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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>All subjects will receive NK infusions. | Drug: Donor-Derived Ex-Vivo Expanded Natural Killer Cell Infusions<br>* 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).<br>|

What is the study measuring?
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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 |