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1957 First-in-Human Phase I Dose Escalation and Expansion Study Evaluating the Fc Optimized FLT3 Antibody Flysyn in Acute Myeloid Leukemia Patients with Minimal Residual Disease

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
AML, Biological, antibodies, Adult, Diseases, Therapies, Study Population, Myeloid Malignancies, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Jonas S. Heitmann, MD1*, Daniela Dörfel, MD1,2*, Sabine Kayser, MD3,4, Michael Heuser5, Felicitas Thol5, Silke Kapp-Schwoerer, MD6*, Wolfgang Bethge, MD7*, Ludger Grosse-Hovest8*, Martin Steiner8*, Melanie Märklin, PhD1*, Juliane S. Walz, MD1,2*, Richard F. Schlenk9,10, Gundram Jung, MD11* and Helmut R. Salih12

1Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
2Department of Hematology and Oncology, University Hospital Tuebingen, Tuebingen, Germany
3Department of Hematology, University Hospital of Leipzig, Leipzig, Germany
4German Cancer Research Center (DKFZ), Heidelberg, Germany
5Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
6Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
7University Hospital Tübingen, Tübingen, Germany
8SYNIMMUNE GmbH, Tübingen, Germany
9Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
10National Center of Tumor Diseases, NCT-Trial Center, German Cancer Research Center, Heidelberg, Germany
11Department for Immunology, Eberhard Karls University, Tuebingen, Germany
12Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tuebingen, Germany

Even when achieving morphological complete remission (CR) after induction therapy, roughly half of acute myeloid leukemia (AML) patients display measurable residual disease (MRD) and eventually relapse. The surface receptor FLT3/CD135 is expressed on AML cells in almost all patients and constitutes a highly selective target antigen for immunotherapy, as expression on healthy tissues is limited to low levels on dendritic cells, monocytes and hematopoietic progenitor cells. FLYSYN is a chimeric Fc-optimized IgG1 antibody that binds specifically and with high avidity to human FLT3 (CD135). Here we report updated results of an open-label, single-arm, first in man multicenter trial (recruitment March 2017 to March 2020) evaluating safety/tolerability and preliminary efficacy of FLYSYN in patients with AML (NCT02789254). Morphological CR with stable or increasing MRD in two sequential measurements using central RT-qPCR and/or next generation sequencing (NGS) constituted the main inclusion criterion. FLYSYN was administered i.v. over 3 h as single application in cohorts 1-5 (0.5 mg/m², 1.5 mg/m², 5 mg/m², 15 mg/m², 45 mg/m²); in cohort 6, 15 mg/m² were applied on day 1, 15 and 29. Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to comprise 9 and 10 patients, respectively. Molecular response was defined as >1 log MRD reduction or negativity in bone marrow (BM). In total, 31 patients (median age 58 years; range, 21-80 years; male:female ratio: 1:1.8) were enrolled, of which 27, 3 and 1 were MRD-positive for mutated NPM1, mutated IDH2 and RUNX1-RUNX1T1, respectively. Based on pharmacokinetic analysis, the half-life of FLYSYN was estimated to be 6.5 days. In 8 patients (26%), a transient decrease of neutrophil count (2 adverse events (AEs) grade 3, others ≤ grade 2) was observed. No relevant effect on stem cell reserve as assessed by colony forming unit assays was detected in the so far analyzed 26 patients. No other AE > grade 2 or dose-limiting toxicity were observed. The most frequent AEs were unspecific and comprised fatigue and flu like symptoms (12%), musculoskeletal symptoms (8%) and laboratory abnormalities (42%). With regard to efficacy, molecular response to treatment was achieved in 11/31 patients (35%), with so far two patients achieving MRD negativity documented one year after treatment. Among the patients receiving 45 mg/m2 FLYSYN (in total, upon single or repetitive dosing), objective responses were achieved in 46% (6/13) cases, whereas 28% (5/18) responded to treatment with lower doses.

Together, the results of our phase I trial demonstrate that FLYSYN is safe and very well tolerated as monotherapy in AML patients with molecular MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II clinical trial.

Disclosures: Heuser: PriME Oncology: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy; Janssen: Consultancy; Astellas: Research Funding; Roche: Research Funding; BerGenBio ASA: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Abbvie: Consultancy. Thol: Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kapp-Schwoerer: Jazz Pharmaceuticals: Honoraria, Research Funding. Grosse-Hovest: Synimmune: Current Employment. Steiner: Synimmune: Current Employment. Schlenk: Roche: Research Funding; Novartis: Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; PharmaMar: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Salih: Pfizer: Consultancy; Medigene: Consultancy; Novartis: Consultancy; Philogen: Consultancy; Synimmune: Consultancy, Research Funding.

*signifies non-member of ASH