Natural Killer-cell Therapy for Acute Myeloid Leukemia

NCT ID: NCT04347616

Last Updated: 2024-04-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE1/PHASE2

Total Enrollment

23 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-12-03

Study Completion Date

2025-09-01

Brief Summary

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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

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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.

Conditions

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Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia, Relapsed, Adult

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

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.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type EXPERIMENTAL

UCB-NK cells

Intervention Type BIOLOGICAL

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

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

Group Type ACTIVE_COMPARATOR

UCB-NK cells

Intervention Type BIOLOGICAL

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

IL-2

Intervention Type DRUG

In vivo cytokine support

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

Group Type ACTIVE_COMPARATOR

UCB-NK cells

Intervention Type BIOLOGICAL

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

IL-2

Intervention Type DRUG

In vivo cytokine support

Interventions

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UCB-NK cells

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

Intervention Type BIOLOGICAL

IL-2

In vivo cytokine support

Intervention Type DRUG

Other Intervention Names

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Aldesleukin

Eligibility Criteria

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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


* 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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Dutch Cancer Society

OTHER

Sponsor Role collaborator

Radboud University Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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N.P.M. Schaap

Role: PRINCIPAL_INVESTIGATOR

Department of Hematology

Locations

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Radboud University Medical Center

Nijmegen, , Netherlands

Site Status RECRUITING

Countries

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Netherlands

Central Contacts

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P.M.M. van Hauten, MSc

Role: CONTACT

0031 24 36 13223

H. Dolstra, Ass. Prof.

Role: CONTACT

0031 24 36 13223

Facility Contacts

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H. Dolstra, Ass. Prof.

Role: primary

0031 24 36 13223

References

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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.

Reference Type RESULT
PMID: 28280089 (View on PubMed)

Other Identifiers

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2019-001929-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

HEMAML42

Identifier Type: -

Identifier Source: org_study_id

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