NK4AML: Natural Killer-cell Therapy for Acute Myeloid Leukemia
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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 Design
Arms and Interventions
| 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. |
Biological: UCB-NK cells
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 |
Biological: UCB-NK cells
Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood
Drug: IL-2
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 |
Biological: UCB-NK cells
Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood
Drug: IL-2
In vivo cytokine support
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Phase I: Evaluate Safety and Toxicity using the CTCAE toxicity criteria [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.
- Phase IIa: % blasts or % minimal residual disease (MRD) in the bone marrow [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.
Secondary Outcome Measures
- Evaluation of the in vivo lifespan and expansion potential of the NK cells following adoptive transfer and IL-2 administration. [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.
- Exploration of the functional activity of the donor NK cells in PB and BM, with or without SC IL-2 administration. [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.
- 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]
This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.
- Number of patients eligible for allo-SCT based on hematologic response [28 days]
Only in Phase IIa.
Eligibility Criteria
Criteria
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:
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Relapsed/refractory disease after treatment with intensive chemotherapy, hypomethylating agents, targeted agents, autologous or allo-SCT (at least 6 months ago) and DLI
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Newly diagnosed, untreated patients ineligible for allo-SCT
Other inclusion criteria:
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Age ≥ 18 years
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WHO performance 0-2
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Life expectancy of > 4 months
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Written informed consent
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Hydrea is allowed as pre-treatment to control blast count until day -3
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Other disease controlling medication is allowed until day -7
Exclusion Criteria:
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Progressive disease according to ELN criteria in case of previous therapy
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Patients on immunosuppressive drugs or active GvHD
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Patients with active infections (viral, bacterial or fungal); acute anti-infectious therapy must have been completed within 14 days prior to study treatment
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Severe cardiovascular disease (CTCAE III-IV)
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Severe pulmonary dysfunction (CTCAE III-IV)
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Severe renal dysfunction (CTCAE III-IV)
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Severe hepatic dysfunction (CTCAE III-IV)
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Severe neurological or psychiatric dysfunction (CTCAE III-IV)
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Presence of anti-HLA class I antibodies
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Patients on concurrent chemotherapy or interferon-alpha treatment
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Pregnancy or breastfeeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Radboud University Medical Center | Nijmegen | Netherlands |
Sponsors and Collaborators
- Radboud University Medical Center
- Dutch Cancer Society
Investigators
- Principal Investigator: N.P.M. Schaap, Department of Hematology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HEMAML42
- 2019-001929-27