FLYSYN in MRD Positive AML

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Biological: FLYSYN

• Registration Number: NCT02789254
• Lead Sponsor: Synimmune GmbH

Brief Summary

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.

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 Timeline

• Study First Submitted: 2016-05-13
• Study First Submitted QC: 2016-05-27
• Study First Posted: 2016-06-02
• Study Start: 2017-02-07
• Primary Completion: 2021-09-27
• Study Completion: 2021-09-27
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-21
• Last Update Posted: 2023-12-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental: FLYSYN	FLYSYN	IV infusion over a 3-hr duration

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Pharmacokinetics and pharmacodynamics	Visit 1 to 13
Duration of response, time to MRD progression (log step), time to relapse	BSL; Visits1;4-13
Change in cytokines from baseline	Visits 1-3;5 +6
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
Incidence and severity of adverse events (AE) (CTCAE V 4.03)	until 180 days (i.e.Visit 11, day 180) after last dosing
Absolute and percent change from baseline in measurements of B, T, and NK cell populations and activation	Visits 1;3;4;5;9	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.
Overall response rate, defined as MRD negativity or reduction of at least one log step,	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

Trial Locations

Locations (5)

University Hospital Tuebingen; 🇩🇪 Tuebingen, Baden-Wuerttemberg, Germany

Hannover Medical School; 🇩🇪 Hannover, Niedersachsen, Germany

University Hospital of Heidelberg; 🇩🇪 Heidelberg, Germany

University Hospital Ulm; 🇩🇪 Ulm, Baden-Wuerttemberg, Germany

University of Leipzig Medical Center; 🇩🇪 Leipzig, Germany