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Purpose IMC-C103C is an ImmTAC bispecific (MAGE-A4×CD3) T cell engager targeting a peptide from the cancer-testis antigen MAGE-A4 presented by HLA-A*02:01. This phase 1/2 study in advanced solid tumors (IMC-C103C-101; NCT03973333) investigated the safety and preliminary anti-tumor activity of IMC-C103C.Methods HLA-A*02:01 + patients with previously treated advanced solid tumors received IMC-C103C by weekly intravenous infusion, with step-up dosing introduced at higher dose levels. Dose-escalation decisions were guided by the mTPI-2 method. Key objectives included evaluating safety and preliminary anti-tumor activity; pharmacokinetics, pharmacodynamics, and biomarkers were also assessed.Results 68 patients were enrolled in 10 dose-escalation cohorts (n=56; 64% ovarian carcinoma (OC)) and one OC expansion cohort (n=12). In dose escalation, patients received doses ranging from 0.5 to 240 µg. The dose-limiting toxicity rate at the two highest dose levels (1/6 and 2/10) did not exceed the maximum tolerated dose. A lower-dose regimen of 15–45-140 µg, with clinical activity, and a more favorable tolerability profile, was selected as the expansion dose. There were no treatment-related discontinuations or deaths. The most common treatment-related adverse events were cytokine-mediated, including grade 1/2 cytokine release syndrome and associated symptoms. While MAGE-A4 expression was observed in most patient’s tumors (71% positive), the level of expression was low (median H-score=16). Initial clinical and pharmacodynamic activity was observed at doses of 15 µg, with more consistent activity observed at doses ≥90 µg. At doses ≥90 µg, patients with MAGE-A4 + OC had deeper reductions in tumor size and circulating tumor DNA and trended to have longer overall survival than patients with MAGE-A4– OC.Conclusions IMC-C103C was well tolerated at doses up to 140 µg, induced dose-dependent pharmacodynamic changes, and demonstrated clinical activity in multiple patients with MAGE-A4 + solid tumors. Clinical activity was dependent on MAGE-A4 expression; however, expression was especially low in the higher dosing cohorts, limiting adequate efficacy assessment.Trial registration number NCT03973333.