Natural Killer-cell Therapy for Acute Myeloid Leukemia (NK4AML)

March 28, 2023 updated by: Radboud University Medical Center

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

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.

Study Overview

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 twelve patients. The second phase of the study is designed as a Simon's optimal two-stage single-arm phase IIa study, comprising seventeen 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, n=6 in the highest tolerable dose). After establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase IIa of the study, with ten patients in the first stage (including the six patients from phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional seven patients in the second stage.

Study Type

Interventional

Enrollment (Anticipated)

23

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Nijmegen, Netherlands
        • Recruiting
        • Radboud University Medical Center
        • Contact:
          • H. Dolstra, Ass. Prof.
          • Phone Number: 0031 24 36 13223

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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 patients (de novo and secondary) or patients with MDS excess blasts-2 according to WHO criteria 2016, who have stable disease or non-rapidly progressive disease with or without disease controlling medication who are (at time of inclusion) ineligible for allo-SCT.
  • Patients may belong to any of the following categories:

    • Relapsed/refractory disease after treatment with intensive chemotherapy, hypomethylating agents, targeted agents, autologous or allo-SCT (at least 6 months ago) and DLI
    • Newly diagnosed, untreated patients ineligible for allo-SCT

Other inclusion criteria:

  • Age ≥ 18 years
  • WHO performance 0-2
  • 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 in case of previous therapy
  • 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)
  • Patients on concurrent chemotherapy or interferon-alpha treatment
  • Pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NK cells without IL-2
On 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.
Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood
Active Comparator: NK cells with low dose IL-2
On 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
Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood
In vivo cytokine support
Other Names:
  • Aldesleukin
Active Comparator: NK cells with higher dose IL-2
On 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. N=6
Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood
In vivo cytokine support
Other Names:
  • Aldesleukin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I: Evaluate Safety and Toxicity using the CTCAE toxicity criteria
Time Frame: 28 days
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.
28 days
Phase IIa: % blasts or % minimal residual disease (MRD) in the bone marrow
Time Frame: 28 days

The primary objective of phase IIa of the study is to evaluate the effect of UCB-NK cell adoptive immunotherapy in combination with SC IL-2 following a non-myeloablative immunosuppressive conditioning regime on disease activity in patients with AML. At day 28 a bone marrow biopsy will be performed to evaluate % blasts or % minimal residual disease (MRD) in the bone marrow. A complete remission is defined as BM blasts <5%; marrow should not be merely 'aplastic': at least 200 cells should be enumerated or cellularity should be at least 10%. MRD will be evaluated by flow cytometry (leukemia associated phenotypes (LAPs)) and/or molecular quantification of patient specific mutations (PCR).

For phase IIa of the study the clinical evaluation data (% blasts and % MRD positivity) will be translated in a clinical response (stable disease, partial remission, complete remission) and quantitative presented.

28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of the in vivo lifespan and expansion potential of the NK cells following adoptive transfer and IL-2 administration.
Time Frame: 28 days
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.
28 days
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
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.
28 days
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
This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.
28 days
Number of patients eligible for allo-SCT based on hematologic response
Time Frame: 28 days
Only in Phase IIa.
28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: N.P.M. Schaap, Department of Hematology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 3, 2020

Primary Completion (Anticipated)

September 1, 2023

Study Completion (Anticipated)

September 1, 2023

Study Registration Dates

First Submitted

April 6, 2020

First Submitted That Met QC Criteria

April 14, 2020

First Posted (Actual)

April 15, 2020

Study Record Updates

Last Update Posted (Actual)

March 29, 2023

Last Update Submitted That Met QC Criteria

March 28, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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