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

Primary Purpose

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

Status
Unknown status
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Blinatumomab in combination with donor lymphocyte infusion
Sponsored by
Ludwig-Maximilians - University of Munich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B Cell Precursor Acute Lymphoblastic Leukemia With Mixed Chimerism or Minimal Residual Disease After Allogeneic Stem Cell Transplantation focused on measuring donor lymphocyte infusion, blinatumomab, combinatorial, minimal residual disease, MRD, mixed chimerism, MC, DLI-TARGET, acute lymphoblastic leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Klinikum der Universität MünchenRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

DLI-TARGET

Arm Description

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.

Outcomes

Primary Outcome Measures

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
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

Efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response
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
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.

Full Information

First Posted
June 3, 2019
Last Updated
June 13, 2019
Sponsor
Ludwig-Maximilians - University of Munich
Collaborators
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT03982992
Brief Title
Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab
Acronym
DLI-TARGET
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Unknown status
Study Start Date
June 1, 2019 (Actual)
Primary Completion Date
May 31, 2021 (Anticipated)
Study Completion Date
November 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ludwig-Maximilians - University of Munich
Collaborators
Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
donor lymphocyte infusion, blinatumomab, combinatorial, minimal residual disease, MRD, mixed chimerism, MC, DLI-TARGET, acute lymphoblastic leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
DLI-TARGET
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Blinatumomab in combination with donor lymphocyte infusion
Intervention Description
Continuous blinatumomab infusion in combination with allogeneic donor lymphocyte infusion
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
18 weeks
Secondary Outcome Measure Information:
Title
Efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response
Description
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].
Time Frame
18 weeks
Title
Duration of the response and survival after combined treatment of DLI and blinatumomab
Description
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.
Time Frame
18 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. 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. 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. 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. Availability of allogeneic donor lymphocytes from the subject's donor (at least 2 x 10^8 T cells/kg). Subject has provided written informed consent prior to initiation of any study-specific activities/procedures. Subject has provided informed consent to be followed up in the GMALL-Registry. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min. 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) For female subjects only: Women of child-bearing age have to use a reliable method of contraception. Exclusion Criteria: Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician. Eligibility for standard chemotherapy, as considered by the treating physician. 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. Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment. Any grade of GvHD currently requiring treatment. Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy). Evidence of current CNS involvement by ALL.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
DLI-TARGET Investigator Team
Phone
+49 (0)89 4400-73133
Email
dli-target@med.uni-muenchen.de
First Name & Middle Initial & Last Name or Official Title & Degree
Christian Schmidt, MD
Phone
+49 (0)89 4400-77907
Email
Christian_Schmidt@med.uni-muenchen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marion Subklewe, MD
Organizational Affiliation
Klinikum der Universität München
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Christian Schmidt, MD
Organizational Affiliation
Klinikum der Universität München
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sascha Haubner, MD
Organizational Affiliation
Klinikum der Universität München
Official's Role
Principal Investigator
Facility Information:
Facility Name
Klinikum der Universität München
City
Munich
ZIP/Postal Code
81377
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marion Subklewe, MD
Phone
+49 (0)89 4400-73133
Email
dli-target@med.uni-muenchen.de
First Name & Middle Initial & Last Name & Degree
Christian Schmidt, MD
Phone
+49 (0)89 4400-77907
Email
Christian_Schmidt@med.uni-muenchen.de
First Name & Middle Initial & Last Name & Degree
Marion Subklewe, MD
First Name & Middle Initial & Last Name & Degree
Christian Schmidt, MD
First Name & Middle Initial & Last Name & Degree
Sascha Haubner, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab

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