First-in-Human Study of JNJ-63709178, a CD123/CD3 Targeting Antibody, in Relapsed/Refractory Acute Myeloid Leukemia.

This study aimed to identify a recommended Phase 2 dose and evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity of JNJ-63709178, a CD123/CD3 dual-targeting antibody, in patients with relapsed or refractory acute myeloid leukemia. Intravenous (IV) and subcutaneous (SC) administration of JNJ-63709178 were evaluated. IV infusions were administered once every two weeks (Cohorts 1-5 [n = 17]) or twice weekly (Cohorts 6-11 [n = 36]). A twice-weekly subcutaneous (SC) dosing regimen with step-up dosing was also studied (SC Cohorts 1-2 [n = 9]). Treatment-emergent adverse events (TEAE) ≥ Grade 3 were observed in 11 (65%) patients in Cohorts 1-5 and 33 (92%) patients in Cohorts 6-11. At the highest IV dose (4.8 μg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For SC administration (n=9), 8 (89%) patients experienced TEAEs ≥ Grade 3 and injection site reactions (≤ Grade 3) emerged in all patients. At 4.8 μg/kg (IV and SC), the mean maximum serum concentrations were 30.3 ng/mL and 3.59 ng/mL, respectively. Increases in multiple cytokines were observed following IV and SC administrations, and step-up dosing strategies did not mitigate cytokine production or improve the safety profile and led to limited duration of treatment. Minimal clinical activity was observed across all cohorts. IV and SC dosing of JNJ-63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended Phase 2 dose.