Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patents With Refractory or Relapsed AML

Study Overview
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Brief Summary
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This phase 2 clinical trial investigates the effectiveness of cytokine-induced memory-like natural killer (CIML NK) cells in combination with FLAG chemotherapy as a treatment for refractory or relapsed AML. Previous studies in adults with AML sowed successful induction of remission and a previous phase 1 study demonstrated that CIML NK cells can be used safely in pediatric patients. This phase 2 study uses FLAG chemotherapy to lower leukemic burden and suppress the recipient's immune system to provide an optimal environment for CIML NK cell expansion and anti-leukemic activity.

Official Title
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A Phase 2 Study of Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed AML

Conditions
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Refractory Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Cytokine induced memory-like NK cells
* Drug: Fludarabine
* Drug: Ara-C
* Drug: G-CSF
* Drug: Interleukin-2
* Procedure: Leukapheresis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. Disease defined by one of the following: *≥ 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease *absolute blast count greater than 1,000 per microliter in the peripheral blood with or without extramedullary disease. Age requirement for pediatric cohort: 1-21 years of age. Available HLA-haploidentical donor that meets the following criteria: Related donor (parent, sibling, offspring, or offspring of sibling) At least 18 years of age HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus. In general, good health and medically able to tolerate leukapheresis required for harvesting the NK cells for this study. Negative for hepatitis, HTLV, and HIV on donor viral screen Not pregnant Voluntary written consent to participate in this study Patients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment. Karnofsky/Lansky performance status > 50 % Adequate organ function as defined below: Total bilirubin < 2 mg/dL AST(SGOT)/ALT(SGPT) < 3.0 x upper limit of normal (ULN) Creatinine within normal institutional limits OR creatinine clearance > 50 mL/min/1.73 m2 by Schwartz formula or GFR (See Appendix B) Oxygen saturation ≥90% on room air Ejection fraction ≥35% Able to be off corticosteroids and any other immune suppressive medications beginning on Day -3 and continuing until 30 days after the infusion of the CIML NK cells. However, use of low-level corticosteroids is permitted if deemed medically necessary. Low-level corticosteroid use is defined as 10mg or less of prednisone (or equivalent for other steroids) per day. Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study and throughout the DLT evaluation period. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Relapsed after allogeneic transplantation. Isolated extramedullary relapse Circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed). Patients with any of the following diagnoses: Down's syndrome Acute promyelocytic leukemia (APL) Juvenile myelomonocytic leukemia (JMML) Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection. 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. Pregnant

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recipient: FLAG + CIML NK Cells + IL-2<br>-The recipient will begin a chemotherapy regimen of fludarabine, cytarabine and GCSF starting on Day -7. The haploidentical donor identified by HLA matching of the immediate family members will undergo non-mobilized large volume (20 L) leukapheresis on Day -1, and the NK cell product will be infused into the recipient on Day 0. CIML NK cells will be infused at maximum cell dose of 10 x 106/kg. Subcutaneous IL-2 will begin approximately 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses. | Biological: Cytokine induced memory-like NK cells<br>* -The CIML NK cells (maximum dose capped at 10 x 106/kg, minimum dose allowed is 0.5 x 106/kg) will be infused on Day 0 without a filter or pump.<br>* Other names: CIML NK cells;Drug: Fludarabine<br>* -Fludarabine (dose: 30 mg/m^2 per dose) will be given daily beginning on Day -7 for a total of 5 doses administered as an IV infusion over 30 minutes.<br>Drug: Ara-C<br>* -Ara-C (dose: 2000mg/m^2 per dose) will be given daily for a total of 5 doses administered as IV infusion over 3 hours, starting the same day as fludarabine.<br>* Other names: Cytarabine;Drug: G-CSF<br>* -Filgrastim (dose: 5 mcg/kg per dose to a maximum of 300 mcg) will be given subcutaneously daily for a total of 5 doses starting the same day as fludarabine and ara-C.<br>* Other names: Filgrastim;Drug: Interleukin-2<br>* -IL-2 will be administered subcutaneously at a dose of 1 million units/m2 every other day from Day 0 to Day +12 (7 doses total).<br>* Other names: IL-2;|
| Other: Donor:<br>-On Day -1 (one day before the planned NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard apheresis over 4-5 hours (with a target volume of at least 20 L) from the identified haploidentical donor. The apheresis procedure will be done as per standard institutional procedures (which may include placement of a central line if necessary). If the goal minimum NK cell dose will not be met based on the initial assessment of the leukapheresis product, a second collection/procedure may be performed. | Procedure: Leukapheresis<br>* -Donor only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (complete remission (CR) plus complete remission with incomplete blood count recovery (CRi)) | Complete remission (CR) requires all of the following: Bone marrow: Morphologically leukemia free state (≤ 5% myeloblasts) with normal maturation of all cell lines. Persistent dysplasia may be noted Peripheral blood: Platelets ≥ 100,000/uL Neutrophils ≥ 1000/uL Complete remission with incomplete blood count recovery (CRi): All of the above criteria for CR must be met, except that absolute neutrophils <1000/μL or platelets <100,000 /μL in the blood. | Day 28 | 
| Percentage of patients able to proceed to stem cell transplant |  | Up to 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | -DFS is defined as the time from the day CR or CRi is documented until disease progression or death. | Up to 2 years | 
| Overall survival (OS) | -OS is defined from the date of first dose of fludarabine on this study until death. | Up to 2 years | 
| Percentage of patients who achieve minimum residual disease (MRD)-negative status |  | Day 28 | 
| Safety of regimen as measured by number of adverse events | -Adverse events will be collected from Day 0 to Day 35; however, bone marrow suppression (ANC ≤ 500/mcL) and adverse events of GVHD involving the liver, skin, or gastrointestinal tract will be recorded to Day 100 | From Day 0 to Day 100 | 
| Duration of remission |  | Up to 2 years | 
| Time to progression |  | Up to 2 years |