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A Phase I Trial of Donor Enriched Activated NK (DEA-NK) Cell Infusion Post Haploidentical Stem Cell Transplant for Refractory Myeloid Malignancies

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ClinicalTrials.gov Identifier: NCT05375253
Recruitment Status : Not yet recruiting
First Posted : May 16, 2022
Last Update Posted : May 16, 2022
Sponsor:
Information provided by (Responsible Party):
Zaid Al-Kadhimi, University of Nebraska

Brief Summary:

Patients with relapse refractory myeloid malignancies [acute myeloid leukemia (AML) myelodysplastic(MDS)/myeloproliferative(MPD) disorders] have no therapeutic options for long term remission. Haploidentical cytokine activated (IL-12, IL-18, IL-15) natural killer (NK) cell immunotherapy has been used with some success in treating patients with refractory relapsed AML. One limiting factor to the in-vivo expansion of infused activated NK cells is the recovery of recipient's immune system rejecting the infused NK cells. The use of haploidentical activated NK cell therapy post haploidentical transplant is an attractive option to induce in-vivo persistence of the infused NK cells and support anti leukemic efficacy.

This is a pilot phase Ib trial testing the feasibility, safety and immunologic effects of dose escalated donor enriched (αβ-TCR+/CD19+ double depleted mononuclear cells) activated natural killer cell infusion (DEA-NK) on day +7 post haploidentical stem cell transplantation (Haplo-Tx) with post-transplant cyclophosphamide (PTCY). Inclusion criteria include: adult patient with relapse refractory AML, MDS, or MPD, available haploidentical related donor, and adequate organ functions to undergo reduced intensity allogenic stem cell transplant. The clinical trial will enroll 12-18 subjects in a 3+3 phase I dose escalation fashion over 24 months. Subjects will be followed for 6 months and 1 year following Haplo-Tx.


Condition or disease Intervention/treatment Phase
Leukemia Biological: Donor Enriched Activated Natural Killer Cell Infusion Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Donor Enriched Activated NK (DEA-NK) Cell Infusion Post Haploidentical Stem Cell Transplant for Refractory Myeloid Malignancies
Estimated Study Start Date : November 1, 2022
Estimated Primary Completion Date : February 1, 2025
Estimated Study Completion Date : February 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Organ Donation

Arm Intervention/treatment
Experimental: Donor Enriched Activated NK Infusion (DEA-NK)
Infusion of DEA-NK on day +7 post-transplant
Biological: Donor Enriched Activated Natural Killer Cell Infusion
αβ TCR/CD19 depleted (DEA-NK) cells on day +7 post T-cell replete Haplo-Tx with PTCY




Primary Outcome Measures :
  1. Feasibility of DEA-NK cell infusions [ Time Frame: 100 Days ]
    Assess the feasibility of infusing activated enriched donor natural killer cell infusion (DEA-NK) at day +7 post-transplant by the ability to manufacture and administer the DEA-NK cells at study dose levels.

  2. Safety of DEA-NK cell infusions [ Time Frame: 100 Days ]
    Assess safety of the DEA-NK cell infusions by recording adverse events experienced by subjects at each dose level.

  3. Maximum tolerated dose of DEA-NK cell infusions [ Time Frame: 100 Days ]
    To determine the maximum tolerated dose (MTD) of DEA-NK cell infusion as determined by dose limiting toxicities (DLT) observed.


Secondary Outcome Measures :
  1. Non-Relapse Mortality Rate [ Time Frame: 1 year ]
    Non-Relapse Mortality (NRM) at 100 days, 180 days and 1 year

  2. Time to neutrophil recovery [ Time Frame: 21 Days ]
    Time to neutrophil recovery defined as the first of 3 consecutive days following the nadir that the absolute neutrophil count is at least 500/µl

  3. Time to platelet recovery [ Time Frame: 21 Days ]
    Time to platelet recovery defined as the first day that the platelet count is at least 20,000/µl without a transfusion in the preceding 7 days

  4. Incidence of graft failure [ Time Frame: 35 Days ]
    Incidence of graft failure as defined by ANC < 500/µl by Day +35 in the absence of disease recurrence



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Ages Eligible for Study:   19 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able to understand and sign informed Consent
  2. Age > 19 years and ≤ 70 years.
  3. Deemed eligible for allogeneic stem cell transplantation with a minimum KPS of 70% (Appendix A).
  4. Available HLA-haploidentical related donor as defined in section 5.2.1
  5. Subjects with adequate organ functions as measured by:

    1. Cardiac: Left ventricular ejection fraction at rest must be >45%,
    2. Hepatic: Bilirubin < 2.5 mg/dL except for Gilbert syndrome; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.
    3. Renal: GFR > 50 mL/min/1.73m2,
    4. Pulmonary: FEV 1, FVC, DLCO ion capacity) > 45% predicted (corrected for hemoglobin); or 02 saturation > 92% on room air.
  6. Able to be off of corticosteroids (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) and any other immune suppressive medications beginning on Day -3
  7. Subjects with prior central nervous system (CNS) involvement are eligible provided that it has been treated and cerebral spinal fluid (CSF) is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
  8. Clinical diagnosis of one of the following:

A. Refractory AML without complete remission (CR) after 2 or more cycles of induction therapy (primary induction failure), or AML relapsed after obtaining a CR and failed one or more cycles of re-induction therapy. decitabine or azacytidine with venetoclax will be considered as one cycle of induction therapy.

B. Myelodysplastic Syndrome+/- myeloproliferative neoplasm MDS/MPN which failed to adequately respond (persistence of blasts >5%) to hypomethylating agents and or chemotherapy (minimum of 3 cycles of hypomethylating agents or 2 cycles of hypomethylating + venetoclax or one cycle of induction chemotherapy)

Exclusion Criteria:

  1. Autologous hematopoietic stem cell transplant < 3 months prior to enrollment.
  2. Circulating peripheral blood blast count > 1000/µl (despite hydroxyurea and or leukapheresis).
  3. Previous allogeneic stem cell transplant.
  4. Presence of donor specific antibodies (DSA) with Mean Fluorescence Intensity (MFI) of ≥5000 as assessed by the single antigen bead assay, < 6 weeks prior to starting transplant conditioning
  5. Uncontrolled angina, severe uncontrolled ventricular arrhythmias.
  6. Received any investigational drugs within the 14 days prior to the first day of transplant conditioning (starting on day -6)
  7. Women of child-bearing potential must not be pregnant and/or breastfeeding

    a. Note: All females with intact ovaries and uterus will have two pregnancy tests as part of standard of care pre-transplant protocols.

  8. Evidence of HIV infection or known HIV positive serology (completed as part of pre-transplant testing).
  9. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
  10. Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05375253


Contacts
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Contact: Marnee Strege, BSN 402-559-8155 marnee.strege@unmc.edu

Sponsors and Collaborators
University of Nebraska
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Responsible Party: Zaid Al-Kadhimi, Associate Professor, Internal Medicine, University of Nebraska
ClinicalTrials.gov Identifier: NCT05375253    
Other Study ID Numbers: 158-22
First Posted: May 16, 2022    Key Record Dates
Last Update Posted: May 16, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms