB-409