Cytokine-induced Memory-like NK Cells in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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This phase I/2 trial studies the side effects and best dose of activated natural killer cells in treating patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes. Giving chemotherapy before a donor natural killer cell infusion helps stop the growth of cancer cells and stops the patient's immune system from rejecting the donor's natural killer cells. Modified natural killer cells may help the body build an immune response to kill cancer cells. Aldesleukin (interleukin-2) may stimulate the white blood cells (including natural killer cells) to kill leukemia cells. In the phase II and pediatric portion of the study, the investigators intend to use maximal tolerated or tested (MT/TD) CIML NK cell dose as determined from the phase I part of this study. The phase II portion of the study also replaces IL-2 with ALT-803. The rationale for this change is to support the donor derived NK cells in vivo after adoptive transfer. Update with Amendment 16: The first two patients treated in the Phase II ALT-803 lead in cohort experienced a set of symptoms consistent with cytokine release syndrome (CRS).The Phase II ALT-803 lead in cohort was closed and a decision was made to return to rhIL-2 support for the remainder of enrollments in the Phase II portion of the study.

Official Title
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A Phase 1/2 Study of Cytokine-Induced Memory-Like NK Cells in Patients With AML or MDS

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Procedure: Leukapheresis
* Biological: Cytokine-induced killer cells
* Biological: IL-2
* Drug: ALT-803
* Procedure: Peripheral blood for correlative studies
* Procedure: Bone marrow for correlative studies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis requirement for phase I patients: Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. OR High-risk AML (by ELN criteria; See Appendix C) in complete remission (CR) and has either refused hematopoietic stem cell transplantation OR is currently not eligible for hematopoietic stem cell transplantation OR for whom hematopoietic stem cell transplantation is being reserved for later relapse. This is inclusive of patients with minimal residual disease evidenced by cytogenetics, molecular testing, and/or flow cytometry. OR Myelodysplastic syndrome (MDS) with excess blasts (>5%) and progressive disease at any time after initiation of DNA hypomethylator treatment during the past 2 years, OR failure to achieve complete or partial response or hematological improvement (see section 12.4) after at least six cycles of azacytidine or four cycles of decitabine administered during the past 2 years, OR intolerance to azacytidine or decitabine. MDS patients with isolated 5q- abnormalities that meet these criteria after lenalidomide therapy and DNA hypomethylator therapy are also eligible. Diagnosis requirement for phase II patients: *Refractory AML without CR after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. Favorable-risk core binding factor (CBF) mutated AML and acute promyelocytic leukemia (APL) will be excluded. Diagnosis requirement for pediatric cohort patients: *Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. Age requirement for phase I and phase II patients: At least 18 years of age. Age requirement for pediatric cohort: 2-17 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 IULN Creatinine within normal institutional limits OR creatinine clearance ≥ 50 mL/min/1.73 m2 by Cockcroft-Gault Formula (adults) or Schwartz formula (pediatric cohort) 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 (phase II only). More than one course of salvage chemotherapy for primary induction failure or AML relapsing after CR1 (phase II only). Circulating blast count ≥30,000/µL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed). Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities. 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. Pregnant and/or breastfeeding.

Ages Eligible for Study
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Minimum Age: 2 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells<br>Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses) | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Biological: IL-2<br> <br> * Other names: Aldesleukin;Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| Experimental: Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells<br>Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses) | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Biological: IL-2<br> <br> * Other names: Aldesleukin;Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| Experimental: Phase I Dose Level 3: Maximum NK cell/number kg<br>Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses) | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Biological: IL-2<br> <br> * Other names: Aldesleukin;Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| Experimental: Phase II (IL-2): Maximum NK cell/number kg<br>The recipient will begin a lymphodepleting preparative regimen of fludarabine and cyclophosphamide on Day -6. 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. 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. | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Biological: IL-2<br> <br> * Other names: Aldesleukin;Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| Experimental: Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg<br>Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1. CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0. Subcutaneous ALT-803 will begin approximately 4 hours after the infusion and will continue for a total of 2 doses (Days 0 and 5). | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Drug: ALT-803<br> <br> Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| Experimental: Pediatric Cohort: Maximum NK cell/number kg<br>Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1 CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0 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 | Drug: Fludarabine<br> <br> * Other names: fludarabine-5'-monophosphate;Drug: Cyclophosphamide<br> <br> * Other names: CPM;Procedure: Leukapheresis<br> <br> Biological: Cytokine-induced killer cells<br> <br> * Other names: CIK cells;Biological: IL-2<br> <br> * Other names: Aldesleukin;Procedure: Peripheral blood for correlative studies<br>* -Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse<br>Procedure: Bone marrow for correlative studies<br>* -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse<br>|
| No Intervention: Donors<br>-The haploidentical donor identified by HLA matching of the immediate family members (parents, siblings, and children) will undergo non-mobilized leukapheresis on Day -1. Peripheral blood mononuclear cells (PBMCs) will be collected using standard collection techniques. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I) | Defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity (DLT) or the maximum dose if less than or equal to 1 patient suffers a DLT at the maximum dose. | 35 days | 
| Complete Remission Rate (CR/CRi) in Participants With Relapsed or Refractory AML Following CIML NK Therapy (Phase II) | Complete remission rate (CR): Morphologically leukemia free state (i.e. bone marrow with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions 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. | Up to 3 years | 
| Safety of CIML NK Cells as Measured by the Number of Participants With Treatment Related Adverse Events (Pediatric Cohort) | Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC < 500/uL/µL) and AEs of GVHD involving the liver, skin, or GI tract will be recorded to Day 100. | Through Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric) |  | 35 days | 
| Duration of Remission (DOR) (Phase I, Phase II, and Pediatric) | DOR is defined only for patients who achieve a complete remission (CR), complete remission with incomplete blood count recovery (CRi), marrow complete response (mCR), or partial remission (PR), and is measured from the first date of attaining CR or PR until the date of disease progression or death. | Up to 3 years | 
| Time to Progression (Phase I, Phase II, and Pediatric) | TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression. | Up to 3 years | 
| Disease Free Survival (DFS) (Phase I, Phase II, and Pediatric) | DFS is defined as the time from the day CR, mCR, or CRi is documented until disease progression or death. | Up to 3 years | 
| Overall Survival (OS) (Phase I, Phase II, and Pediatric) | OS is defined from the date of first dose of fludarabine on this study until death. | Up to 3 years | 
| Toxicity as Measured by the Number of Participants With Treatment Related Adverse Events (Phase I and Phase II) | Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. AEs will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC < 500/uL/µL) and AEs of GVHD involving the liver, skin, or GI tract will be recorded to Day 100. | Through Day 100 |