| Abstract: |
Background. This first-in-human study evaluated EGFRvIII × CD3 TCB, a novel T cell bispecific antibody, in patients with newly diagnosed EGFRvIII-positive glioblastoma. Methods. Patients with newly diagnosed glioblastoma received escalating doses of EGFRvIII × CD3 TCB following chemoradiation. The primary objectives were to evaluate safety/tolerability and define the maximum tolerated dose (MTD); secondary objectives included pharmacokinetics (PK), immunogenicity, pharmacodynamics, and clinical activity. Results. Thirty-six patients were enrolled, 32 with unmethylated and 4 with methylated MGMT promoter. EGFRvIII × CD3 TCB doses ranged from 0.004 to 10 mg Q3W, administered either on a flat or step-up dose schedule. One DLT occurred (grade 3 seizure). The MTD was not reached. Most adverse events (AEs) were of grade 1-2 severity, with headache being the most common treatment-related AE (22%). EGFRvIII × CD3 TCB showed dose-proportional PK in serum and cerebrospinal fluid (CSF), with a CSF/serum ratio of 0.08. At the highest dose tested, 10 mg Q3W, maximum serum concentrations remained 6-fold below the lower boundary of the predicted anticipated therapeutic dose. Conclusions. The administration of EGFRvIII × CD3 TCB in a maintenance setting, following standard of care treatment, was safe and well tolerated up to the highest tested dose of 10 mg Q3W. However, evidence of efficacy was not observed at the evaluated doses, suggesting that a study of higher dose levels may be warranted. © 2025 Elsevier B.V., All rights reserved. |
