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

Summary

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 1-24.99 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 pediatric and young adult patients with relapsed/refractory AML. SECONDARY OBJECTIVES: I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in pediatric and young adult 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.

Eligibility

Inclusion Criteria:

* Patients with relapsed or primary refractory AML, including:

  * Patients with relapsed AML (Any patient in first or subsequent relapse are eligible. Patients with relapse after HSCT are eligible)
  * Primary refractory AML defined as failure to achieve a complete response after 2 cycles of induction chemotherapy, including persistent MRD positivity
  * Patients with isolated CNS or extramedullary disease are eligible Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease
* Patient age 1-24.99 years old
* Negative serum test to rule out pregnancy within 2 weeks prior to enrollment in females of childbearing potential

  o 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 and ALT ≤ 5 times the upper limit of normal (unless related to leukemic involvement). Upper limit of normal should be determined by the institutional defined normal laboratory range.
  * 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
* All prior treatment related non-hematologic toxicities must have resolved to ≤ Grade 2 prior to enrollment unless granted approval by study PI and/or Co-Is.
* 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)

  o Note: There is no waiting period required for patients having received intrathecal cytarabine, methotrexate and/or hydrocortisone
* Patients on immunosuppressive therapy

  o 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 or cellular therapy 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 or does not show evidence of significant resolution after initiating appropriate therapy

  o 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
* Patients with a history of adoptive cell therapy are excluded unless at least 30 days from infusion and with evidence of recovery of normal hematopoiesis (ANC ≥ 500/μL, platelet count ≥ 50,000/μL).

Conditions2

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