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Daratumumab and Donor Lymphocyte Infusion in Treating Participants With Relapsed Acute Myeloid Leukemia After Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT03537599
Recruitment Status : Recruiting
First Posted : May 25, 2018
Last Update Posted : June 4, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sumithira Vasu, Ohio State University Comprehensive Cancer Center

Study Description
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Brief Summary:
This phase I/II trial studies the side effects and best dose of donor lymphocyte infusions when given together with daratumumab and to see how well they work in treating participants with acute myeloid leukemia that has come back after a stem cell transplant. A donor lymphocyte infusion is a type of therapy in which lymphocytes (white blood cells) from the blood of a donor are given to a participant who has already received a stem cell transplant from the same donor. The donor lymphocytes may kill remaining cancer cells. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Giving daratumumab and donor white blood cells may work better in treating participants with acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Minimal Residual Disease Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Myeloid Leukemia Biological: Daratumumab Procedure: Donor Lymphocyte Infusion Other: Laboratory Biomarker Analysis Phase 1 Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Clinical Trial of Daratumumab and Donor Lymphocyte Infusion in Patients With Relapsed Acute Myeloid Leukemia Post-Allogeneic Hematopoietic Stem Cell Transplant
Actual Study Start Date : July 31, 2019
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Daratumumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (DLI, daratumumab)
Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity.
 Biological: Daratumumab
Given IV
Other Names:
  • Anti-CD38 Monoclonal Antibody
  • Darzalex
  • HuMax-CD38
  • JNJ-54767414

Procedure: Donor Lymphocyte Infusion
Given via infusion
Other Names:
  • DLI
  • Donor Leukocyte Infusion

Other: Laboratory Biomarker Analysis
Correlative studies


Outcome Measures
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Primary Outcome Measures :
  1. Safety and feasibility defined as the establishment of the appropriate dose level of donor lymphocyte infusion when given with a fixed dose of daratumumab [ Time Frame: Up to 6 months ]

Secondary Outcome Measures :
  1. Rates of complete remission [ Time Frame: Up to 6 months ]
    Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values <0.05 will be considered statistically significant in all analyses.

  2. Post-relapse progression-free survival [ Time Frame: At 6 months ]
    Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values <0.05 will be considered statistically significant in all analyses.

  3. Post-relapse overall survival [ Time Frame: Up to 6 months ]
    Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values <0.05 will be considered statistically significant in all analyses.

  4. Minimal residual disease (MRD) conversion rates [ Time Frame: Up to 6 months ]

Other Outcome Measures:
  1. Expression of CD38 on bone marrow [ Time Frame: Up to 6 months ]
    CD38 expression on bone marrow is checked prior to transplant. Most patients are in remission prior to transplant. Patients who were initially treated at Ohio State University (OSU) will have banked leukemia samples at the time of diagnosis. Expression of CD38 on samples at diagnosis and prior to transplant by immunohistochemical staining will be performed.

  2. Expression of CD38 in lymphocytes in bone marrow [ Time Frame: Baseline to 6 months ]
    Percentage of lymphocytes in bone marrow pre- and post-treatment with daratumumab will be studied. In addition to percentage, expression of CD38 on lymphocytes will be evaluated by immunohistochemistry (IHC).

  3. Phenotypic studies to evaluate T cell exhaustion/function [ Time Frame: Baseline to 6 months ]
    This will be performed on bone marrow samples pre-and post-treatment with Daratumumab at the specified time points.

  4. Phenotypic studies to evaluate activation status of natural killer (NK) cells [ Time Frame: Up to 6 months ]
    This will be performed on bone marrow samples pre-and post-treatment with daratumumab.

  5. T-cell, NK cell, B-cell, and myeloid-derived suppressor cells (MDSC) infiltration in bone marrow [ Time Frame: Baseline to 6 months ]
    This will be evaluated on bone marrow samples pre-and post-treatment with daratumumab.

  6. Exosomes from bone marrow [ Time Frame: Up to 6 months ]
    This will be examined for both number and also content (protein, messenger ribonucleic acid [mRNA], and micro RNAs [mIRs]).

  7. Serial assessment of microenvironment [ Time Frame: Up to 6 months ]
    Will be assessed with with stromal cell cultures.

  8. Chimerism analysis [ Time Frame: Up to 6 months ]
    Using single-nucleotide polymorphisms, relative contributions from donor vs. recipient in sorted CD3+ and CD33+ cells will be measured and expressed as a percentage.

  9. Immune reconstitution [ Time Frame: Up to 6 months ]
    Dr.Gerard Lozanski has developed a panel called the Immunome to study reconstitution of T cells, NK cells and B cells post-transplant. Specific information regarding stages of activation of T cells is also available from this panel.

  10. Immune response post daratumumab [ Time Frame: Up to 6 months ]
  11. Phenotypic studies to evaluate T cell exhaustion [ Time Frame: Baseline to 6 months ]
    This will be performed on bone marrow samples pre-and post-treatment with daratumumab.

  12. Phenotypic studies to evaluate activation status of NK cells [ Time Frame: Baseline to 6 months ]
    This will be performed on bone marrow samples pre-and post-treatment with daratumumab.

  13. Measurements of cytokines including but not limited to interferon gamma (IFN-y) [ Time Frame: Up to 6 months ]
    This will be measured at relapse, pre and post daratumumab treatment. Exosomes from bone marrow will be examined at these serial times for both number and also content (protein, messenger ribonucleic acid [mRNA], and micro RNA [mIRs]).


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • AML relapse following Allo-HSCT (Morphological relapse, or MRD positive verified by flow cytometry, cytogenetics, and molecular mutations)
  • MDS transformed to AML following Allo-HCT
  • Patients who received a 10/10 HLA-matched allogeneic HCT either from sibling donors or unrelated donors or atleast a 5/10 haploidentical transplant.

  • Engraftment must have occurred as defined by platelet (PLT) count > 20,000/µL and ANC

    • 0.5
  • Eastern Cooperative Oncology Group (ECOG) performance status < 3
  • Creatinine clearance > 40 ml/min (calculated or measured)
  • Aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN), alanine aminotransferase (ALT) < 3 x ULN
  • Total bilirubin < 1.5 x ULN
  • Off calcineurin inhibitors for at least 2 weeks
  • Prednisone dose ≤ 20 mg/day
  • Patients with proliferative disease can be cytoreduced with cytotoxic chemotherapy at Investigator discretion, but there should be at least a 14 day window between start of cytoreductive therapy and start of daratumumab
  • Blast count ˂20K/day (hydrea use is allowed)

Exclusion Criteria:

  • No demonstrable evidence of donor chimerism (˂ 55% donor CD3 or CD33 chimerism)
  • Patients with a molecular mutation without chromosomal abnormalities or declining chimerisms (MRD status must be verified by surface marker and mutational analyses)
  • Active graft-versus-host disease (GvHD) grades II-IV; prior acute GVHD could have occurred but resolved at time of initiation of daratumumab
  • Extensive chronic GvHD requiring ongoing immunosuppression with calcineurin inhibitors
  • Patients with FLT3+ AML or blast crisis CML who have not yet received post-transplant TKI therapy
  • Active central nervous system (CNS) disease testicular disease

EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.; seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

  • Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification.
  • History of grade IV anaphylactic reaction to monoclonal antibody therapy
  • Active autoimmune disease prior to transplant
  • Concurrent use of any other investigational drugs
Contacts and Locations
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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): NCT03537599


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrials@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Sumithira Vasu, MBBS    614-293-8197    Sumithira.Vasu@osumc.edu   
Principal Investigator: Sumithira Vasu, MBBS         
Sponsors and Collaborators
Sumithira Vasu
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sumithira Vasu, MBBS Ohio State University Comprehensive Cancer Center
More Information
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Additional Information:

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Responsible Party: Sumithira Vasu, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03537599    
Other Study ID Numbers: OSU-17102
NCI-2018-00616 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016058 ( U.S. NIH Grant/Contract )
First Posted: May 25, 2018    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasm, Residual
Neoplasms by Histologic Type
 Neoplasms
Neoplastic Processes
Pathologic Processes
Daratumumab
Antineoplastic Agents