Clinical Trials

Inclusion Criteria - General:

- Male or female ≥18 years of age at the time of signing the ICF. Age < 75 years for Cohort 7U.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 .

Inclusion Criteria - Disease Related:

- Cohort 1, 2U, 4, 7U, and 8U:

- R/R AML per standard European LeukemiaNet (ELN) criteria who have received at most 3 lines of previous anti-leukemia therapy (Döhner 2022). Subjects in CR with minimal residual disease (CRMRD+) may be enrolled;

- White blood cell count of ≤2 5 × 10^9 /L;

- 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;

- For cohorts 2U and 8U: Disease limited to the bone marrow, as evidenced by ≤ 5% peripheral blasts and no evidence of extramedullary disease;

- For cohorts 2U, 7U, and 8U: Additional subjects with specifically high-risk genetic mutations may be enrolled as per Section 1.2.3.8. High risk genetic mutation per ELN 2022 (e.g. TP53, monosomy 7) (Döhner 2022) should be evaluated as per local assay and discussed with the Sponsor prior to study entry;

- For cohorts 2U, 7U, and 8U: Additional subjects who have relapsed following HCT may be enrolled as per Section 1.2.3.9 . These subjects should not have received post-transplant anti-AML therapy with the exception of DLI; OR

- Cohort 1, 2U, 4, 7U, and 8U:

- R/R AML per standard European LeukemiaNet (ELN) criteria who have received at most 3 lines of previous anti-leukemia therapy (Döhner 2022). Subjects in CR with minimal residual disease (CRMRD+) may be enrolled;

- White blood cell count of ≤ 25 × 10^9 /L;

- 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;

- For cohorts 2U and 8U: Disease limited to the bone marrow, as evidenced by ≤ 5% peripheral blasts and no evidence of extramedullary disease;

- For cohorts 2U, 7U, and 8U: Additional subjects with specifically high-risk genetic mutations may be enrolled as per Section 1.2.3.8. High risk genetic mutation per ELN 2022 (e.g. TP53, monosomy 7) (Döhner 2022) should be evaluated as per local assay and discussed with the Sponsor prior to study entry;

- For cohorts 2U, 7U, and 8U: Additional subjects who have relapsed following HCT may be enrolled as per Section 1.2.3.9 . These subjects should not have received post-transplant anti-AML therapy with the exception of DLI.

Adequate Organ Function:

Adequate organ function is defined as the following:

- Serum creatinine value ≤1.5 mg/dL;

- Total bilirubin value ≤1.5 × upper limit of normal (ULN) or ≤3.0 × ULN for subjects with hereditary benign hyperbilirubinemia;

- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) value ≤ 3 × ULN and alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) value ≤ 3 × ULN;

- Ejection fraction ≥ 40% and the subject does not require oxygen therapy at baseline;

- Platelet count ≥ 30,000/μL (platelet transfusions acceptable)

Other:

- Willing and able to provide written informed consent, adhere to the study visit schedule, and comply with other requirements of the study as specified in the protocol;

Subjects who are fertile agree to use an effective barrier method of birth control (e.g., latex condom, diaphragm, cervical cap) to avoid pregnancy. Female subjects with childbearing potential must have negative serum or urine pregnancy test results within 7 days of LD initiation (non-childbearing is defined as ≥ 1 year postmenopausal or surgically sterilized).

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, except hydroxyurea therapy, within 14 days prior or 5 half-lives (whichever is shorter) and use of any anti-AML/MDS monoclonal antibody, including gemtuzumab ozogamicin, 28 days prior to the first dose of NKX101 Note: Treatment with hydroxyurea is allowed up to 48 hours prior to NKX101 treatment administration;

- Presence of Grade ≥ 2 acute GVHD or ≥ moderate chronic GVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) and NIH consensus criteria respectively (Appendix 5 Table D); or active acute or chronic GVHD requiring systemic immunosuppression;

- In addition to the required organ function specified in Inclusion Criterion #6, presence of other residual nonhematologic toxicity from prior therapies that has not resolved to ≤ Grade 1 (Note: Grade 2 residual alopecia is not an exclusion);

- Radiotherapy within 14 days prior to the first dose of NKX101, or not recovered from acute toxic effects of radiotherapy;

- Any hematopoietic cell transplantation within 16 weeks prior to the first dose of NKX101

Comorbid Conditions and Concomitant Medications:

- Use of any investigational agent within 14 days prior to the first dose of NKX101;

- Use of any prior chimeric antigen receptor (CAR) T or allogeneic adoptive NK cell therapy at any time prior to the first dose of NKX101. Note: Subjects with prior exposure to NKX101 are allowed if entering retreatment;

- Ongoing treatment with chronic immunosuppression or chronic systemic corticosteroids at stable dose levels of > 5 mg/day prednisone or glucocorticoid equivalent within 14 days prior to the first dose of NKX101. Inhaled and topical steroids are permitted;

- Previous or concomitant malignancy, except for basal cell or squamous cell carcinoma of the skin, prostate cancer with stable prostate specific antigen, carcinoma-in-situ of the uterine cervix, or other malignancies that are treated with resection alone. Subjects with other malignancies are eligible if they have remained disease free for at least 2 years prior to study entry;

- Major surgery within 28 days prior to the first dose. Subjects must have recovered from surgery and be without current complications;

- Active autoimmune disease;

- Active, uncontrolled, systemic infection necessitating systemic anti-infective therapy, or considered by the Investigator to be clinically uncontrolled or would make the subject inappropriate for study entry. Note: Subjects receiving prophylactic anti-infectives are allowed on study;

- Known HIV infection or acquired immunodeficiency syndrome-related illness;

- Known active or latent hepatitis B virus or hepatitis C virus infection;

- Major cardiac abnormalities as defined by, but not limited to, the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction within 12 weeks prior to the first dose of NKX101, ≥ Class III New York Heart Association congestive heart failure, or severe cardiac insufficiency, persistent prolongation of the QT interval corrected for heart rate (QTc) (Fridericia) interval of >480 msec;

- Cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, pulmonary embolism, or other thrombotic or embolic events within 12 weeks prior to the first dose of NKX101. Superficial thromboembolism stable on anticoagulation may be eligible after discussion with Medical Monitor;

- Any other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or NKX101 administration, interfere with the informed consent process and/or with compliance with the requirements of the study, interfere with the interpretation of the study results, or, in the Investigator's opinion, would make the subject inappropriate for entry into this study;

- A condition that is expected to require concomitant use of any medication that is listed as prohibited while on study;

- Known hypersensitivity or contraindications to the study treatment, including cyclophosphamide or fludarabine, components of the study treatment, including dimethyl sulfoxide (DMSO), human serum albumin, or fetal bovine serum

Other:

- Is a pregnant or lactating female.

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.