- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04347616
Natural Killer-cell Therapy for Acute Myeloid Leukemia (NK4AML)
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
Study Overview
Status
Intervention / Treatment
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
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: P.M.M. van Hauten, MSc
- Phone Number: 0031 24 36 13223
- Email: paulien.vanhauten@radboudumc.nl
Study Contact Backup
- Name: H. Dolstra, Ass. Prof.
- Phone Number: 0031 24 36 13223
- Email: harry.dolstra@radboudumc.nl
Study Locations
-
-
-
Nijmegen, Netherlands
- Recruiting
- Radboud University Medical Center
-
Contact:
- H. Dolstra, Ass. Prof.
- Phone Number: 0031 24 36 13223
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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:
|
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:
|
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
Collaborators
Investigators
- Principal Investigator: N.P.M. Schaap, Department of Hematology
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- HEMAML42
- 2019-001929-27 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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