Clinical Trials /

Natural Killer-cell Therapy for Acute Myeloid Leukemia

NCT04347616

Description:

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Natural Killer-cell Therapy for Acute Myeloid Leukemia
  • Official Title: Infusion of ex Vivo-generated Allogeneic Natural Killer Cells in Combination With Subcutaneous IL-2 in Patients With Acute Myeloid Leukemia: a Phase I/IIa Study

Clinical Trial IDs

  • ORG STUDY ID: HEMAML42
  • SECONDARY ID: 2019-001929-27
  • NCT ID: NCT04347616

Conditions

  • Acute Myeloid Leukemia Refractory
  • Acute Myeloid Leukemia, Relapsed, Adult

Interventions

DrugSynonymsArms
UCB-NK cellsNK cells with higher dose IL-2
IL-2AldesleukinNK cells with higher dose IL-2

Purpose

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

Detailed Description

      This study investigates an innovative treatment for relapsed or refractory acute myeloid
      leukemia (AML) exploiting administration of ex vivo-generated allogeneic natural killer (NK)
      cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent
      in vivo IL-2 cytokine support.

      This is a prospective phase I/IIa study. The first phase is a IL-2 dose-escalating safety
      study in nine patients. The second phase of the study is designed as a Simon's optimal
      two-stage single-arm phase IIa study, comprising eighteen patients. Prior to NK cell
      infusion, all patients will receive cyclophosphamide and fludarabine (Cy/Flu) based
      lymphodepleting chemotherapy. On day 0, all patients will receive a fixed dose of 1.0-3.0 x
      10^9 allogeneic umbilical cord blood-derived NK cells (UCB-NK cells). These cells are
      generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB
      unit.

      In phase I of the study patients will receive UCB-NK cells without subcutaneous (SC) IL-2,
      with lower dose SC IL-2 or with higher dose SC IL-2 (n=3 per treatment group). After
      establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase
      IIa of the study, with eight patients in the first stage (including the three patients from
      phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional ten
      patients in the second stage.
    

Trial Arms

NameTypeDescriptionInterventions
NK cells without IL-2ExperimentalOn day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. NK cells administration will not be followed by sc IL-2. N=3.
  • UCB-NK cells
NK cells with low dose IL-2Active ComparatorOn day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 3.0 x 10^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=3
  • UCB-NK cells
  • IL-2
NK cells with higher dose IL-2Active ComparatorOn day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 6.0 x 10^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total.
  • UCB-NK cells
  • IL-2

Eligibility Criteria

        Inclusion Criteria:

          -  AML patients (de novo and secondary) other than acute promyelocytic leukemia according
             to WHO criteria who should have (at least) stable disease with or without disease
             controlling medication who are (at time of inclusion) ineligible for allo-SCT.

        They meet one of the following disease criteria:

          -  Primary AML induction failure: no CR or CR MRD+ after two or more induction attempts
             with chemotherapy or after autologous SCT and (at time of inclusion) ineligible for
             allo-SCT

          -  Relapsed refractory AML (including relapse after SCT and DLI):

               -  No CR after one or more cycles of re-induction therapy

               -  Relapse without SCT in the past, not eligible for reinduction chemotherapy and/or
                  stem cell transplantation. Relapse after SCT without need for re-induction
                  therapy

        Other inclusion criteria:

          -  Age ≥ 18 years

          -  WHO performance 0-1

          -  Life expectancy of > 4 months

          -  Written informed consent

          -  Hydrea is allowed as pre-treatment to control blast count until day -3

          -  Other disease controlling medication is allowed until day -7

        Exclusion Criteria:

          -  Progressive disease according to ELN criteria

          -  Patients on immunosuppressive drugs or active GvHD

          -  Patients with active infections (viral, bacterial or fungal); acute anti-infectious
             therapy must have been completed within 14 days prior to study treatment

          -  Severe cardiovascular disease (CTCAE III-IV)

          -  Severe pulmonary dysfunction (CTCAE III-IV)

          -  Severe renal dysfunction (CTCAE III-IV)

          -  Severe hepatic dysfunction (CTCAE III-IV)

          -  Severe neurological or psychiatric dysfunction (CTCAE III-IV)

          -  Presence of anti-HLA class I antibodies

          -  Patients on concurrent chemotherapy or interferon-alpha treatment

          -  Pregnancy or breastfeeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Evaluate Safety and Toxicity using the CTCAE toxicity criteria
Time Frame:28 days
Safety Issue:
Description:Patients will be evaluated intensively using the CTCAE toxicity criteria and graft versus host disease (GvHD) classification criteria, defining dose limiting toxicities (DLTs): 1. Any treatment-emergent non-hematologic grade 3 toxicity lasting >72 hours, except for transient constitutional symptoms, diarrhea, fatigue or skin rash not requiring systemic steroid therapy. 2. Acute GvHD >grade 2 within 6 weeks of the first IL-2 dose. If in any of the three patients of each individual cohort of the phase I study a DLT occurs, the cohort will be extended to 6 patients. If 2 patients experience DLT within a cohort of 3 or 6 patients the study will be stopped in case the patients were only receiving NK cells or the study will be continued without IL-2 or the lower dose of IL-2 in case the patients were receiving NK cells in combination with IL-2. Serious, life threatening adverse events or grade 4 toxicity will be a reason to terminate the study or continue without IL-2 cytokine support.

Secondary Outcome Measures

Measure:Evaluation of the in vivo lifespan and expansion potential of the NK cells following adoptive transfer and IL-2 administration.
Time Frame:28 days
Safety Issue:
Description:We will determine the percentage and absolute number of donor-derived NK cells in peripheral blood and bone marrow after infusion using flow cytometry and DNA chimerism analysis. A positive expansion rate of the infused NK cells requires an absolute number of ≥100 donor-derived NK cells per μl blood at day +7 and/or +14.
Measure:Exploration of the functional activity of the donor NK cells in PB and BM, with or without SC IL-2 administration.
Time Frame:28 days
Safety Issue:
Description:NK cells from peripheral blood and bone marrow will be obtained. These cells will be stimulated in vitro for 4 hours and subsequently the degranulation marker CD107a and immunoregulatory marker IFNy will be measured by flow cytometry. These results can be compared between patients that did receive IL-2 or did not.
Measure:Evaluation of plasma cytokine concentrations (IL-2, IL-15, IL-7, IFN-γ, TNFα, IL-6) pre- and post-infusion of IL-2.
Time Frame:28 days
Safety Issue:
Description:This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.
Measure:Number of patients eligible for allo-SCT based on hematologic response
Time Frame:28 days
Safety Issue:
Description:Only in Phase IIa.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Radboud University

Trial Keywords

  • Natural Killer cells
  • Acute Myeloid Leukemia
  • Cellular Immunotherapy

Last Updated

April 14, 2020