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NCT Number: NCT04836390

Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions in Children and Young Adults With High Risk Acute Myeloid Leukemia Receiving Myeloablative HLA-Haploidentical Hematopoietic Cell Transplant

This is a Phase II pilot study to determine the efficacy of three fixed dose (1 x 108/kg) infusions of ex-vivo expanded human leukocyte antigen (HLA)-haploidentical donor natural killer (NK) cells (haploNK) in children and young adults with high risk acute myeloid leukemia (AML) undergoing HLA-haploidentical hematopoietic cell transplant (haploHCT) with a busulfan and cyclophosphamide-based myeloablative conditioning regimen and post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. The investigators will also demonstrate the feasibility of performing this trial in a multi-center study.

The investigators hypothesize that the infusion of haploNK in this setting will facilitate immune reconstitution and decrease relapse rates and infectious complications without increasing GVHD, resulting in improved survival as compared to recent historical cohorts of haploHCT without NK cell infusion.

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Key information

Conditions

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

Age range

0 year–25 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Phoenix Children's Hospital, Phoenix, Arizona, United States

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age ≤ 25 years at time of enrollment
  • High-risk AML, as defined by one of the following:
  • AML in CR1 (defined as <5% blasts in BM by morphology and flow cytometry) having at least one of these high-risk features:
  • Mutations associated with high risk disease (Appendix A). Other high-risk features not explicitly stated in Appendix A can be considered after discussion/approval with the protocol chair/team
  • MRD-positive at the end of Induction I chemotherapy (defined as flow cytometry ≥ 0.1% blasts)
  • AML in ≥CR2 (defined by <5% blasts in BM by morphology and flow cytometry)
  • Recovery from prior cycle of chemotherapy as defined by an absolute neutrophil count ≥ 500/mm3
  • AML secondary to select germline marrow failure disorders (with exception of Fanconi Anemia) may be eligible but require approval from Protocol Chairs prior to enrollment.
  • Performance status ≥70% (Lansky for <16 years; Karnofsky for ≥16 years)
  • Adequate major organ system function as demonstrated by:
  • Renal: Creatinine clearance (CrCl) ≥60 mL/min/1.73m2 by Cockcroft-Gault formula, Schwartz formula, or nuclear GFR study (Table 3)
  • Hepatic: Total bilirubin <2 mg/dL (unless due to Gilbert syndrome) and ALT and AST < 5x ULN
  • Cardiac: LVEF at rest ≥50% or SF ≥27% (by MUGA or ECHO)
  • Pulmonary: DLCO, FEV1, and FVC ≥ 50% of predicted corrected for hemoglobin. For patients <7 years of age or those unable to perform PFTs: O2 Sat >92% on room air by pulse oximetry and on no supplemental O2 at rest
  • The patient, patient's parent, guardian, or legal representative can provide written informed consent

Exclusion criteria

  • Active extramedullary disease
  • Unresolved/ongoing and serious viral, bacterial, or fungal infection despite appropriate treatment
  • Positive pregnancy test in a female of child-bearing potential (FCBP)
  • Inability to comply with medical therapy or follow-up
  • Prior allogeneic transplant
  • Patients with Fanconi Anemia and Down syndrome

Treatment and study plan

Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions

Drug

Peripheral blood (PB) ≤ 450 mL and based on donor weight (minimum 10 ml/kg) will be drawn from the HLA-haploidentical donor at least 16 days before the scheduled day of transplant (Day 0). HaploNK cells will be manufactured from the PB of the donor after co-culture with irradiated feeder cells (IFC) as described in Section 2.4. The recipients will receive three NK cell infusions on Day-1, Day+7 (± 1 day) and Day+42 (up to Day+90) from day of transplant (Day 0).

Primary outcomes

  1. 1-year RFS

    Time frame: 1 year

    The proportion and corresponding 95% exact binomial CI of patients who are relapse-free at 1-year from day of transplant (Day 0)

Secondary outcomes

  1. Number of functional donor-derived NK cells generated from the device

    Time frame: 2 years

    Product manufacturing failure is defined as inability to generate sufficient NK cell product due to failure to meet release criteria or insufficient cells for at least one full dose (≤10^8/NK cells/kg ABW).

  2. GVHD incidence

    Time frame: 2 years

    The incidence of Grade II- IV aGVHD (Day +100) and cGVHD (Day+180, +1 year), opportunistic infections (+1 year), and OS (+1 year and +2 year).

  3. KIR ligand-ligand mismatch

    Time frame: 2 years

    The presence of KIR ligand-ligand mismatch between HLA-haploidentical donor and host and the impact on relapse rate.

  4. Incidence of mixed donor chimerism

    Time frame: 2 years

    Mixed donor chimerism is defined as >5%, but <95%, donor cells detected. Full donor chimerism is defined as >95% donor.

  5. Cumulative incidence of neutrophil engraftment

    Time frame: 2 years

    The cumulative incidence of neutrophil engraftment from the time of transplant will be estimated using the cumulative incidence function with death and relapse prior to engraftment as the competing risk. The definition of neutrophil engraftment is a post-nadir ANC > 500/mm3 for three consecutive laboratory values obtained on different days. The first of the three days will be designated as the day of neutrophil recovery.

  6. Cumulative incidence of platelet engraftment

    Time frame: 2 years

    The cumulative incidence of platelet engraftment from the time of transplant will be estimated using the cumulative incidence function with death and relapse prior to engraftment as the competing risk. The definition of platelet engraftment is sustained platelet count > 20,000/mm3 with no platelet transfusions in the preceding seven days. The first of three consecutive measurements on different days will be designated as the day of initial platelet recovery.

Sponsors and collaborators

Lead sponsor

Michael Pulsipher

Other

Collaborators

  • Nationwide Children's Hospital
  • Seattle Children's Hospital

Registry information

Official study title

A Phase II Pilot Study of Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions in Children and Young Adults With High Risk Acute Myeloid Leukemia Receiving Myeloablative HLA-Haploidentical Hematopoietic Cell Transplant: A Multicenter Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) Study

Acronym: EXCEL

Important dates

Study start
2021
Primary completion
2026
Study completion
2028
First posted
Apr 8, 2021
Registry last updated
May 4, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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