NKX101, Intravenous Allogeneic CAR NK Cells, in Adults With AML or MDS

This is a single-arm, open-label, multi-center, Phase 1 study to determine safety and tolerability of an experimental therapy called NKX101 (allogeneic CAR NK cells targeting NKG2D ligands) in patients with relapsed/refractory AML or intermediate, high and very high risk relapsed/refractory MDS.

This is a dose-finding study of NKX101 and will be conducted in 2 parts:

Part 1: dose finding with two dosing regimens, utilizing modified "3+3" enrollment schema.

Part 2: dose expansion to further evaluate safety and tolerability, cellular kinetics, pharmacodynamics and anti-tumor response in expansion cohorts of patients with either AML or MDS.

Eligibility Criteria:
Inclusion Criteria:

* General:

  * ECOG performance status ≤2
* Disease related:

  * For AML subjects:

    * Previously treated relapsed/refractory AML, including subjects with MRD+ disease
    * Received at most 3 lines of previous anti-leukemia therapy
    * For subjects with targetable fms-like tyrosine kinase 3 (FLT3)-mutated or isocitrate dehydrogenase (IDH)1/2 mutated disease, subjects must have received at least 1 prior respective targeted therapy and may receive up to 4 lines of prior therapy
    * White blood cell count of ≤25 × 10\^9/L
    * For groups receiving NKX101 after lymphodepletion with fludarabine/cyclophosphamide +/- decitabine: Disease localized to the bone marrow, as evidenced by ≤ 5% peripheral blasts and no evidence of extramedullary disease
    * For groups receiving NKX101 after lymphodepletion with fludarabine/ cyclophosphamide +/- decitabine, group receiving NKX101 after lymphodepletion with fludarabine/ara-C: Additional subjects with specifically high-risk genetic mutations may be enrolled. High risk genetic mutation per ELN 2022 should be evaluated as per local assay and discussed with the Sponsor prior to study entry
    * For groups receiving NKX101 after lymphodepletion with fludarabine/cyclophosphamide +/- decitabine, group receiving NKX101 after lymphodepletion with fludarabine/ara-C: Additional subjects who have relapsed following HCT may be enrolled.
  * For MDS subjects:

    * Intermediate-, high-, or very high-risk MDS
    * Previously treated relapsed/refractory MDS
    * Received at least 1 and at most 3 lines of previous standard anti-MDS therapy
    * For groups receiving NKX101 after lymphodepletion with fludarabine/ cyclophosphamide +/- decitabine: Additional subjects with specifically high-risk disease may be enrolled. High-risk genetic mutation should be evaluated as per local assay
    * For group receiving lymphodepletion with fludarabine/cyclophosphamide +/- decitabine and NKX101: Additional subjects who have relapsed following HCT may be enrolled.
* Adequate Organ Function
* Platelet count ≥30,000/uL (platelet transfusions acceptable)
* Other:

  * Signed informed consent
  * Agree to use an effective barrier method of birth control

Exclusion Criteria:

* Disease related:

  * Acute promyelocytic leukemia with t(15;17) (q22;q12); or abnormal promyelocytic leukemia/retinoic acid receptor alpha (APML-RARA) and AML arising from chronic myelomonocytic leukemia (CMML)
  * Evidence of leukemic meningitis or known active central nervous system disease
  * Peripheral leukocytosis with ≥ 20,000 blasts/μL or other evidence of rapidly progressive disease that would preclude subject from completing at least 1 cycle of treatment
  * Use of any anti-AML/MDS chemotherapeutic or targeted small molecule drug within protocol specified window prior to the first dose of NKX101
  * Presence of residual non-hematologic toxicity from prior therapies that has not resolved to ≤ Grade 1
  * Any hematopoietic cell transplantation within 16 weeks
* Other comorbid conditions and concomitant medications prohibited as per study protocol
* Other:

  * Pregnant or lactating female