Acute Myeloid Leukemia Clinical Trial
Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Relapsed/Refractory AML
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.
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
I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in patients with relapsed/refractory AML
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.
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:
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.
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
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
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