Eiu-104101: A first-in-human phase 1a/1b study of EVOLVE104, a trispecific CD3×CD2×ULBP2/5/6 T-cell engager, in advanced urothelial and squamous cell carcinomas.

Abstract

TPS2682 Background: EVOLVE T cell engagers (TCEs) bind to a tumor antigen and to both CD3 and CD2 on T cells, thereby providing integrated costimulation via CD2 binding. EVOLVE TCEs demonstrate superior T cell activation and tumor cell killing compared to first generation TCEs, without excess cytokine release or tonic T cell activation, and may offer clinical benefits such as enhanced potency and duration of activity. UL16 binding proteins 2, 5 and 6 (ULBP2/5/6) belong to a family of cell surface proteins that are ligands for the NKG2D receptor. We have previously reported that cell-surface ULBP2/5/6 is not present in vital organs and found in some mucosal epithelia. Cell surface ULBP2/5/6 is found in urothelial carcinomas and squamous cell carcinomas (SCCs). With high expression on malignant cells and limited normal tissue expression, ULBP2/5/6 are intriguing targets for cancer immunotherapy. EVOLVE104 is a trispecific TCE that binds ULBP2/5/6 and both CD3 and CD2 on T cells. Preclinical studies with EVOLVE104 demonstrated enhanced T cell activation and killing of ULBP2/5/6-positive tumor cells compared to bispecific TCEs, and no safety concerns were identified in preclinical toxicity studies. With this encouraging preclinical profile, EVOLVE104 represents a novel approach to redirected T cell therapy in solid tumors. Methods: EIU-104101 is a first-in-human phase 1a/1b study evaluating EVOLVE104 monotherapy in adults with advanced solid tumors. Eligible tumor types include urothelial carcinoma of the bladder and SCCs of the bladder, lung, esophagus, tongue, skin, and anogenital region (penis, anus, vagina, vulva, cervix, and urethra). Subjects must have locally advanced or metastatic disease that has relapsed from, or is refractory to, standard-of-care therapies. Study objectives include assessing the safety, efficacy, pharmacokinetics and pharmacodynamics of EVOLVE104 and identifying the recommended phase 2 dose (RP2D). The phase 1a portion of the study will enroll up to 80 subjects using a Bayesian optimal interval (BOIN) dose-escalation scheme including backfill at dose levels deemed safe, with a key objective to identify one or more recommended doses for expansion (RDEs). Phase 1b includes two expansion cohorts: Cohort A, which will be a dose optimization cohort in a single indication (to be determined based on the phase 1a observations) in which 40 subjects will be randomized 1:1 to two RDEs to determine the RP2D; and Cohort B, which will enroll up to 40 subjects in other relevant indications. The study opened in October 2025 and is actively enrolling at US sites. ClinicalTrials.gov Identifier: NCT07217171. Clinical trial information: NCT07217171 .