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FLYSYN in MRD Positive AML (FLYSYN-101)

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ClinicalTrials.gov Identifier: NCT02789254
Recruitment Status : Recruiting
First Posted : June 2, 2016
Last Update Posted : October 24, 2018
Sponsor:
Collaborator:
Synimmune GmbH
Information provided by (Responsible Party):
University Hospital Tuebingen

Brief Summary:
This is a first in human, prospective, monocentric, 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: FLYSYN Phase 1 Phase 2

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 13-28: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 14.5 mg/m² BSA day 2


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 7, 2017
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : October 31, 2021


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 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 13-28*: FLYSYN 0.5 mg/m² body surface area (BSA) day 1, FLYSYN 14.5** mg/m² BSA day 2 * If the maximum tolerated dose (MTD) is reached in Cohorts 1-3, the respective cohort will be expanded by additional 16 patients for assessment of efficacy.

** 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.





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

Secondary Outcome Measures :
  1. Incidence and severity of adverse events (AE) (CTCAE V 4.03) [ Time Frame: until 180 days (i.e.Visit 11, day 180) after last dosing ]
  2. Pharmacokinetics and pharmacodynamics [ Time Frame: Visit 1 to 13 ]
  3. 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 [ Time Frame: BSL; Visits 5-7;9-13 ]
  4. Absolute and percent change from baseline in measurements of B, T, and NK cell populations and activation [ Time Frame: 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.

  5. Change in cytokines from baseline [ Time Frame: Visits 1-3;5 +6 ]
  6. Overall response rate, defined as MRD negativity or reduction of at least one log step, [ Time Frame: BSL; Visits1;4-13 ]
  7. Duration of response, time to MRD progression (log step), time to relapse [ Time Frame: BSL; Visits1;4-13 ]
  8. Absolute change from baseline in overall quality of life scores (EORTC QLQ C-30) [ Time Frame: Visit 1, Visit 6,Visit 9,Visit 10, Visit 11, Visit 12, Visit 13 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 with NPM1 mutation 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 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/myelodysplastic syndrome (MDS), unless the subject has (i) been free of the disease for ≥ 2 years. (ii) Exceptions include the following: Basal cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02789254


Contacts
Contact: Ludger Grosse-Hovest, Dr. +49-7071-7708381 info@synimmune.de
Contact: Daniela Dörfel, Dr. +49-7071-2983275 daniela.doerfel@med.uni-tuebingen.de

Locations
Germany
University Hospital Tuebingen Recruiting
Tuebingen, Baden-Wuerttemberg, Germany, 72076
Contact: Helmut Salih, Prof. Dr. med.    +49 7071 29-83275    helmut.salih@med.uni-tuebingen.de   
Contact: Daniela Doerfel, Dr. med.    +49 7071 29-87305    daniela.doerfel@med.uni-tuebingen.de   
University Hospital Ulm Recruiting
Ulm, Baden-Wuerttemberg, Germany, 89081
Contact: Konstanze Döhner, Prof. Dr. med.    + 49-731-500-45543    konstanze.doehner@uniklinik-ulm.de   
Contact: Peter Paschka, PD Dr. med.    +49-731-500-45746    peter.paschka@uniklinik-ulm.de   
Hannover Medical School Recruiting
Hannover, Niedersachsen, Germany, 30625
Contact: Felicitas Thol, PD Dr. med.    +49-(0)511 532 3009    Thol.Felicitas@mh-hannover.de   
Contact: Michael Heuser, Prof. Dr. med.    +49-(0)511 532 3720    heuser.michael@mh-hannover.de   
University Hospital of Heidelberg Recruiting
Heidelberg, Germany, 69120
Contact: Sabine Kayser, Dr.med.    +49-6221-56 8006    Sabine.Kayser@med.uni-heidelberg.de   
Contact: Tilman Bochtler, PD Dr.med.       tilman.bochtler@med.uni-heidelberg.de   
Sponsors and Collaborators
University Hospital Tuebingen
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

Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT02789254     History of Changes
Other Study ID Numbers: FLYSYN_Version 3.6-10102017
First Posted: June 2, 2016    Key Record Dates
Last Update Posted: October 24, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: publication

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital Tuebingen:
acute myeloid leukemia
Fms-like receptor tyrosine kinase (FLT3)
stem cell transplantation
complete remission
CD135
antibodies
Leukemia
AML
Fc-optimized

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Antibodies
Immunologic Factors
Physiological Effects of Drugs