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

Abstract

Background: Natural Killer (NK) cells are central to anti-tumor immunity, with the capacity to directly kill tumor cells by recognizing markers of cellular stress or abnormality. Through cytokine reprogramming, NK cells can gain memory-like features that augment their anti-tumor potential. WU-NK-101 is a non-engineered, cytokine-reprogrammed, expanded, and cryopreserved off-the-shelf NK cell product derived from peripheral blood mononuclear cells. WU-NK-101 demonstrates many features synonymous with memory NK cells, such as enhanced activity, proliferation, and persistence without the requirement of additional engineering strategies, overcoming limitations associated with conventional NK cell therapies. In addition, WU-NK-101 demonstrates potent in vitro and in vivo cytotoxicity against tumor cells, and an enhanced and adaptive metabolic fitness contributing to resilience within an adverse and immunosuppressive TME. Through large-scale feeder-cell-free expansion, WU-NK-101 enables multi-dose treatment of several patients from a single apheresis product (Mathyer M et al. SITC 2021) Multi-dosing may further augment anti-tumor activity leading to enhanced patient benefit without a substantial increase in patient risk. Methods: This is a Phase 1, open-label, dose escalation, and cohort expansion study (NCT05470140) designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML. In the Dose Escalation Phase, up to 18 patients will be treated in up to 3 dose levels (DL), starting with 300 x 106 for DL 1, 900 x 106 for DL2 and 1800 x 106 for DL3, with 1 potential de-escalation DL. Successive cohorts of 3 to 6 patients will be enrolled using a standard 3 + 3 design. Once the maximum tolerated/administered dose is defined, 6 additional patients will be enrolled in the Cohort Expansion Phase to further characterize the safety, tolerability, as well as determine the recommended Phase 2 dose of WU-NK-101. Patients will receive a lymphodepleting chemotherapy regimen (cyclophosphamide 50mg/kg and fludarabine 125mg/kg) starting on days -6 to -2 prior to receiving WU-NK-101. WU-NK-101 will be administered on Days 1, 8, and 15 in a 28-day cycle. All patients will be hospitalized for a minimum of 3 days following the first infusion of WU-NK-101 and will receive with recombinant human interleukin-2 every other day of the cycle. Treatment will be limited to 1 cycle in dose escalation. Patients achieving partial or complete remission in cohort expansion may receive re-induction and/or consolidation, for a total of up to 4 cycles. Eligible patients must have a confirmed diagnosis of primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization 2016 classification and be unlikely to benefit from standard of care chemotherapy. Eastern Cooperative Oncology Group Performance Status must be ≤ 2 at screening. Patients with known central nervous system involvement are eligible if they have been treated and cerebrospinal fluid is clear for at least 2 weeks prior to enrollment. Patients with extramedullary disease are permitted if bone marrow blast count is >5%. Key exclusions are circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive therapies such as leukapheresis or hydroxyurea are allowed); uncontrolled or untreated bacterial or viral infections; uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG suggestive of acute ischemia or active conduction system abnormalities; and severe renal impairment. Response assessment will take place on Day 28 (+/-3 days), by bone marrow aspirate and core biopsy, and response will be defined per 2022 European LeukemiaNet criteria. Response rate, duration of response, and mortality rate at 1 and 3 months will be evaluated.