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 (EXCEL)

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
    • St. Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University, St. Louis
  • New York
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Lerner College of Medicine
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 95109
      • Fred Hutchinson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment Arm; All subjects will receive NK infusions.

Drug: Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions; 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).

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of functional donor-derived NK cells generated from the device	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 years
GVHD incidence	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).	2 years
KIR ligand-ligand mismatch	The presence of KIR ligand-ligand mismatch between HLA-haploidentical donor and host and the impact on relapse rate.	2 years
Incidence of mixed donor chimerism	Mixed donor chimerism is defined as >5%, but <95%, donor cells detected. Full donor chimerism is defined as >95% donor.	2 years
Cumulative incidence of neutrophil engraftment	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.	2 years
Cumulative incidence of platelet engraftment	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.	2 years

Collaborators and Investigators

• Sponsor: Michael Pulsipher
• Collaborators: Seattle Children's Hospital; Nationwide Children's Hospital
• Investigators: Study Director: Michael L Pulsipher, MD, Children's Hospital Los Angeles

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2021
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: March 18, 2021
• First Submitted That Met QC Criteria: April 5, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): May 4, 2025
• Last Update Submitted That Met QC Criteria: May 1, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: CHLA-20-00314

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data analysis and protocol can be made available to researchers upon request after publication.
• IPD Sharing Time Frame: Data will be available for an additional 2-3 years.
• IPD Sharing Access Criteria: Contact Principal Investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No