Background: TRX518 is a novel, fully humanized agylcosyl IgG1 anti-GITR mAb. GITR is a member of the tumor necrosis factor receptor family expressed on T, B, & NK cells, and antigen presenting cells. GITR is expressed at high levels by Tregs and up-regulated following T cell activation; minimally expressed by nazve CD4+ and CD8+ T cells. Signaling through GITR abrogates Treg mediated suppression and enhances CD4+ and CD8+ T cell proliferation and TCR stimulation. GITR signaling may enhance host immune responses against tumor and aid in tumor rejection. This study evaluated the safety of a single dose of TRX518 in pts with advanced refractory solid tumors. Methods: Pts received a single dose of TRX518 on Day 1; doses ranged from 0.0001 to 8 mg/kg in 9 cohorts of up to 6 pts/cohort. The study was to determine safety and tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK), and pharmacodynamic (PD) profiles of TRX518. Efficacy was evaluated with the immune related response criteria (irRC). Results: 40 pts enrolled; 10 melanoma; 9 NSCLC; 7 colorectal cancer; and 14 pts with 13 other solid tumors; Median age 57.5 yrs; Male 60%; Karnofsky PS 70-80% in 35% pts. Median prior systemic therapies 3 (range 1, 9); 30% with prior immunotherapy. TRX518 was well tolerated with no dose limiting toxicities, related serious adverse events or related treatment emergent adverse events (TEAE) > Grade 2. TEAE ≥ 15% included: cough, fatigue (28% each); vomiting, abdominal pain, nausea (18% each); dyspnea and anorexia (15% each). TRX518 exposure increased dose proportionally; mean half-life ranged from 179 to 364 hours. Saturation of T lymphocytes in peripheral blood was observed in all doses ≥ 0.5 mg/kg. Low levels of anti-drug antibodies was observed in 21 pts with a median titer of 1:184; little-to-no impact on TRX518 levels. Limited efficacy data was available (n = 28); 4 pts achieved a best response of stable disease (irSD). Conclusions: Single dose of TRX518 up to 8 mg/kg was safe and well tolerated. Further investigation is ongoing; a multi-dose study is planned to further evaluate anti-tumor activity. Clinical trial information: NCT01239134.