Pilot Study of Memory-like Natural Killer (ML NK) Cells After TCRαβ T Cell Depleted Haploidentical Transplant in AML

NCT06158828 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 202401147
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

This trial represents a single institution phase I/II pilot study with the primary objective of establishing the safety and feasibility of generating and infusing ML NK cells after TCRαβ haplo-HCT.

Conditions

AML, Childhood; Aml; Acute Myeloid Leukemia, Pediatric; Acute Myeloid Leukemia

Keywords

high-risk AML; haploidentical transplant; high-risk acute myeloid leukemia; AML from MDS; memory-like natural killer cells; ML NK cells

Outcome Measures

Primary Outcomes (2)

• Safety of patients being administered donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant

  Safety will be determined by events occurring following transplant. Non-relapse mortality, engraftment failure, and development of severe GvHD will be considered events.

  From transplant through Day +100

• Feasibility of manufacturing and administering donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant

  Feasibility is defined by product manufacture failure, i.e., the inability to infuse ML NK cells due to product contamination or insufficient cell dose (\<0.5x10\^6 / kg recipient weight).

  Through time of ML NK cell infusion (around Day +7)

Secondary Outcomes (7)

• Relapse Free Survival (RFS)

  From transplant through Month 12

• Overall Survival (OS)

  From transplant through Month 12

• Development of acute graft versus host disease (aGvHD)

  From transplant through Day +100

• Development of chronic graft versus host disease (cGvHD)

  From transplant through Day +180

• Development of chronic graft versus host disease (cGvHD)

  From transplant through Day +365

Study Arms (3)

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

EXPERIMENTAL

* Patients with high-risk genetic features \&/or poor response to upfront therapy * Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR * Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2 * Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

Drug: Rabbit Anti thymocyte globulin; Drug: Busulfan; Drug: Fludarabine; Drug: Thiotepa; Biological: TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft; Biological: memory-like natural killer cells; Biological: IL-2; Drug: Plerixafor; Device: CliniMACS

Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

EXPERIMENTAL

* Patients with high-risk AML who meet certain criteria listed in the protocol * Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR * Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2 * Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

Drug: Rabbit Anti thymocyte globulin; Drug: Busulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Melphalan; Biological: TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft; Biological: memory-like natural killer cells; Biological: IL-2; Device: CliniMACS

Donor

OTHER

Donors who meet the eligibility criteria will be mobilized as per institutional standard practice using G-CSF 10 mcg/kg/day for 5 consecutive days. Leukapheresis will be performed after 5 days of G-CSF administration (on Day -1) with a target volume for collection of 20 liters. If additional collection days are necessary to ensure target CD34+ doses, G-CSF administration may be extended per institutional standard and adjusted per physician discretion. Up to 4 days of pheresis are permitted.

Drug: Plerixafor; Biological: Granulocyte Colony-Stimulating Factor

Interventions

Melphalan DRUG

Melphalan is administered intravenously at a dose of 70 mg/m\^2/dose once daily for 2 days.

Also known as: Evolema, Alkeran

Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

CliniMACS DEVICE

After stem cells are collected by leukapheresis, in order to create the HPC product, the stem cells will be washed to remove platelets and the cell concentration will be adjusted per laboratory and CliniMACS technology recommendations. The cells are then labeled using the CliniMACS TCRαβ Biotin Kit and CD19+ immunomagnetic microbeads. After labeling, the cells are washed to remove unbound microbeads. The partially processed product is loaded on the CliniMACS device where labeled cells are depleted and the negative fraction is eluted off the device. The negative fraction is centrifuged and volume reconstituted to obtain the final product.

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft BIOLOGICAL

The HPC product obtained from a haploidentical donor will undergo ex vivo TCR alpha beta and CD19+ depletion, and will be infused fresh on Day 0. There is no maximum limit for CD34+ dose. A maximum dose of 1 x 10\^5/kg recipient weight of TCRαβ cells should not be exceeded in the final HPC product.

Also known as: TCRab/CD19+ depleted haploidentical HPC graft

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

Rabbit Anti thymocyte globulin DRUG

rATG is administered intravenously over 6-18 hours for a total of 2 to 3 doses. The daily dose is based on body weight and lymphocyte count.

Also known as: rATG

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

Busulfan DRUG

Busulfan is administered intravenously either Q6H or Q24H, with a recommended target Busulfan AUC of 70-90 mg\*h/L.

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

Fludarabine DRUG

Fludarabine is administered intravenously at a dose of 40 mg/m\^2/dose once daily for 4 days.

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

Thiotepa DRUG

Thiotepa is administered intravenously at a dose of 5 mg/kg/dose Q12H for 2 doses.

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

memory-like natural killer cells BIOLOGICAL

The ML NK cells (dose: max capped at 20 x 10\^6/kg recipient weight, minimum dose allowed is 0.5 x 10\^6/kg recipient weight) will be infused on Day +7.

Also known as: ML NK cells

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

IL-2 BIOLOGICAL

IL-2 is administered subcutaneously at a dose of 1 million units/m\^2 on Days +7, +9, +11, +13, +15, +17, and +19 (7 doses total).

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

Plerixafor DRUG

If suboptimal collection of stem cells is predicted, plerixafor may be administered at a dose of 0.24 mg/kg subcutaneous injection once (maximum 40mg/dose). For patients with renal impairment, plerixafor will be administered at a dose of 0.16 mg/kg subcutaneous injection (maximum 27 mg/day).

Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion; Donor

Granulocyte Colony-Stimulating Factor BIOLOGICAL

G-CSF will be administered at a dose of 10 mcg/kg/day for 5 days, or 6 days if two days of collection are needed.

Also known as: G-CSF

Donor

Eligibility Criteria

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

You may qualify if:

• High risk acute myeloid leukemia (AML) in either:
• Complete remission (CR) defined by \< 5% marrow blasts by morphology in the context of hematological recovery (ANC ≥ 0.5× 10\^9/L, platelet count ≥ 50 × 10\^9/L).
• Morphological leukemia free state (MLFS) defined by the absence of hematological recovery and \< 5% marrow blasts by morphology
• De novo AML in CR1 with any of the following high-risk features:
• MRD ≥ 1% after first induction course
• MRD ≥ 0.1% after second induction course
• RPN1-MECOM
• RUNX1-MECOM
• NPM1-MLF1
• DEK-NUP214
• KAT6A-CREBBP (if ≥ 90 days at diagnosis)
• FUS-ERG
• KMT2A-AFF1
• KMT2A-AFDN
• KMT2A-ABI1

You may not qualify if:

• Active GvHD. If patient had prior GvHD, patient must be off immunosuppression for at least 3 months prior to starting study treatment.
• Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been completed and there is no current evidence of disease.
• Currently receiving any other investigational agents at the time of transplant.
• Active CNS or extramedullary disease. History of CNS or extramedullary disease currently in remission is acceptable.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study.
• Inability to discontinue medications that are likely to interfere with ML NK cell activity, i.e., glucocorticoids and other immunosuppressants.
• Presence of significant anti-donor HLA antibodies per institutional standards. Anti-donor HLA - Antibody Testing is defined as a positive crossmatch test of any titer (by complement dependent cytotoxicity or flow cytometric testing) or the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay \> 3000.
• Presence of a second major disorder deemed a contraindication for HCT.
• Patients with Fanconi Anemia or Down Syndrome.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (bacterial, viral with clinical instability, or fungal), symptomatic congestive heart failure, or unstable cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of the start of conditioning.
• Donor Eligibility Criteria - Both Cohorts
• The preferred donor should be an adult aged 18 years or older. However, in circumstances where no suitable adult donor is available, consideration may be given to a minor donor aged 12 years or older. This exception only applies when all identified, otherwise eligible adult donors meet one or more of the following criteria:
• A medical condition that poses unacceptable risk, including autoimmune disease, infection, hematologic disorder, malignancy or a pathogenic germline mutation.
• Comorbidities that preclude safe administration of granulocyte colony-stimulating factor (G-CSF), placement of a pheresis catheter and/or stem cell collection.

Sponsors & Collaborators

• Children's Discovery Institute: collaborator
• St. Louis Children's Hospital Foundation: collaborator
• Washington University School of Medicine: lead
• The Leukemia and Lymphoma Society: collaborator
• Rising Tide Foundation: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Antilymphocyte Serum; Busulfan; fludarabine; Thiotepa; Melphalan; Receptors, Antigen, T-Cell, alpha-beta; Interleukin-2; plerixafor; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Receptors, Antigen, T-Cell; Receptors, Antigen; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Lymphokines; Biological Factors; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors

Study Officials

• Thomas M Pfeiffer, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Thomas M Pfeiffer, M.D.

CONTACT

314-273-2070; pthomas@wustl.edu

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 will enroll both transplant recipients and their haploidentical donors.

Study Record Dates

• First Submitted: November 27, 2023
• First Posted: December 6, 2023
• Study Start: November 15, 2024
• Primary Completion (Estimated): September 15, 2028
• Study Completion (Estimated): May 31, 2030
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)