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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 : April 13, 2021
Sponsor:
Collaborator:
PHARMALOG Institut für klinische Forschung GmbH
Information provided by (Responsible Party):
Cellex Patient Treatment GmbH

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) B-cell Acute Lymphoblastic Leukemia (b-ALL) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Drug: Cyclophosphamide (Non-IMP) Drug: Fludarabine (Non-IMP) Drug: TM123 (IMP) Drug: UniCAR02-T (IMP) Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: Dose escalation follows an adaptive design.
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 : February 2022
Estimated Study Completion Date : April 2022


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 for 3 days

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

Drug: TM123 (IMP)
Intravenous Infusion for 25 days

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




Primary Outcome Measures :
  1. Safety and tolerability [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 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

  2. Incidence of dose limiting toxicity (DLT) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 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. Maximum tolerated dose (MTD) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 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.


Secondary Outcome Measures :
  1. Recommended phase 2 dose (RP2D) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 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 remission (CR), incomplete remission (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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 at screening of AML, B-ALL or BPDCN (according to standard of care testing) and CD123 positivity of more than 20 % of blasts.

    • Relapsed or refractory AML,
    • Relapsed or refractory B-ALL (in patients aged over 25 years or over 18 years without access to an approved chimeric antigen receptor (CAR)-T cell product at time point of potential inclusion into this study),
    • Patients with histological and/or cytological evidence of BPDCN in the peripheral blood, bone marrow (BM), spleen, lymph nodes, skin, and/or other sites that is persistent/recurrent following prior standard of care treatment for 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, i.e. left ventricular ejection fraction (LVEF) of ≥ 45 % as assessed by transthoracic two-dimensional echocardiography
  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) and T-ALL
  2. Manifestation of AML, ALL or BPDCN in central nervous system
  3. Bone marrow failure syndromes
  4. 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
  5. Patients undergoing renal dialysis
  6. Pulmonary disease with clinical relevant hypoxia
  7. Parkinson, epilepsy and, stroke or presence or history of seizures, paresis, aphasia or intracranial hemorrhage
  8. History or presence of disseminated intravascular coagulation (DIC) or thromboembolism
  9. Hemolytic anemia
  10. Multiple sclerosis
  11. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
  12. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction
  13. Allogeneic stem cell transplantation within last two months or Graft versus host disease (GvHD) requiring immunosuppressive therapy
  14. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy
  15. Major surgery within 28 days
  16. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed
  17. 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
  18. Prior treatment with gene therapy products
  19. Use of checkpoint inhibitors within 5 half-lives of the respective substance
  20. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants
  21. Pregnant or breastfeeding women
  22. Psychologic disorders, drug and/or significant active alcohol abuse
  23. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
  24. Presence of autoantibodies against La/Sjögren syndrome (SS)-B or presence or history of autoimmune diseases
  25. Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting module (TM123) excipients or to compounds of the lymphodepletion therapy or tocilizumab or corticosteroids
  26. Evidence suggesting that the patient is not likely to follow the study protocol
  27. Incapability of understanding purpose and possible consequences of the trial
  28. Patients who should not be included according to the opinion of the investigator

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@cellex-treatment.me
Contact: Antje Schubert, Dr. +493514466450 ext 0 UC02-123-01@cellex-treatment.me

Locations
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Germany
Universitätsklinikum Ulm Recruiting
Ulm, Baden-Württemberg, Germany, 89081
Contact: Elisa Sala, MD       elisa.sala@uniklinik-ulm.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   
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
Cellex Patient Treatment GmbH
PHARMALOG Institut für klinische Forschung GmbH
Investigators
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Principal Investigator: Martin Wermke, MD Universitätsklinikum Carl Gustav Carus Dresden
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Cellex Patient Treatment 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: April 13, 2021
Last Verified: November 2020
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
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System 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