Natural Killer-cell Therapy for Acute Myeloid Leukemia

NCT04347616 | Terminated Phase 1 DMC

• 2 other identifiers: HEMAML422019-001929-27
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia Refractory; Acute Myeloid Leukemia, Relapsed, Adult

Keywords

Natural Killer cells; Acute Myeloid Leukemia; Cellular Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Phase I: Evaluate Safety and Toxicity using the CTCAE toxicity criteria

  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

  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 Outcomes (4)

• Evaluation of the in vivo lifespan and expansion potential of the NK cells following adoptive transfer and IL-2 administration.

  28 days

• Exploration of the functional activity of the donor NK cells in PB and BM, with or without SC IL-2 administration.

  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.

  28 days

• Number of patients eligible for allo-SCT based on hematologic response

  28 days

Study Arms (3)

NK cells without IL-2

EXPERIMENTAL

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.

Biological: UCB-NK cells

NK cells with low dose IL-2

ACTIVE COMPARATOR

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

Biological: UCB-NK cells; Drug: IL-2

NK cells with higher dose IL-2

ACTIVE COMPARATOR

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

Biological: UCB-NK cells; Drug: IL-2

Interventions

UCB-NK cells BIOLOGICAL

Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood

NK cells with higher dose IL-2; NK cells with low dose IL-2; NK cells without IL-2

IL-2 DRUG

In vivo cytokine support

Also known as: Aldesleukin

NK cells with higher dose IL-2; NK cells with low dose IL-2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Dutch Cancer Society: collaborator

Study Sites (1)

Radboud University Medical Center

Nijmegen, Netherlands

Location

Related Publications (1)

• Dolstra H, Roeven MWH, Spanholtz J, Hangalapura BN, Tordoir M, Maas F, Leenders M, Bohme F, Kok N, Trilsbeek C, Paardekooper J, van der Waart AB, Westerweel PE, Snijders TJF, Cornelissen J, Bos G, Pruijt HFM, de Graaf AO, van der Reijden BA, Jansen JH, van der Meer A, Huls G, Cany J, Preijers F, Blijlevens NMA, Schaap NM. Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients. Clin Cancer Res. 2017 Aug 1;23(15):4107-4118. doi: 10.1158/1078-0432.CCR-16-2981. Epub 2017 Mar 9.

  PMID: 28280089 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• N.P.M. Schaap

  Department of Hematology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study is divided in two phases. In phase I, we will determine the safety of our UCB-NK cell product with or without sc IL-2, following a non-myeloablative immunosuppressive conditioning regimen in patients with AML. Three patients will receive NK cells without IL-2. If no dose limiting toxicities occur another three patients will receiving NK cells with a low dose IL-2, and if safe, another six patients will receive NK cells with a higher dose IL-2. 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. Therefore 17 patients will be evaluated using a Simon's optimal two-stage single-arm study design, with 10 patients in the first stage and an additional 7 patients in the second stage. These patients will receive NK cells with the highest tolerable dose IL-2, established after phase I.

Study Record Dates

• First Submitted: April 6, 2020
• First Posted: April 15, 2020
• Study Start: December 3, 2020
• Primary Completion: January 30, 2026
• Study Completion: January 30, 2026
• Last Updated: March 16, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)