Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Relapsed/Refractory AML

Study Overview
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Brief Summary
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This is a phase I/II dose escalation study designed to determine the safety and estimate the efficacy of UD-NK cells combined with FLA chemotherapy in patients age 18-24.99 with relapsed or refractory acute myeloid leukemia. PRIMARY OBJECTIVE: I. To determine the safety and recommended phase II dose of adoptive NK cell therapy using UD-NK cells in patients with relapsed/refractory AML SECONDARY OBJECTIVES: I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in patients with relapsed/refractory AML EXPLORATORY OBJECTIVES: I. To determine the immunophenotype and function of UD-NK cells II. To characterize in vivo expansion of UD-NK cells III. To determine the persistence of UD-NK cells Six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.

Detailed Description
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The treatment plan consists of Fludarabine/Cytarabine chemotherapy followed by six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant. In this study the first NK cell infusion is referred as day zero (D0), treatment plan activities prior or after D0 are denominated as day minus (D-) or day plus (D+). FLA will be give as follows: Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2) Six doses of UD-NK cells will be given thrice weekly for two weeks beginning day 0. NK cell administration schedule may vary and doses may be given from day 0 to 21. A minimum of 2 days between NK cell doses is required. Patients must meet eligibility criteria for NK cell infusion as described in the protocol. Patients will be eligible to receive a second cycle of chemotherapy for the following reasons: <CR after cycle 1 Additional cycle is needed to bridge the patient to HSCT Criteria to begin Cycle 2: ≥28 days since the first NK Cell infusion ≥2 days since the last NK Cell infusion in cycle 1 Bone marrow evaluation after cycle 1 complete It is suggested but not required for ANC > 500/uL AND platelets >50,000/uL prior to beginning cycle 2 Prior treatment related toxicities must have resolved to ≤ Grade 2 NK Cell Dose Levels: Dose level 1: 1.00x10^7 NK cell/kg (±20%) each dose for 6 doses per cycle Dose level 2: 3.00x10^7 NK cell/kg (±20%) each dose for 6 doses per cycle Dose level 3: 1.00x10^8 NK cell/kg (±20%) each dose for 6 doses per cycle The NK dose will be calculated based on actual body weight. Dose escalation will proceed according to the study design outlined in Section 9.1 to determine the MTD. Once a patient is enrolled at a dose level, the dose will remain at the enrolled dose level for all subsequent NK cell infusions.

Official Title
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Killer Cells Against Relapsed/Refractory Myeloid Acute Leukemia (KARMA): A Clinical Trial Evaluating the Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Treatment of Young Adults With Relapsed/Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Universal Donor Natural Killer Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed or primary refractory AML, including: Patients with relapsed AML after allogeneic stem cell transplantation Isolated CNS or extramedullary disease Primary refractory AML defined as failure to achieve a complete response (<5% BM blasts) after 2 cycles of induction chemotherapy Patient age 18-24.99 years old Negative serum test to rule out pregnancy within 2 weeks prior to enrollment in females of childbearing potential Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator for 6 months after the last dose of chemotherapy and/or NK cell infusion Negative serology for human immunodeficiency virus (HIV) Both males and females and members of all races and ethnic groups are eligible Organ function requirements: Renal function: Creatinine ≤ 2 mg/dl OR creatinine clearance > 60 ml/min/1.73m2. Liver function: Total bilirubin ≤ 2 mg/dl (unless Gilbert's syndrome), AST ≤ 150, and ALT ≤108 (unless related to leukemic involvement) Cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥20%. May be eligible after cardiology clearance if qualitatively normal function or repeat measures are normal. CNS: Patients with seizure disorder may be eligible if seizures well controlled Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, stem cell transplant or radiotherapy prior to entering this study All prior treatment related toxicities must have resolved to ≤ Grade 2 prior to enrollment All patients and/or their legal guardians must be able to understand and willing to sign a written informed consent document Exclusion Criteria: AML directed therapies in the 2 weeks prior to beginning treatment on this protocol (except for hydroxyurea) Note: There is no waiting period required for patients having received intrathecal cytarabine, methotrexate and/or hydrocortisone Patients on immunosuppressive therapy Patients must be off of all systemic immunosuppressive therapy for at least 2 weeks prior to enrollment with no evidence of recurrent GVHD Patients with a history of donor lymphocyte infusion within the last 30 days are not eligible for this study Allogeneic SCT < 3 months prior to study enrollment Any comorbidities that in the opinion of the investigator will preclude receiving study therapy Performance status: Karnofsky or Lansky Performance Scale (PS) < 50 Uncontrolled infection, defined as an infection which has not resolved spontaneously or does not show evidence of significant resolution after initiating appropriate therapy Asymptomatic viremia such as CMV, HPV, BK virus, HCV, etc. is NOT considered as an exclusion criterion Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease History of autoimmune disease Active GVHD at the time of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2) Six doses of universal donor IL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks starting on day 0. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant. | Biological: Universal Donor Natural Killer Cells<br>* Six doses of UD-NK cells will be given thrice weekly for two weeks for up to 2 cycles of treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events |  | Up to 56 days after the first NK cell infusion | 
| Rate of dose limiting toxicities |  | Up to 56 days after the first NK cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) negative response rate by flow cytometry |  | At the end of Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| CR rate after first cycle |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Relapse free survival and overall survival |  | 1 year | 
| Median time to neutrophil and platelet count recovery |  | 1 year | 
| Median duration of remission for patients who do not go onto transplant |  | 1 year | 
| Incidence of infectious complications |  | 1 year | 
| Percentage of patients receiving this regimen who are rendered transplant-eligible |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML