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

Primary Purpose

Minimal Residual Disease, Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Recurrent Adult Acute Myeloid Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Daratumumab
Donor Lymphocyte Infusion
Laboratory Biomarker Analysis
Sponsored by
Sumithira Vasu
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Minimal Residual Disease

Eligibility Criteria

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

Inclusion Criteria:

  • AML relapse following Allo-HSCT (Morphological relapse, or MRD positive verified by flow cytometry, cytogenetics, and molecular mutations)
  • Relapsed/Refractory AML must not be candidates for available therapies known to be effective for treatment of their AML.
  • 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

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (DLI, daratumumab)

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety and feasibility defined as the establishment of the appropriate dose level of donor lymphocyte infusion when given with a fixed dose of daratumumab

Secondary Outcome Measures

Rates of complete remission
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.
Post-relapse progression-free survival
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.
Post-relapse overall survival
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.
Minimal residual disease (MRD) conversion rates

Full Information

First Posted
May 15, 2018
Last Updated
March 2, 2022
Sponsor
Sumithira Vasu
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1. Study Identification

Unique Protocol Identification Number
NCT03537599
Brief Title
Daratumumab and Donor Lymphocyte Infusion in Treating Participants With Relapsed Acute Myeloid Leukemia After Stem Cell Transplant
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
January 10, 2020 (Actual)
Primary Completion Date
August 4, 2021 (Actual)
Study Completion Date
February 3, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Sumithira Vasu

4. Oversight

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

5. Study Description

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.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate safety and tolerability of daratumumab and escalating doses of donor lymphocyte infusions (DLI) in post-hematopoietic cell transplantation (HCT) patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transformed to AML (phase I). II. To evaluate overall response rate to daratumumab and DLI in patients with post-HCT relapsed AML and MDS (phase II). SECONDARY OBJECTIVES: I. To assess overall response rates in minimal residual disease (MRD) positive patients and in patients with overt morphological relapse. II. To assess MRD conversion rates from MRD positive to MRD negative. III. To determine the post-relapse 6-month overall response (OS) rates of patients with relapsed AML and MDS following allogeneic hematopoietic stem cell transplantation (allo-HSCT) who are treated with daratumumab. IV. To determine the rates of graft-versus-host disease (GVHD) (both grades II-IV and III-IV) and autoimmune side effects of daratumumab. V. To determine the post-relapse 6-month progression-free survival (PFS) rates of patients with relapsed AML and MDS following allo-HSCT who are treated with daratumumab. EXPLORATORY OBJECTIVES: I. To compare CD38 expression levels in myeloid blasts and interferon gamma (IFN-y) levels in plasma at the time of relapse before starting daratumumab and at progression or relapse after daratumumab. II. To compare peripheral blood T cell number and subsets (CD3, CD4, CD8, (CD38 expression on regulatory T cells [T-regs], CD4 and CD8), T regs, B-regulatory cells, natural killer (NK) cell numbers and bone marrow T cell subsets at the time of relapse before starting daratumumab, at the time of partial/complete response to daratumumab, and at the time of progression or relapse after daratumumab. III. To evaluate whether daratumumab has (i) direct anti-leukemia effects (ii) antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and (III) immune modulation of autologous immune system (NK cells, T cells, T-regs, B-regulatory cells [B-regs], and myeloid-derived suppressor cells [MDSCS]) in AML. IV. To evaluate the effect of daratumumab on exosome content and clearance along with other soluble factors in AML. V. To evaluate serum interferon (IFN) levels pre-daratumumab, during and post-daratumumab. VI. To evaluate whether fratricide occurs in patients treated with daratumumab. OUTLINE: This is a phase I, dose escalation study of donor lymphocyte infusions followed by a phase II study. 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. Participants found to be in complete response (CR) at the end of 8 weeks may receive daratumumab IV once every 2 weeks for 8 weeks, and then once monthly for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up for 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Minimal Residual Disease, Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (DLI, daratumumab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Daratumumab
Other Intervention Name(s)
Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Donor Lymphocyte Infusion
Other Intervention Name(s)
DLI, Donor Leukocyte Infusion
Intervention Description
Given via infusion
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Rates of complete remission
Description
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.
Time Frame
Up to 6 months
Title
Post-relapse progression-free survival
Description
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.
Time Frame
At 6 months
Title
Post-relapse overall survival
Description
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.
Time Frame
Up to 6 months
Title
Minimal residual disease (MRD) conversion rates
Time Frame
Up to 6 months
Other Pre-specified Outcome Measures:
Title
Expression of CD38 on bone marrow
Description
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.
Time Frame
Up to 6 months
Title
Expression of CD38 in lymphocytes in bone marrow
Description
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).
Time Frame
Baseline to 6 months
Title
Phenotypic studies to evaluate T cell exhaustion/function
Description
This will be performed on bone marrow samples pre-and post-treatment with Daratumumab at the specified time points.
Time Frame
Baseline to 6 months
Title
Phenotypic studies to evaluate activation status of natural killer (NK) cells
Description
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time Frame
Up to 6 months
Title
T-cell, NK cell, B-cell, and myeloid-derived suppressor cells (MDSC) infiltration in bone marrow
Description
This will be evaluated on bone marrow samples pre-and post-treatment with daratumumab.
Time Frame
Baseline to 6 months
Title
Exosomes from bone marrow
Description
This will be examined for both number and also content (protein, messenger ribonucleic acid [mRNA], and micro RNAs [mIRs]).
Time Frame
Up to 6 months
Title
Serial assessment of microenvironment
Description
Will be assessed with with stromal cell cultures.
Time Frame
Up to 6 months
Title
Chimerism analysis
Description
Using single-nucleotide polymorphisms, relative contributions from donor vs. recipient in sorted CD3+ and CD33+ cells will be measured and expressed as a percentage.
Time Frame
Up to 6 months
Title
Immune reconstitution
Description
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.
Time Frame
Up to 6 months
Title
Immune response post daratumumab
Time Frame
Up to 6 months
Title
Phenotypic studies to evaluate T cell exhaustion
Description
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time Frame
Baseline to 6 months
Title
Phenotypic studies to evaluate activation status of NK cells
Description
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time Frame
Baseline to 6 months
Title
Measurements of cytokines including but not limited to interferon gamma (IFN-y)
Description
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]).
Time Frame
Up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: AML relapse following Allo-HSCT (Morphological relapse, or MRD positive verified by flow cytometry, cytogenetics, and molecular mutations) Relapsed/Refractory AML must not be candidates for available therapies known to be effective for treatment of their AML. 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sumithira Vasu, MBBS
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline

Learn more about this trial

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

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