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

A Phase 1 Study of NKX101, an Activating Chimeric Receptor Natural Killer Cell Therapy, in Subjects With Hematological Malignancies or Dysplasias

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.

NKG2D, CAR, Allogeneic, Natural killer, ACR, NKX101, IL15, Interleukin 15, NK cell, Cell Therapy, Immunotherapy, Adoptive cell therapy, r/r AML, Off-the-shelf

All subjects in Part 1 will receive lymphodepletion with fludarabine/cyclophosphamide followed by 3 or 2 (Regimen A or B, respectively) weekly doses of NKX101. Subjects in Part 2 will receive lymphodepletion with either fludarabine/cyclophosphamide or fludarabine/cytarabine (ara-C), or if the optional arm is opened, lymphodepletion with fludarabine/cyclophosphamide and decitabine, followed by 3 weekly doses of NKX101. Part 2: unrelated off-the-shelf donor derived NKX101 will be used.

NKX101 is an investigational allogeneic CAR NK product targeting NKG2D ligands on cancer cells. Part 2 will use the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of NKX101 as determined in Part 1.

Incidence, nature, and severity of treatment related adverse events will be evaluated. An adverse event is any unfavorable and unintended sign including clinically significant abnormal laboratory findings, symptom or disease.

Responses will be assessed per modified ELN criteria and will include complete and partial remission with and without varying degrees of hematologic recovery

Time-to-first response, time-to-best response, duration of response, transfusion independent rate, bridge-to-transplant rate, event-free survival, progression-free survival (PFS), overall survival (OS) (for all subjects), and hematologic improvement rates (for subjects with myelodysplastic syndrome [MDS])

Primary assessment: 28 days after first dose of NKX101 followed up to 2 years after last dose of NKX101

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