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Dose-escalating Trial With UniCAR02-T Cells and CD123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies

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ClinicalTrials.gov Identifier: NCT04230265
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : August 18, 2023
Sponsor:
Collaborator:
PHARMALOG Institut für klinische Forschung GmbH
Information provided by (Responsible Party):
AvenCell Europe GmbH

Study Description
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Brief Summary:
This dose-escalating phase I trial assesses for the first time the safety, the side effects and the harmlessness, as well as the therapeutical benefit of the new study drug UniCAR02-T-CD123 in patients with hematologic and lymphatic malignancies positive for CD123 marker. The UniCAR02-T-CD123 drug is a combination of a cellular component (UniCAR02-T) with a recombinant antibody derivative (TM123) which together forms the active drug.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Drug: Cyclophosphamide (Non-IMP) Drug: Fludarabine (Non-IMP) Drug: TM123 (IMP) Drug: UniCAR02-T (IMP) Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 1a Dose Escalation: Initial dose escalation followed an adaptive design.

Phase 1a Re-initiated Dose Escalation in 3+3 design: Dose escalation includes 2 additional dose levels of TM123. Patients will be treated according to a classical 3+3 design.

Phase 1b Dose Expansion: Once the re-initiated dose escalation phase has been completed, an expansion cohort of up to 20 patients will be initiated.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter, Open-label, Adaptive Design Phase I Trial With Genetically Modified T-cells Carrying Universal Chimeric Antigen Receptors (UniCAR02-T) in Combination With CD123 Target Module (TM123) for the Treatment of Patients With Hematologic and Lymphatic Malignancies Positive for CD123
Actual Study Start Date : January 28, 2020
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : September 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: UniCAR02-T-CD123
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with the recombinant antibody derivative TM123.
 Drug: Cyclophosphamide (Non-IMP)
Intravenous infusion over 3 days

Drug: Fludarabine (Non-IMP)
Intravenous infusion over 3 days

Drug: TM123 (IMP)
Intravenous Infusion for 20 days

Drug: UniCAR02-T (IMP)
Intravenous infusion of single dose


Outcome Measures
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Primary Outcome Measures :
  1. Phase 1a Dose Escalationand Re-initiated Dose Escalation in 3+3 design: Safety and tolerability [ Time Frame: DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) until Safety Follow-up 1 (infusion period of TM123 + 28 days + 3 months) ]
    Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS

  2. Phase 1a Dose Escalation and Re-initiated Dose Escalation in 3+3 design: Incidence of dose limiting toxicity (DLT) [ Time Frame: DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) ]
    DLT is defined as any adverse Event at least possible related to TM123 and/or UniCAR02-T

  3. Phase 1a Dose Escalation and Re-initiated Dose Escalation in 3+3 design: Maximum tolerated dose (MTD) [ Time Frame: DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) ]
    The dose for which the isotonic estimate of the DLT probability is closest to the target DLT probability of 0.2.

  4. Ph1b Dose Expansion: Safety and tolerability [ Time Frame: Infusion period of TM123 (up to 20 days) ]
    Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS

  5. Ph1b Dose Expansion: Establishing recommended phase 2 dose (RP2D) [ Time Frame: Infusion period of TM123 (up to 20 days) ]
  6. Ph1b Dose Expansion: Response evaluation [ Time Frame: Infusion period of TM123 (up to 20 days) ]
    Complete and partial remission at any time point and durability of response


Secondary Outcome Measures :
  1. Establishing recommended phase 2 dose (RP2D) [ Time Frame: DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) ]
    The RP2D will be determined based on MTD, all available efficacy data, and all available safety data, including information derived from additional treatment cycles.

  2. Complete (CR, CRh, CRi ) and partial remission (PR) [ Time Frame: until fifteen years after last UniCAR02-T administration ]

    CR: Bone marrow blasts < 5%, absence of extramedullary disease, absolute neutrophil count > 1 Gpt/L and platelet count > 100 Gpt/L. Level of MRD should be measured in patients achieving CR in case as suitable marker exists.

    CRi: All criteria for CR except residual thrombocytopenia (platelets < 100 Gpt/L) and/or neutropenia (absolute neutrophil count < 1 Gpt/L).

    PR: All hematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50 %.


  3. Disease stabilization (DS) [ Time Frame: until fifteen years after last UniCAR02-T administration ]
    Reduction of blast percentage by 25% compared to baseline without normalization of peripheral blood counts to levels not qualifying for PR or CR.

  4. Best response rate [ Time Frame: until fifteen years after last UniCAR02-T administration ]
    The best observed response during observational period. Response states are ordered descending as follows: CR > CRi > PR > DS > refractory disease.

  5. Progression free survival (PFS) [ Time Frame: until fifteen years after last UniCAR02-T administration ]
    The time from first treatment with TM123 and UniCAR02-T until disease progression or death. If no progress of death was observed during the observational period, the patient's progression free survival time will be censored on the date the patient was last seen progression-free and alive.

  6. Overall survival (OS) [ Time Frame: until fifteen years after last UniCAR02-T administration ]
    The number of days between the first study drug administration and death from any cause. If death was not observed during the observational period, the patient's overall survival time will be censored on the date the patient was last seen alive.

  7. Toxicity and efficacy in repeated cycles of TM123 administration [ Time Frame: duration of consolidation cycle treatment ]
    Patients who tolerate TM123 and UniCAR02-T without DLT and achieve a clinical benefit are candidates for consolidation cycles


Eligibility Criteria
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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:

  1. Male or female patients, age ≥ 18 years

  2. Documented definitive diagnosis of AML or BPDCN (according to standard of care testing) and CD123 positivity of ≥20 % of blasts. In the case of MRD+ AML, if there are insufficient blasts at screening for CD123 testing, the most recent available sample with sufficient blasts should be used.

    - Relapsed or refractory AML/BPDCN

  3. Eastern Cooperative Oncology Group (ECOG) of 0 to 1
  4. Life expectancy of at least 2 months
  5. Adequate renal and hepatic laboratory assessments
  6. Adequate cardiac function
  7. Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device
  8. Able to give written informed consent
  9. Weight ≥ 45 kg
  10. Negative pregnancy; routinely using a highly effective method of birth control

Exclusion Criteria:

  1. Acute promyelocytic leukemia (t15;17)
  2. Refractory disease under anti-leukemic treatment lasting longer than 6 months
  3. Manifestation of AML or BPDCN in central nervous system
  4. Bone marrow failure syndromes
  5. Cardiac disease: i.e. heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 6 months prior to study entry
  6. Patients undergoing renal dialysis
  7. Pulmonary disease with clinical relevant hypoxia
  8. Parkinson, epilepsy and, stroke or presence or history of seizures, paresis, aphasia or intracranial hemorrhage
  9. Presence of disseminated intravascular coagulation (DIC) or thromboembolism, or history of such within 3 months prior to start of treatment
  10. Hemolytic anemia
  11. Multiple sclerosis
  12. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
  13. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction
  14. Allogeneic stem cell transplantation within last two months or Graft versus host disease (GvHD) requiring immunosuppressive therapy
  15. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy
  16. Major surgery within 28 days
  17. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed
  18. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to the day of apheresis
  19. Prior treatment with gene therapy products
  20. Use of checkpoint inhibitors within 5 half-lives of the respective substance
  21. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants
  22. Pregnant or breastfeeding women
  23. Psychologic disorders, drug and/or significant active alcohol abuse
  24. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
  25. Presence of autoantibodies against La/Sjögren syndrome (SS)-B or presence or history of autoimmune diseases
  26. Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting module (TM123) excipients or to compounds of the lymphodepletion therapy or tocilizumab or corticosteroids
  27. Evidence suggesting that the patient is not likely to follow the study protocol
  28. Incapability of understanding purpose and possible consequences of the trial
  29. Patients who should not be included according to the opinion of the investigator
Contacts and Locations
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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): NCT04230265


Contacts
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Contact: Martin Lorkowski, Dr. +493514466450 ext 0 UC02-123-01@avencell.com
Contact: Antje Schubert, Dr. +493514466450 ext 0 UC02-123-01@avencell.com

Locations
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Germany
Universitätsklinikum Ulm Recruiting
Ulm, Baden-Württemberg, Germany, 89081
Contact: Elisa Sala, MD       elisa.sala@uniklinik-ulm.de   
Klinikum der Universität München Not yet recruiting
Munich, Bavaria, Germany, 81377
Contact: Marion Subklewe, Prof.       Marion.Subklewe@med.uni-muenchen.de   
Universitätsklinikum Würzburg Recruiting
Würzburg, Bayern, Germany, 97080
Contact: Sabrina Kraus, MD       kraus_s3@ukw.de   
Philipps-Universität Marburg Recruiting
Marburg, Hessen, Germany, 35032
Contact: Stephan Metzelder, MD       metzelde@med.uni-marburg.de   
Uniklinik RWTH Aachen Recruiting
Aachen, NRW, Germany, 52074
Contact: Edgar Jost, Prof.       ejost@ukaachen.de   
Universitätsklinikum Dresden Recruiting
Dresden, Sachsen, Germany, 01307
Contact: Martin Wermke, MD       martin.wermke@ukdd.de   
Principal Investigator: Martin Wermke, MD         
Universitätsklinikum Leipzig Recruiting
Leipzig, Sachsen, Germany, 04103
Contact: Vladan Vucinic, MD       vladan.vucinic@medizin.uni-leipzig.de   
Universitätsklinikum Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20246
Contact: Walter Fiedler, Prof.       fiedler@uke.de   
Sponsors and Collaborators
AvenCell Europe GmbH
PHARMALOG Institut für klinische Forschung GmbH
Investigators
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Principal Investigator: Martin Wermke, MD Universitätsklinikum Carl Gustav Carus Dresden
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AvenCell Europe GmbH
ClinicalTrials.gov Identifier: NCT04230265    
Other Study ID Numbers: UC02-123-01
2019-001339-30 ( EudraCT Number )
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: August 18, 2023
Last Verified: August 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
 Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists