Interim Results of a First in Man Study with the Fc-Optimized FLT3 Antibody Flysyn for Treatment of Acute Myeloid Leukemia with Minimal Residual Disease
Authors: Kayser Sabine , Heitmann Jonas S. , Dörfel Daniela , Thol Felicitas , Heuser Michael , Märklin Melanie , Müller-Tidow Carsten , Steiner Martin , Grosse-Hovest Ludger , Jung Gundram , Schlenk Richard F. , Salih Helmut R. 
Published: November 2019

Background: Substantial surface expression of the FLT3 receptor can be measured on blast cells in 70% to 100% of acute myeloid leukemia (AML) patients, while no or only low levels are expressed on healthy cells like monocytes and progenitor stem cells. Thus, FLT3 is a suitable and highly selective target for therapeutic antibodies.
FLYSYN is a chimeric Fc-optimized IgG1 antibody and binds specifically and with high avidity to human FLT3 (CD135). Despite achievement of complete remission, roughly half of AML patients display minimal residual disease (MRD) after end of therapy and relapse.
Methods: We perform an open-label, single-arm, first in man multicenter trial to assess safety and tolerability as well as preliminary efficacy of FLYSYN as monotherapy in adult (≥18 years) AML patients in complete remission with MRD (NCT02789254). FLYSYN is administered as IV infusion over a 3 hour period. Recruitment started in March 2017 with an estimated maximum number of 31 patients and estimated recruitment until January 2020.
The main inclusion criterion was confirmed stable or increasing MRD positivity in two sequential measurements. MRD was measured by central RT-qPCR and/or next generation sequencing (NGS). Sensitivity with RT-qPCR (for NPM1 only) was 10-6 and 10-4 with NGS. Patients with acute promyelocytic leukemia as well as prior hematopoietic stem cell transplantation were excluded.
Using a "3 + 3" dose escalation design, five of the planned six cohorts with escalating doses have currently completed treatment (cohort 1: 0.5 mg/m² BSA; cohort 2: 1.5 mg/m² BSA; cohort 3: 5 mg/m² BSA; cohort 4: 15 mg/m² BSA; cohort 5: 45 mg/m²; cohort 6: in total 45 mg/m²; 15 mg/m² on day 1, 15 and 29). Three patients were treated per cohort, except for cohort 4, which was expanded to nine patients. The interim analysis for preliminary efficacy was performed after 18 patients were treated in cohorts 1-4. Response is defined as 1 log MRD reduction.
Results: Median age was 60 years (range, 21-80 years). Sixteen patients were MRD positive for NPM1 and one patient each for RUNX1-RUNX1T1 and IDH2.
So far, FLYSYN was well tolerated. Only one temporary grade 3 adverse event (AE) occurred (neutrophil decrease on day 3 only) in a patient of cohort 3, which was suspected to be related to FLYSYN treatment. There were no reported dose-limiting toxicities. The most frequently reported AEs were grade 1 and 2 gastrointestinal toxicities and laboratory abnormalities, which all were manageable with supportive care. After treatment, neither human anti-mouse nor anti-human antibodies were detected in any of the patients. Preliminary pharmacokinetic analysis was performed in the first 12 patients of the study and revealed a half-life of FLYSYN of roughly 6.5 days.
Regarding preliminary efficacy, 1 patient of cohort 1 achieved permanent MRD negativity in bone marrow (BM; lasting until day 545) and 1 patient a temporary BM MRD reduction (at day 15). One patient of cohort 2 achieved BM MRD negativity (day 22) with MRD progression on day 365, whereas the other 2 patients were BM MRD progressive. None of the patients of cohort 3 achieved a MRD response in BM, but 2 patients achieved a temporary MRD response in peripheral blood. Four patients of cohort 4 achieved non-permanent BM MRD negativity. Overall, 6 patients achieved BM MRD negativity (33 %, 6/18), enduring more than 1 year in 1 patient.
Conclusions: Our data suggest that FLYSYN is safe and very well tolerated as monotherapy in MRD positive AML patients. Preliminary efficacy data are promising, and recruiting is ongoing in cohort 6 in which 15 mg/m² FLYSYN is given for three times. Up-dated results will be presented at the ASH meeting.

Disclosures
Heuser: Bayer Pharma AG, Berlin: Research Funding; Synimmune: Research Funding. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Steiner:Synimmune: Employment, Other: shareholder interest. Grosse-Hovest:SYNIMMUNE: Employment, Other: shareholder interest. Jung:Synimmune: Other: shareholder interest. Salih:SYNIMMUNE: Consultancy, Research Funding.