Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease

Journal of Hematology & Oncology

Research

Melanie Märklin¹  Helmut R. Salih¹  Jonas S. Heitmann¹  Juliane S. Walz²  Daniela Dörfel³  Felicitas Thol⁴  Michael Heuser⁴  Wolfgang Bethge⁵  Wichard Vogel⁵  Konstanze Döhner⁶  Silke Kapp-Schwoerer⁶  Gundram Jung⁷  Jannik Labrenz⁸  Richard F. Schlenk⁹  Dominic Edelmann^1,10  Sabine Kayser^1,11  Martin Steiner^1,12  Ludger Große-Hovest^1,12 

[1] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, University of Tübingen, Tübingen, Germany;Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany;Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, University of Tübingen, Tübingen, Germany;Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany;Department of Peptide-Based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany;Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany;Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, University of Tübingen, Tübingen, Germany;Department of Hematology, Oncology and Immunology, KRH Klinikum Siloah, Hannover, Germany;Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany;Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany;NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany;NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany;Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany;NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany;Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany;NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany;Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany;Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany;Synimmune GmbH, Tübingen, Germany;

关键词: AML;    MRD;    FLT3;    Fc-optimized antibody;    Immunotherapy;   

DOI  :  10.1186/s13045-023-01490-w

 received in 2023-05-30, accepted in 2023-07-28,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAbout half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells.MethodsThis first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1–5: single dose of 0.5 mg/m2, 1.5 mg/m2, 5 mg/m2, 15 mg/m2, 45 mg/m2; cohort 6: 15 mg/m2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow.ResultsOverall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses.ConclusionsFLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial.Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254).

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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