Scientific publications
First-in-human study of JNJ-67571244, a CD33 × CD3 bispecific antibody, in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. Scientific Publication
Rupa Narayan 1 , Ana Alfonso Piérola 2 , William B Donnellan 3 , Antonieta Molero Yordi 4 , Maher Abdul-Hay 5 , Uwe Platzbecker 6 , Marion Subklewe 7 , Tapan Mahendra Kadia 8 , Juan Manuel Alonso-Domínguez 9 , James McCloskey 10 , Kathryn Bradford 11 , Martin Curtis 12 , Nikki Daskalakis 11 , Christina Guttke 11 , Karim Safer 11 , Brett Hiebert 13 , Joseph Murphy 14 , Xiang Li 11 , Ken Duchin 11 , Daniel Esteban 15
Abstract
Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ-67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS.
This first-in-human, open-label, phase I, dose-escalation/dose-expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ-67571244 was administered intravenously or subcutaneously using step-up dosing until ≥1 discontinuation condition was met.
Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose-escalation cohorts (n = 68) and before starting dose-expansion.
Overall, 11 (16.2%) patients experienced ≥1 dose-limiting toxicity; all experienced ≥1 treatment-emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ-67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion-related reactions, and elevated liver function tests.
A prolonged step-up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T-cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ-67571244 efficacy was not achieved, thus MTD and RP2D were not determined.
CITATION Clin Transl Sci. 2024 Mar;17(3):e13742. doi: 10.1111/cts.13742
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