Background: T cell-based bispecific agents have shown activity in hematologic cancers, but solid tumor efficacy remains elusive. IMCgp100 is a bispecific biologic comprising an affinityenhanced TCR specific for gp100 and an anti-CD3 scFV. In vitro, IMCgp100 binds gp100+ melanoma cells causing redirection of cytotoxicity and induction of potent immune effects. Methods: The Phase I was conducted in HLA-A2+ pts with advanced melanoma, using a 3+3 design to define the MTD. Pts were treated with IMCgp100 (iv) weekly (QW, Arm 1) or daily (4QD3W, Arm 2) to evaluate safety, PK and efficacy. The recommended phase 2 regimen (RP2D-QW) was defined. Results: In the Ph I dose escalation,31 pts received doses from 5ng/kg to 900ng/kg. In arm 1 dose-limiting toxicity of gr 3 or 4 hypotension was seen and associated with rapid trafficking of peripheral lymphocytes to skin and tumor. The MTD was determined to be 600ng/kg QW. IMCgp100 has an approximately dose-proportional profile with a plasma T_1/2 of 5-6 hrs at the RP2D; pharmacodynamic effects of chemokine/cytokine release and lymphocyte infiltration into tumors was observed over 2 days post dose. Frequent related AEs (any grade) include rash (100%), pruritus (64%), pyrexia (50%), and periorbital edema (46%). Gr 3 or 4 related AE were observed in the first 3 weeks and include rash (23%), hypotension (6%) and lymphopenia (8%). Hypotension observed at the first doses was consistent with chemokine release (CXCL9, CXCL10) and movement of lymphocytes into tissues and, rarely associated with cytokine release syndrome (IL-6, IL-10, IFNg). To mitigate risk of severe hypotension, flat dosing and an intra-patient escalation regimen of IMCgp100 were implemented. At the RP2D, 26 pts were evaluable for efficacy; confirmed PR were seen in 4 pts (2 uveal (UM) and 2 cutaneous (CM), including patients refractory to checkpoint agents) and 12 pts had SD. Of the 12 pts with SD, minor responses (>10% shrinkage) were seen in 3 pts. Conclusions: IMCgp100 is a first in class TCR anti-CD3 bispecific T cell redirector with a favorable safety profile and durable responses in melanoma (CM and UM). Ph II development in CM and UM is ongoing. Clinical trial information: NCT01211262