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

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia in Remission; B-Cell Acute Lymphoblastic Leukemia; B Cell Precursor Acute Lymphoblastic Leukemia With Mixed Chimerism or Minimal Residual Disease After Allogeneic Stem Cell Transplantation
• Intervention / Treatment: Drug: Blinatumomab in combination with donor lymphocyte infusion

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: DLI-TARGET Investigator Team; Phone Number: +49 (0)89 4400-73133; Email: dli-target@med.uni-muenchen.de
• Study Contact Backup: Name: Christian Schmidt, MD; Phone Number: +49 (0)89 4400-77907; Email: Christian_Schmidt@med.uni-muenchen.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Klinikum der Universität München

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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].	18 weeks
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.	18 weeks

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Amgen
• Investigators: 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

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2019
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): November 30, 2021

Study Registration Dates

• First Submitted: June 3, 2019
• First Submitted That Met QC Criteria: June 8, 2019
• First Posted (Actual): June 12, 2019

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: minimal residual disease; blinatumomab; acute lymphoblastic leukemia; MRD; donor lymphocyte infusion; combinatorial; mixed chimerism; MC; DLI-TARGET
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Neoplastic Processes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neoplasm, Residual; Antineoplastic Agents; Blinatumomab
• Other Study ID Numbers: 2017-002314-31

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No