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

Phase I/II Clinical Trial of Daratumumab and Donor Lymphocyte Infusion in Patients With Relapsed Acute Myeloid Leukemia Post-Allogeneic Hematopoietic Stem Cell Transplant

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Minimal Residual Disease
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Daratumumab; Procedure: Donor Lymphocyte Infusion

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

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

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: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Daratumumab; Given IV; Other Names: Darzalex; Anti-CD38 Monoclonal Antibody; HuMax-CD38; JNJ-54767414; Procedure: Donor Lymphocyte Infusion; Given via infusion; Other Names: DLI; Donor Leukocyte Infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and feasibility defined as the establishment of the appropriate dose level of donor lymphocyte infusion when given with a fixed dose of daratumumab	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 6 months
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.	At 6 months
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.	Up to 6 months
Minimal residual disease (MRD) conversion rates		Up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expression of CD38 on bone marrow	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.	Up to 6 months
Expression of CD38 in lymphocytes in bone marrow	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).	Baseline to 6 months
Phenotypic studies to evaluate T cell exhaustion/function	This will be performed on bone marrow samples pre-and post-treatment with Daratumumab at the specified time points.	Baseline to 6 months
Phenotypic studies to evaluate activation status of natural killer (NK) cells	This will be performed on bone marrow samples pre-and post-treatment with daratumumab.	Up to 6 months
T-cell, NK cell, B-cell, and myeloid-derived suppressor cells (MDSC) infiltration in bone marrow	This will be evaluated on bone marrow samples pre-and post-treatment with daratumumab.	Baseline to 6 months
Exosomes from bone marrow	This will be examined for both number and also content (protein, messenger ribonucleic acid [mRNA], and micro RNAs [mIRs]).	Up to 6 months
Serial assessment of microenvironment	Will be assessed with with stromal cell cultures.	Up to 6 months
Chimerism analysis	Using single-nucleotide polymorphisms, relative contributions from donor vs. recipient in sorted CD3+ and CD33+ cells will be measured and expressed as a percentage.	Up to 6 months
Immune reconstitution	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.	Up to 6 months
Immune response post daratumumab		Up to 6 months
Phenotypic studies to evaluate T cell exhaustion	This will be performed on bone marrow samples pre-and post-treatment with daratumumab.	Baseline to 6 months
Phenotypic studies to evaluate activation status of NK cells	This will be performed on bone marrow samples pre-and post-treatment with daratumumab.	Baseline to 6 months
Measurements of cytokines including but not limited to interferon gamma (IFN-y)	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]).	Up to 6 months

Collaborators and Investigators

• Sponsor: Sumithira Vasu

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2020
• Primary Completion (Actual): August 4, 2021
• Study Completion (Actual): February 3, 2022

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 25, 2018

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 2, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Neoplastic Processes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Neoplasm, Residual; Antineoplastic Agents; Daratumumab
• Other Study ID Numbers: OSU-17102; NCI-2018-00616 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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