Clinical Trials /

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

NCT03537599

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: OSU-17102
  • SECONDARY ID: NCI-2018-00616
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03537599

Conditions

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

Interventions

DrugSynonymsArms
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (DLI, daratumumab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (DLI, daratumumab)ExperimentalParticipants 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.
  • Daratumumab

Eligibility Criteria

        Inclusion Criteria:

          -  AML or MDS relapse following allo-HSCT (morphological relapse, or MRD positive by flow
             cytometry, cytogenetics, molecular mutations)

          -  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?s discretion, but there should be at least a 14 day window between start
             of cytoreductive therapy and start of daratumumab

        Exclusion Criteria:

          -  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

          -  Active central nervous system (CNS) disease

          -  History of grade IV anaphylactic reaction to monoclonal antibody therapy

          -  Active autoimmune disease prior to transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Rates of complete remission
Time Frame:Up to 6 months
Safety Issue:
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.
Measure:Post-relapse progression-free survival
Time Frame:At 6 months
Safety Issue:
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.
Measure:Post-relapse overall survival
Time Frame:Up to 6 months
Safety Issue:
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.
Measure:Minimal residual disease (MRD) conversion rates
Time Frame:Up to 6 months
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sumithira Vasu

Last Updated

August 21, 2019