IRB Study Number 21-744
Status Recruiting
Phase Phase 2
Institutes Taussig Cancer Institute, Pediatric Institute
Description
Primary Objective
To estimate the 1-year relapse free survival (RFS) in children and young adults with high risk AML receiving donor-derived NK cell infusions following a haploHCT.
Secondary Objectives
To demonstrate the safety and feasibility of manufacturing and administering donor derived ex-vivo expanded haploNK infusions concomitantly with a myeloablative haploHCT in children and adolescents with high risk AML.
To quantitate and characterize NK- and T-cell immune reconstitution and function following HLA-haploHCT and donor-derived ex-vivo expanded NK cells at Days+30, +100, and +180, and +1 year.
To estimate the incidence of Grade II- IV aGVHD (Day +100) and cGVHD (Day+180, +1 year), infections (Days +100, +180), and OS (+1 year and +2 year).
To estimate the incidence of mixed donor chimerism (Day +42, +100, +1 year).
To determine the presence of KIR ligand-ligand mismatch between HLA-haploidentical donor and host and the impact on relapse rate.
To characterize the phenotype and function of the donor-derived ex-vivo expanded NK cell product.
Inclusion Criteria
2.3.1 Recipient 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:
a. Renal: Creatinine clearance (CrCl) ≥60 mL/min/1.73m2 by Cockcroft-Gault formula, Schwartz formula, or nuclear GFR study (Table 3)
b. Hepatic: Total bilirubin <2 mg/dL (unless due to Gilbert syndrome) and ALT and AST < 5x ULN
c. Cardiac: LVEF at rest ≥50% or SF ≥27% (by MUGA or ECHO)
d. 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
2.3.2 Recipient Exclusion Criteria
Active extramedullary disease 2. 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
2.3.3 Donor Inclusion Criteria
HLA haploidentical (≥ 4/8 and ≤ 7/8 allele match at the -A, -B, -C, -DRB1 loci) by high-resolution HLA typing and related to the patient
Weight ≥ 50kg
Age ≥ 17 years
Willing and able to undergo:
a. PB collection for NK cell production approximately 2-3 weeks before the recipient's admission for transplant
b. BM harvest (PBSC allowed in rare cases per Section 2.4.1)
- Meets current 21 CFR 1271 criteria for donor eligibility of therapeutic cells and hematopoietic stem cells
Refer to Section 2.3.5 for recommendations related to HLA-haploidentical donor prioritization.
2.3.4 Donor Exclusion Criteria
- Per treating physician, determined unable to discontinue medication likely to interfere with adequate NK cell expansion (e.g., high dose steroids or immunosuppression) given at the time of PB collection for NK cell production
