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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Elsevier
2025-08-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328025000457 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Martin Hutchings |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0ddd98b17c994f3c99282e6a7bf0c763 |
| institution | Kabale University |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | Blood Neoplasia |
| spelling | doaj-art-0ddd98b17c994f3c99282e6a7bf0c7632025-08-20T03:32:40ZengElsevierBlood Neoplasia2950-32802025-08-012310011010.1016/j.bneo.2025.100110Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemiaMartin Hutchings0Koorosh Korfi1Pau Montesinos2Armando Santoro3Hsin-An Hou4Pilar Martinez-Sanchez5Susana Vives6Sara Galimberti7Tsai-Yun Chen8Marco Frigeni9Sylvain Garciaz10Olga Salamero Garcia11Su-Peng Yeh12Karen Yee13Jordi Esteve14Ashish Bajel15Shaun Fleming16Anne Catherine Bretz17Jan Attig18Min Sun19Sina Nassiri20Tobias Rutishauser21Christian Klein22Y. May Ma23Gabriel Schnetzler24Stephanie Vauleon25Huixin Yu26Teresa Barata27Muriel Richard28Silke Simon29Heather Hinton30Nino Keshelava31Marion Subklewe32Department of Hematology and Phase 1 Unit, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkRoche Pharma Research and Early Development, Oncology, Roche Innovation Center Zurich, Schlieren, SwitzerlandDepartment of Hematology, University Hospital of La Fe in Valencia, Valencia, SpainDepartment of Biomedical Sciences, Humanitas University, Milan, Italy; Medical Oncology and Hematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital - Humanitas Cancer Center, Milan, ItalyDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanDepartment of Hematology, Hospital Universitario 12 de Octubre, Madrid, SpainDepartament de Medicina, Hospital Universitario Germans Trias i Pujol-Institut Català d'Oncologia Badalona, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona, SpainDepartment of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, ItalyDivision of Hematology-Oncology, National Cheng Kung University Hospital, Tainan, TaiwanDepartment of Oncology and Hematology, Azienda Sociosanitaria Territoriale Papa Giovanni XXIII, Bergamo, ItalyDepartment of Hematology, Aix-Marseille University, INSERM, Centre national de la recherche scientifique, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, FranceDepartment of Hematology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology, Barcelona, SpainDepartment of Internal Medicine, China Medical University Hospital, Taichung, TaiwanCancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, CanadaDepartment of Hematology, Hospital Clinic de Barcelona, Barcelona, SpainDepartment of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, AustraliaDepartment of Hematology, The Alfred Hospital and Australian Centre for Blood Diseases, Monash University, Melbourne, AustraliaRoche Pharma Research and Early Development, Oncology, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandRoche Product Development, Data Science, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, SwitzerlandProduct Development Safety, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Oncology, Roche Innovation Center Zurich, Schlieren, Switzerland; Nino Keshelava, Roche Pharma Research and Early Development, Oncology, Roche Innovation Center Zurich, Wagistrasse 10, 8952 Schlieren, Switzerland;Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; Correspondence: Marion Subklewe, Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Marchioninistrasse 15, 81377 Munich, Germany;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.http://www.sciencedirect.com/science/article/pii/S2950328025000457 |
| spellingShingle | 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 Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia Blood Neoplasia |
| title | Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia |
| title_full | Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia |
| title_fullStr | Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia |
| title_full_unstemmed | Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia |
| title_short | Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia |
| title_sort | dose escalation study of the hla a2 wt1 cd3 bispecific antibody ro7283420 in relapsed refractory acute myeloid leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S2950328025000457 |
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