FLYSYN in MRD Positive AML (FLYSYN-101)

First in Man Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Fc-optimized FLT3 Antibody FLYSYN for the Treatment of Acute Myeloid Leukemia Patients With Minimal Residual Disease

This is a first in human, prospective, multicentric, nonrandomized, open-label study to investigate the safety, tolerability, preliminary efficacy, pharmacokinetics, pharmacodynamics and immunogenicity of the Fc-optimized antibody FLYSYN as monotherapy in adult subjects.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Biological: FLYSYN

Detailed Description

Cohort 1:

Patient 1-3: FLYSYN 0.5 mg/m² body surface area (BSA) day 1

Cohort 2:

Patient 4-6: FLYSYN 0.5 mg/m² body surface area (BSA) day 1 FLYSYN 1.0 mg/m² BSA day 2

Cohort 3:

Patient 7-9: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 4.5 mg/m² BSA day 2

Cohort 4:

Patient 10-12 and 13-18: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 14.5 mg/m² BSA day 2

Cohort 5:

Patient 19-21: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 44.5 mg/m² BSA day 2

Cohort 6:

Patient 22-24 and 25 -31: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 14.5 mg/m² BSA day 2, FLYSYN 15 mg/m² BSA day 15, FLYSYN 15 mg/m² BSA day 29

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Heidelberg, Germany, 69120
    • University Hospital of Heidelberg
  • Leipzig, Germany, 04103
    • University of Leipzig Medical Center
  • Baden-Wuerttemberg
    • Tuebingen, Baden-Wuerttemberg, Germany, 72076
      • University Hospital Tuebingen
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • University Hospital Ulm
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Hannover Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years at the time of voluntarily signing an IEC-approved informed consent, there is no upper age limit
• Diagnosis of AML according to WHO criteria
• Confirmed FLT3 expression on leukemic cells
• Known mutational status of FLT3 (FLT3-ITD, FLT3-TKD, FLT3 wild type)
• Hematological CR (ANC count >1.000/μL, Thrombocytes > 100.000/μL), but MRD positivity (determined by NGS and NPM1 RT-PCR, where applicable) after any therapy except allogeneic stem cell transplantation
• Life expectancy of > 3 months
• ECOG performance status ≤ 2
• Subject must be willing to receive transfusion of blood products
• Be willing and able to comply with the study protocol for the duration of the study
• Females of childbearing potential (FCBP) must undergo repetitive pregnancy testing (serum or urine) and results must be negative
• Reliable contraception should be maintained throughout the study and for 6 months after study treatment
• Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods
• Males (including those who have had a vasectomy) must use an effective barrier method of contraception throughout the study and for 6 months after study treatment if sexually active with a female of childbearing potential

• All subjects must:

  • understand that the investigational product could have a potential teratogenic risk.
  • be counseled about pregnancy precautions and risks of fetal exposure.
  • be able to comply with all study-related procedures, medication use, and evaluations.

Exclusion Criteria:

The presence of ANY of the following criteria will exclude a patient from study enrollment:

• Patients proceeding to hematopoietic stem cell transplantation (suitable candidate and donor available, informed consent of patient)
• Pregnant or breast feeding females
• >5% blasts in bone marrow or extramedullary disease
• Treatment with monoclonal antibody within 3 months before treatment with FLYSYN or known immunoglobulin intolerance
• Known positivity for HIV, active HBV, HCV, or Hepatitis A infection
• No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician and/or other physicians involved in the treatment about study participation
• No consent for biobanking
• Presence of any medical/psychiatric condition or laboratory abnormalities which may limit full compliance with the study, increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• Prior history of malignancies, other than AML/MDS, unless the subject has been free of the disease for ≥ 2 years. Exceptions include the following: Basal cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, histological finding of prostate cancer of TNM stage T1
• Patients receiving any medication listed in the Appendix IV "Prohibited Medications" (within 14 days prior to the first dose of study drug)
• Uncontrolled infection, e.g. infection progressing under adequate antimicrobial/antifungal/antiviral treatment
• Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 14 days of screening
• Current treatment with immunosuppressive agents
• Systemic diseases (cardiovascular, renal, hepatic, etc.) that would prevent study treatment (e.g., creatinine >1.5x upper normal serum level; bilirubin, AST or AP >2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental: FLYSYN; IV infusion over a 3-hr duration

Biological: FLYSYN; Cohort 1: Patient 1-3: FLYSYN 0.5 mg/m² BSA* day 1 Cohort 2: Patient 4-6: FLYSYN 0.5 mg/m² BSA day 1 FLYSYN 1.0 mg/m² BSA day 2 Cohort 3: Patient 7-9: FLYSYN 0.5 mg/m² BSA day 1, FLYSYN 4.5 mg/m² BSA day 2 Cohort 4: Patient 10-12 and 13-18: FLYSYN 0.5 mg/m² BSA day 1, FLYSYN 14.5 mg/m² BSA day 2 Cohort 5: Patient 19-21: FLYSYN 0.5 mg/m² BSA day 1, FLYSYN 44.5 mg/m² BSA day 2 Cohort 6: Patient 22-24 and 25-31: FLYSYN 0.5 mg/m² BSA day 1, FLYSYN 14.5 mg/m² BSA day 2, FLYSYN 15 mg/m² BSA day 15, FLYSYN 15 mg/m² BSA day 29 * The maximum upper limit for calculation of antibody dose is fixed at a body surface of 2.0 m², even if the calculated body surface exceeds this. In this study DLT are defined as the following treatment-related adverse events or laboratory abnormalities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence and severity of adverse events (AE) (CTCAE V 4.03)	until 28 days (i.e. Visit7, day 29) after last dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events (AE) (CTCAE V 4.03)		until 180 days (i.e.Visit 11, day 180) after last dosing
Pharmacokinetics and pharmacodynamics		Visit 1 to 13
Immunogenicity of FLYSYN based on both absolute (number and percentage of subjects who develop HAMA/HAHA) and semi-quantitative (HAMA/HAHA titer determination of confirmed positive samples) assessments		BSL; Visits 5-7;9-13
Absolute and percent change from baseline in measurements of B, T, and NK cell populations and activation	For evaluation of the status of the immune system, B, T, and NK cells will be measured frequently throughout the study (immune status). The percentage and absolute numbers as well as the absolute and percent changes from baseline of NK cells will be evaluated (determination of absolute NK cell numbers). If feasible, CD16 and CD69 expression on NK cells will be evaluated at baseline and after antibody exposition (NK cell activation). Pending sample availability, endogenous antibody titers (e.g., tetanus titers) will be measured from remaining PK back-up samples in order to gain information about the influence of FLYSYN treatment on normal plasma cells and immunity.	Visits 1;3;4;5;9
Change in cytokines from baseline		Visits 1-3;5 +6
Overall response rate, defined as MRD negativity or reduction of at least one log step,		BSL; Visits1;4-13
Duration of response, time to MRD progression (log step), time to relapse		BSL; Visits1;4-13
Absolute change from baseline in overall quality of life scores (EORTC QLQ C-30)		Visit 1, Visit 6,Visit 9,Visit 10, Visit 11, Visit 12, Visit 13

Collaborators and Investigators

• Sponsor: Synimmune GmbH
• Investigators: Principal Investigator: Helmut Salih, Prof. Dr., Department of Internal Medicine, Internal Medicine II; Oncology, haematology, clinical immunology, rheumatology and pneumology University Hospital Tuebingen

Publications and helpful links

General Publications

• Heitmann JS, Schlenk RF, Dorfel D, Kayser S, Dohner K, Heuser M, Thol F, Kapp-Schwoerer S, Labrenz J, Edelmann D, Marklin M, Vogel W, Bethge W, Walz JS, Grosse-Hovest L, Steiner M, Jung G, Salih HR. Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease. J Hematol Oncol. 2023 Aug 17;16(1):96. doi: 10.1186/s13045-023-01490-w.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2017
• Primary Completion (Actual): September 27, 2021
• Study Completion (Actual): September 27, 2021

Study Registration Dates

• First Submitted: May 13, 2016
• First Submitted That Met QC Criteria: May 27, 2016
• First Posted (Estimated): June 2, 2016

Study Record Updates

• Last Update Posted (Actual): December 28, 2023
• Last Update Submitted That Met QC Criteria: December 21, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: stem cell transplantation; AML; Leukemia; acute myeloid leukemia; antibodies; complete remission; Fms-like receptor tyrosine kinase (FLT3); CD135; Fc-optimized
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: FLYSYN_Version 6.1-17.09.2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: publication

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No