Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia

Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia

Abstract: A novel T-cell bispecific antibody (TCB), RO7283420, engaging CD3 and the HLA-A2-Wilms tumor protein 1 complex, was evaluated in this phase 1 study to characterize safety and tolerability, determine the maximum tolerated dose (MTD), and recommend a phase 2 dose for patients with relapsed/r...

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Main Authors: Martin Hutchings, Koorosh Korfi, Pau Montesinos, Armando Santoro, Hsin-An Hou, Pilar Martinez-Sanchez, Susana Vives, Sara Galimberti, Tsai-Yun Chen, Marco Frigeni, Sylvain Garciaz, Olga Salamero Garcia, Su-Peng Yeh, Karen Yee, Jordi Esteve, Ashish Bajel, Shaun Fleming, Anne Catherine Bretz, Jan Attig, Min Sun, Sina Nassiri, Tobias Rutishauser, Christian Klein, Y. May Ma, Gabriel Schnetzler, Stephanie Vauleon, Huixin Yu, Teresa Barata, Muriel Richard, Silke Simon, Heather Hinton, Nino Keshelava, Marion Subklewe
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Blood Neoplasia
Online Access:http://www.sciencedirect.com/science/article/pii/S2950328025000457
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Summary:Abstract: A novel T-cell bispecific antibody (TCB), RO7283420, engaging CD3 and the HLA-A2-Wilms tumor protein 1 complex, was evaluated in this phase 1 study to characterize safety and tolerability, determine the maximum tolerated dose (MTD), and recommend a phase 2 dose for patients with relapsed/refractory acute myeloid leukemia in 2 groups: hematologic (group I, n = 57) and molecular (group 2, n = 5) relapse. In group I, 51 received RO7283420 intravenously (IV) and 6 subcutaneously. The IV doses ranged from 0.15-4 mg (flat; n = 13), 3-18 mg (step-up; n = 34) every 3 weeks, or 9 mg weekly (step-up; n = 4). The MTD was 1/3/12 mg every 3 weeks. The most frequent adverse event in the overall population was cytokine release syndrome (61.3%) with grade ≥3 recorded in 9.7% of patients. Twelve dose-limiting toxicities were reported in 11 patients and 12 (19.4%) grade 5 adverse events, including 1 hemophagocytic lymphohistiocytosis case related to RO7283420. Among the 42 efficacy-evaluable IV patients in group I, 4.8% achieved complete remission (CR), and 2.4% achieved CR with incomplete hematologic recovery. RO7283420 induced pharmacodynamic changes in peripheral blood (PB) at doses ≥1 mg, including significant T-cell activation and expansion in the PB and bone marrow (BM). Significant associations were found between blast reduction and baseline immunophenotype, including lower regulatory T cells and higher non-exhausted CD8+ T cells in BM. Although dose escalation was discontinued because of limited efficacy and lack of an exposure-BM response relationship, the observed pharmacodynamics underscore the promising potential of this class of TCBs targeting intracellular antigens. This trial was registered at www.clinicaltrials.gov as #NCT04580121.
ISSN:2950-3280

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