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

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

Overview

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.

Interventions

• 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).

Primary outcome measures

• 1-year RFS [Time frame: 1 year]

Secondary outcome measures (6)

• Number of functional donor-derived NK cells generated from the device [Time frame: 2 years]
• GVHD incidence [Time frame: 2 years]
• KIR ligand-ligand mismatch [Time frame: 2 years]
• Incidence of mixed donor chimerism [Time frame: 2 years]
• Cumulative incidence of neutrophil engraftment [Time frame: 2 years]
• Cumulative incidence of platelet engraftment [Time frame: 2 years]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• Phoenix Children's Hospital — Phoenix
• Children's Hospital Los Angeles — Los Angeles
• Children's Hospital Colorado — Aurora
• AdventHealth Orlando — Orlando
• Johns Hopkins All Children's Hospital — St. Petersburg
• Ann & Robert H. Lurie Children's Hospital — Chicago
• Washington University, St. Louis — St Louis
• New York Medical College — Valhalla
• … and 5 more centers

Identifiers

NCT: NCT04836390 · CHLA-20-00314

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗