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出境医 / 临床实验 / Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab (DLI-TARGET)

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

Study Description
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

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
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
Arms and Interventions
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
Outcome Measures
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.


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. 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.
Contacts and Locations

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
Tracking Information
First Submitted Date  ICMJE June 3, 2019
First Posted Date  ICMJE June 12, 2019
Last Update Posted Date June 14, 2019
Actual Study Start Date  ICMJE June 1, 2019
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2019) 		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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2019)
  • 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].
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab
Official Title  ICMJE 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
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE Drug: Blinatumomab in combination with donor lymphocyte infusion
Continuous blinatumomab infusion in combination with allogeneic donor lymphocyte infusion
Study Arms  ICMJE 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.

Intervention: Drug: Blinatumomab in combination with donor lymphocyte infusion
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 8, 2019) 		12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 30, 2021
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03982992
Other Study ID Numbers  ICMJE 2017-002314-31
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Christian Schmidt, Ludwig-Maximilians - University of Munich
Study Sponsor  ICMJE Ludwig-Maximilians - University of Munich
Collaborators  ICMJE Amgen
Investigators  ICMJE
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
PRS Account Ludwig-Maximilians - University of Munich
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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