Back to resultsDonor-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)
Primary Purpose
Acute Myeloid Leukemia
Status
Enrolling by invitation
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia
Eligibility Criteria
Inclusion Criteria:
- Age ≤ 25 years at time of enrollment
High-risk AML, as defined by one of the following:
a. AML in CR1 (defined as <5% blasts in BM by morphology and flow cytometry) having at least one of these high-risk features: i. 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 ii. MRD-positive at the end of Induction I chemotherapy (defined as flow cytometry ≥ 0.1% blasts) b. 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
Sites / Locations
- Phoenix Children's Hospital
- Children's Hospital Los Angeles
- Children's Hospital Colorado
- AdventHealth Orlando
- Johns Hopkins All Children's Hospital
- Ann & Robert H. Lurie Children's Hospital
- Washington University, St. Louis
- New York Medical College
- Cleveland Clinic Lerner College of Medicine
- Nationwide Children's Hospital
- University of Utah
- Fred Hutchinson Cancer Center
- Medical College of Wisconsin
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment Arm
Arm Description
All subjects will receive NK infusions.
Outcomes
Primary Outcome Measures
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)
Secondary Outcome Measures
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).
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).
KIR ligand-ligand mismatch
The presence of KIR ligand-ligand mismatch between HLA-haploidentical donor and host and the impact on relapse rate.
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.
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.
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.
Full Information
NCT ID
NCT04836390
First Posted
March 18, 2021
Last Updated
September 5, 2023
Sponsor
Michael Pulsipher, MD
Collaborators
Nationwide Children's Hospital, Seattle Children's Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04836390
Brief Title
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
Acronym
EXCEL
Official 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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
August 24, 2021 (Actual)
Primary Completion Date
May 2026 (Anticipated)
Study Completion Date
May 2028 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Michael Pulsipher, MD
Collaborators
Nationwide Children's Hospital, Seattle Children's Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
All subjects will receive NK infusions.
Intervention Type
Drug
Intervention Name(s)
Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions
Intervention Description
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 Outcome Measure Information:
Title
1-year RFS
Description
The proportion and corresponding 95% exact binomial CI of patients who are relapse-free at 1-year from day of transplant (Day 0)
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Number of functional donor-derived NK cells generated from the device
Description
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).
Time Frame
2 years
Title
GVHD incidence
Description
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).
Time Frame
2 years
Title
KIR ligand-ligand mismatch
Description
The presence of KIR ligand-ligand mismatch between HLA-haploidentical donor and host and the impact on relapse rate.
Time Frame
2 years
Title
Incidence of mixed donor chimerism
Description
Mixed donor chimerism is defined as >5%, but <95%, donor cells detected. Full donor chimerism is defined as >95% donor.
Time Frame
2 years
Title
Cumulative incidence of neutrophil engraftment
Description
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.
Time Frame
2 years
Title
Cumulative incidence of platelet engraftment
Description
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.
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael L Pulsipher, MD
Organizational Affiliation
Children's Hospital Los Angeles
Official's Role
Study Director
Facility Information:
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
AdventHealth Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32803
Country
United States
Facility Name
Johns Hopkins All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Washington University, St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
New York Medical College
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
Cleveland Clinic Lerner College of Medicine
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Fred Hutchinson Cancer Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
95109
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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
Learn more about this trial
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
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