학술논문

First‐in‐human study of JNJ‐63709178, a CD123/CD3 targeting antibody, in relapsed/refractory acute myeloid leukemia
Document Type
article
Source
Clinical and Translational Science, Vol 16, Iss 3, Pp 429-435 (2023)
Subject
Therapeutics. Pharmacology
RM1-950
Public aspects of medicine
RA1-1270
Language
English
ISSN
1752-8062
1752-8054
Abstract
Abstract This study aimed to identify a recommended phase II 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 (i.v.) and subcutaneous (s.c.) administration of JNJ‐63709178 were evaluated. The i.v. infusions were administered once every 2 weeks (cohorts 1–5 [n = 17]) or twice weekly (cohorts 6–11 [n = 36]). A twice‐weekly s.c. dosing regimen with step‐up dosing was also studied (s.c. cohorts 1–2 [n = 9]). Treatment‐emergent adverse events (TEAEs) greater than or equal to grade 3 were observed in 11 (65%) patients in cohorts 1–5 and 33 (92%) patients in cohorts 6–11. At the highest i.v. dose (4.8 μg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For s.c. administration (n = 9), eight (89%) patients experienced TEAEs greater than or equal to grade 3 and injection site reactions (≤ grade 3) emerged in all patients. At 4.8 μg/kg (i.v. and s.c.), the mean maximum serum concentrations were 30.3 and 3.59 ng/ml, respectively. Increases in multiple cytokines were observed following i.v. and s.c. 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. The i.v. and s.c. dosing of JNJ‐63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended phase II dose.