Abstract Background: Survivin, a member of the inhibitors of apoptosis protein gene family, is a compelling molecular target in cancer research. In addition to modulating apoptosis, survivin acts as an essential regulator of mitosis. Overexpression of survivin in many cancers is correlated with advanced disease and reduced survival. EZN-3042 is a potent locked nucleic acid antisense oligonucleotide that down-modulates survivin mRNA and consequently protein in vitro (IC50 <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/recommended dose, PK, pharmacodynamics (PD), and preliminary evidence of antitumor activity of EZN-3042 as a SA and in combination (E+D). Using a novel dose-escalation design, patients with advanced tumors first received SA EZN-3042 as a 2-h IV infusion qwk (2 doses Wk 1). After disease progression following SA therapy, patients could receive EZN-3042 (qwk) + docetaxel (75 mg/m2 q3wk). Dose escalation (3+3) for SA and for the combination of E+D was independently based on toxicities observed during Cycle 1 of SA or E+D, respectively (CASA modified Fibonacci dose escalation). Results: Ten patients (8 men; median age = 64 y [46–70 y]) received SA doses of 2.5 mg/kg (n=3), 5 mg/kg (n=3), and 8 mg/kg (n=4). Tumor types included colorectal (CRC) (n=5), prostate (PC) (n=4), and unknown primary (n=1) cancers. Nine patients had received multiple prior chemotherapies (median number of prior regimens = 2; range = 1–6). Five patients (all men) received E (2.5 mg/kg) + D. Dose-limiting toxicity (DLT) was observed in 1 patient in Cohort 3 who had received 8 mg/kg of SA EZN-3042 (DLT = Grade 3 increased aspartate aminotransferase [AST]) and in 1 patient who had received E+D (DLT = Grade 3 neutropenic fever). The most common drug-related adverse events (AEs) (in >2 patients) for SA EZN-3042 were fatigue (70%); neutropenia (40%); and alopecia, anorexia, AST increase, diarrhea, leukopenia, and nausea (30% each). The most common drug-related AEs (in >2 patients) for E+D were neutropenia and fatigue (80% each); and alopecia, anorexia, and leukopenia (60% each). Overall, most AEs were Grade 1 or 2. All 10 patients who received SA treatment provided data for PK analysis. A qualitative assessment of the PK data indicated that the EZN-3042 concentration appears to increase in a dose-proportional manner at the doses evaluated. Preliminary assessment of antitumor activity indicates that the best response for SA EZN-3042 was stable disease in 1 patient with CRC (8 mg/kg, 6 weeks); the best response for E+D was a confirmed partial response for E+D in 1 patient with PC (21 wks). Conclusions: EZN-3042 was well tolerated in previously treated patients with advanced tumors. Dose escalation is ongoing; updated results will be presented at the meeting. The CASA dose-escalation design is an innovative approach that allows one to follow the safety and efficacy of SA and combination therapy in the same patient. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A99.