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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Biological: WU-NK-101


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) 2016 classification Unlikely to benefit from standard of care therapy defined by any one of the following criteria: 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. 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 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 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 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. Patients with extramedullary disease are permitted if bone marrow blast count is >5% Adequate organ function as defined in the protocol Life expectancy >12 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 at screening Exclusion Criteria: Circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive therapies such as leukapheresis or hydroxyurea are allowed) Uncontrolled or untreated bacterial, fungal, or viral infections, including HIV, Hepatitis B or C infection, or uncontrolled infection of any etiology Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (ECG) suggestive of acute ischemia or active conduction system abnormalities Severe renal impairment, defined as creatinine clearance <40 mL/min 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). Known hypersensitivity to one or more of the study agents 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) Pregnant or nursing (lactating) women Any condition that, in the opinion of the Investigator, would prevent the participant from consenting to or participating in the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This study will determine the safety and tolerability of WU-NK-101 and define the RP2D.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: WU-NK-101<br>A non-engineered Natural Killer (NK) cell derived from peripheral blood mononuclear cells (PBMC) that is cytokine-reprogrammed, expanded, and cryopreserved to create an allogeneic enhanced Memory-like anti-tumor NK cell therapy product. Each 28-day cycle of treatment consists of 3 doses of WU-NK-101 administered on Day 1, Day 8, and Day 15. | Biological: WU-NK-101<br>* WU-NK-101 administered on Day 1, Day 8, and Day 15.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events of WU-NK-101 as assessed by CTCAE v5 | Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of consent until End of Study (EOS) visit. | 24 months | 
| Maximum Tolerated Dose | Maximum Tolerated or Administered Dose of WU-NK-101 | Up to 21 days from first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from study drug administration (Day 1) until death on study. | 3 months | 
| Duration of Response | Time of response to the time of disease relapse, progression, or death due to any cause. | 24 months | 
| Overall Response Rate (ORR) | ORR is defined as proportion of patients that achieve complete remission (CR) + complete remission with incomplete hematologic recover (CRi). | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
relapsed, refractory, leukemia, NK cells