A Phase 1 Study of WU-NK-101 in Patients With Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

This study is a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML.

This is a first in human, multi-center Phase 1 single agent study in patients with R/R AML who have exhausted other treatment options. The study will consist of two phases, dose escalation and cohort expansion. During the Dose Escalation Phase, up to 18 patients will be treated with WU-NK-101 in up to 3 Dose Levels (DL) until maximum tolerated dose (MTD) or maximum administered dose (MAD) is determined.

Once the MTD/MAD is defined, 6 additional patients will be enrolled in the Cohort Expansion Phase to further characterize the safety, tolerability, as well as determining the recommended phase 2 dose (RP2D) of WU-NK-101. Patients in the Cohort Expansion Phase, who achieve a partial response (PR), may receive up to 2 further re-induction cycles contingent on safety in the Dose Escalation Phase; patients who achieve a complete remission with partial hematologic recovery (CRh) or complete remission with incomplete hematologic recovery (CRi) at any point during the course of treatment may receive a further consolidation cycle, for a total of up to 4 cycles per patient. During cohort expansion, dosing breaks of up to two weeks are allowed between cycles.

Eligibility Criteria:
Inclusion Criteria:

1. Confirmed diagnosis of primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) 2016 classification
2. Unlikely to benefit from standard of care therapy defined by any one of the following criteria:

   1. Primary induction failure (PIF) defined as leukemia refractory to ≥ 1 induction attempts. Induction attempts include 1 high-dose and/or 2 standard-dose cytarabine

      * an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens.
   2. For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens:

      * ≥ 2 but ≤ 4 cycles of Bcl-2 inhibitors in combination with azacitidine, decitabine, or low dose cytarabine
      * ≥ 2 but ≤ 4 cycles of gemtuzumab ozogamicin monotherapy
      * ≥ 6 but ≤ 8 cycles ivosidenib or enasidenib
   3. Leukemia in relapse after achieving CR

      * Early Relapse: disease recurrent within ≤ 6 month of documented remission
      * Late Relapse: disease recurrent within \> 6 month of documented remission
      * Refractory-Relapse: refractory to ≥ 1 unsuccessful salvage attempts
3. Patients with AML post hematopoietic stem cell transplant (HSCT) \[permitted in Cohort Expansion Phase only\] must meet the following criteria:

   * There must be histological confirmation of AML relapse after HSCT
   * Undergone allogeneic HSCT (alloSCT) \> 90 days prior to enrollment from a match related donor, matched unrelated donor, cord blood donor, or haplo- identical donor
   * Off all immunosuppressive medications for a minimum of 2 weeks with the exception of physiologic doses (\<10 mg) of corticosteroids
   * No history of Grade ≥ 3 veno-occlusive disease, or active graft versus host disease
4. Patients with known central nervous system (CNS) involvement with AML are eligible if they have been treated and cerebrospinal fluid is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (radiotherapy or chemotherapy) should continue as medically indicated during the study treatment.
5. Patients with extramedullary disease are permitted if bone marrow blast count is \>5%
6. Adequate organ function as defined in the protocol
7. Life expectancy \>12 weeks
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 at screening

Exclusion Criteria:

1. Circulating blast count \>30,000/µL by morphology or flow cytometry (cytoreductive therapies such as leukapheresis or hydroxyurea are allowed)
2. Uncontrolled or untreated bacterial, fungal, or viral infections, including HIV, Hepatitis B or C infection, or uncontrolled infection of any etiology
3. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (ECG) suggestive of acute ischemia or active conduction system abnormalities
4. Severe renal impairment, defined as creatinine clearance \<40 mL/min
5. New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be stable/improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections).
6. Known hypersensitivity to one or more of the study agents
7. Received any investigational drugs within the 14 days prior to the first dose of fludarabine (wash-out period of at least 5 half-lives from the last dose of any investigational therapy prior to screening period or 14 days, whichever is longer)
8. Pregnant or nursing (lactating) women
9. Any condition that, in the opinion of the Investigator, would prevent the participant from consenting to or participating in the study