Journal for immunotherapy of cancer · 2026
Phase 1/2 study of IMC-C103C, a T cell receptor bispecific (MAGE-A4×CD3) ImmTAC targeting MAGE-A4-expressing malignancies.
СтатьяКлиническое исследование I фазыКлиническое исследование II фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Sweis Randy F, Melero Ignacio, Davar Diwakar, Garralda Elena, Hamid Omid, Chen Hui Amy, Evans Thomas R Jeffry, Moore Kathleen N, Sacco Joseph J, Thistlethwaite Fiona, Williams Anja, Blumenschein George R, Callahan Margaret K, Johnson Melissa L, Schenk Erin L, Wustner Jason, Stanhope Sarah, Tao Kaixiang, Marshall Shannon, Lopez Juanita
Аннотация
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.
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.