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Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab (DLI-TARGET)

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ClinicalTrials.gov Identifier: NCT03982992
Recruitment Status : Recruiting
First Posted : June 12, 2019
Last Update Posted : June 14, 2019
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Christian Schmidt, Ludwig-Maximilians - University of Munich

Brief Summary:
This phase 2 study is designed to evaluate the safety, tolerability and efficacy of allogeneic donor lymphocyte infusions (DLI) combined with the bispecific T cell engager blinatumomab in B-precursor ALL patients who have mixed chimerism (MC) or are MRD-positive after allogeneic SCT and are refractory to at least one MRD- or MC-targeted therapy (i.e. blinatumomab, DLI, tyrosine kinase inhibitors or other agents).

Condition or disease Intervention/treatment Phase
B Cell Precursor Acute Lymphoblastic Leukemia With Mixed Chimerism or Minimal Residual Disease After Allogeneic Stem Cell Transplantation B-Cell Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia in Remission Acute Lymphoblastic Leukemia, Adult Drug: Blinatumomab in combination with donor lymphocyte infusion Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab in Patients With Treatment-Resistant Mixed Chimerism or Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia After Allogeneic Stem Cell Transplantation
Actual Study Start Date : June 1, 2019
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : November 30, 2021


Arm Intervention/treatment
Experimental: DLI-TARGET

14d screening period: methotrexate, cytarabine, dexamethasone infusion i.th.

Cycle 1 (all patients): d1-28: blinatumomab continuous infusion i.v., d4: allogeneic donor lymphocyte single infusion i.v., d29: methotrexate, cytarabine, dexamethasone infusion i.th.

Cycle 2 (only patients with toxicity ≤ grade 2 CTCAE in cycle 1): d43-d70: blinatumomab continuous infusion i.v., d46: allogeneic donor lymphocyte single infusion i.v., d71: methotrexate, cytarabine, dexamethasone infusion i.th.

Drug: Blinatumomab in combination with donor lymphocyte infusion
Continuous blinatumomab infusion in combination with allogeneic donor lymphocyte infusion




Primary Outcome Measures :
  1. Safety and tolerability of combined DLI and blinatumomab treatment in subjects with treatment-resistant MC or MRD of CD19+ B-precursor ALL after allogeneic SCT [ Time Frame: 18 weeks ]
    Subject incidence and grade of adverse events (AEs) including graft-versus-host disease (GvHD). The intensity of (S)AEs will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.


Secondary Outcome Measures :
  1. Efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response [ Time Frame: 18 weeks ]

    MRD response based on RT-PCR: Complete MRD response (MolCR): hCR and MRD not detectable by molecular probe[s] with a sensitivity ≥10−4. The MRD response is calculated as: [number of patients achieving complete MRD response after at least one cycle (minimum 4 days blinatumomab) of study treatment] / [number of patients who received at least 1 cycle (minimum 4 days blinatumomab) of study treatment].

    Mixed chimerism response: CC response: only donor STRs in bone marrow; Low-level MC response ≥90% but <100% donor STRs in bone marrow. The MC response is calculated as: [number of patients achieving CC/low-level MC response after at least one cycle (minimum 4 days blinatumomab) of study treatment] / [number of patients who received at least 1 cycle (minimum 4 days blinatumomab) of study treatment].


  2. Duration of the response and survival after combined treatment of DLI and blinatumomab [ Time Frame: 18 weeks ]
    For patients who received at least one cycle (minimum 4 days of blinatumomab), progression-free survival and overall survival will be calculated using kaplan-meier survival estimates. Descriptive summary statistics (N, mean, standard deviation, minimum, median and maximum) for the duration of response will be performed for all patients with an observed complete MRD response or CC/low-level MC response.



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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. Adult patients with CD19+ B-precursor ALL (as determined by immunophenotyping) in hCR (defined as having less than 5% blasts in bone marrow) after allogeneic SCT.
  2. One, or a combination of the following documented after an interval of at least 2 weeks since cessation of the most recent leukemia-targeting therapy (i.e. chemotherapy, immunotherapy or cellular therapy, except for intrathecal prophylaxis):

    • Positivity for CD19+ MRD (molecular failure or molecular relapse), defined as presence of MRD at a level of ≥10^-4 according to an assay with a minimum sensitivity of 10^-4.
    • Donor chimerism <90%, as determined by analysis of host and donor STRs in bone marrow sample engraftment analysis.
  3. At least one previous line of treatment for MRD-positivity and/or reduced donor chimerism (i.e. blinatumomab, DLI, TKI or other agents) after allogeneic SCT.
  4. For those with BCR/ABL-positive B-precursor ALL only: persistence of MRD and/or MC following at least one ≥ second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerance to second generation TKI and intolerance to or persistence of MRD and/or MC following imatinib mesylate.
  5. Availability of allogeneic donor lymphocytes from the subject's donor (at least 2 x 10^8 T cells/kg).
  6. Subject has provided written informed consent prior to initiation of any study-specific activities/procedures.
  7. Subject has provided informed consent to be followed up in the GMALL-Registry.
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
  9. Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min.
  10. Hepatic function as follows:

    • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN)
    • Alkaline phosphatase (ALP) < 3.0 x ULN
    • Bilirubin ≤ 2.0 x ULN (unless considered due to Gilbert's syndrome or hemolysis)
  11. For female subjects only: Women of child-bearing age have to use a reliable method of contraception.

Exclusion Criteria:

  1. Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician.
  2. Eligibility for standard chemotherapy, as considered by the treating physician.
  3. Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) prior to baseline MRD and/or chimerism assessment.
  4. Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment.
  5. Any grade of GvHD currently requiring treatment.
  6. Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy).
  7. Evidence of current CNS involvement by ALL.

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): NCT03982992


Contacts
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Contact: DLI-TARGET Investigator Team +49 (0)89 4400-73133 dli-target@med.uni-muenchen.de
Contact: Christian Schmidt, MD +49 (0)89 4400-77907 Christian_Schmidt@med.uni-muenchen.de

Locations
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Germany
Klinikum der Universität München Recruiting
Munich, Germany, 81377
Contact: Marion Subklewe, MD    +49 (0)89 4400-73133    dli-target@med.uni-muenchen.de   
Contact: Christian Schmidt, MD    +49 (0)89 4400-77907    Christian_Schmidt@med.uni-muenchen.de   
Principal Investigator: Marion Subklewe, MD         
Sub-Investigator: Christian Schmidt, MD         
Sub-Investigator: Sascha Haubner, MD         
Sponsors and Collaborators
Ludwig-Maximilians - University of Munich
Amgen
Investigators
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Principal Investigator: Marion Subklewe, MD Klinikum der Universität München
Principal Investigator: Christian Schmidt, MD Klinikum der Universität München
Principal Investigator: Sascha Haubner, MD Klinikum der Universität München

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Responsible Party: Christian Schmidt, Deputy Principal Investigator, Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier: NCT03982992     History of Changes
Other Study ID Numbers: 2017-002314-31
First Posted: June 12, 2019    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Christian Schmidt, Ludwig-Maximilians - University of Munich:
donor lymphocyte infusion
blinatumomab
combinatorial
minimal residual disease
MRD
mixed chimerism
MC
DLI-TARGET
acute lymphoblastic leukemia
Additional relevant MeSH terms:
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Burkitt Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplastic Processes
Pathologic Processes
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Blinatumomab
Antibodies, Bispecific
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs