Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This pilot trial studies decitabine, donor natural killer cells, and aldesleukin in treating patients with acute myeloid leukemia that has come back after previous treatment (relapsed) or has not responded to previous treatment (refractory). Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving donor natural killer cells after decitabine may boost the patient's immune system by helping it see the remaining cancer cells as not belonging in the patient's body and causing it to destroy them (called graft-versus-tumor effect). Aldesleukin may stimulate natural killer cells to kill acute myeloid leukemia cells. Giving decitabine, donor natural killer cells, and aldesleukin may be a better treatment for acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the feasibility and safety of decitabine followed by natural killer (NK) cells and IL-2 (Interleukin). II. To define the specific toxicities and the dose limiting toxicity (DLT) of decitabine plus NK cells and IL-2. III. To determine the feasibility and safety of manufacturing processes for NK cells. SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR). II. To determine the rate of complete remission (CR) to this regimen of decitabine plus NK cells and IL-2 (interleukin) in acute myeloid leukemia (AML). TERTIARY OBJECTIVES: I. To correlate the biological activity of decitabine as in upregulating ligands that mediate susceptibility to NK mediated cytotoxicity. II. To characterize the biological activity of infused NK cells and persistence as defined by NK chimerism. III. To evaluate if decitabine has immunosuppressive properties or modulates changes in endogenous cytokines in patients. OUTLINE: Patients receive decitabine intravenously (IV) over 60 minutes on days -4 to 0 and undergo infusion of allogeneic NK cells on day 0. Beginning 1 hour after infusion allogeneic NK cells, patients also receive aldesleukin subcutaneously (SC) every other day for 6 doses. After completion of study treatment, patients are followed up for 30 days.

Official Title
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Phase I Study of Decitabine and Haplo-identical Natural Killer Cells in Acute Myeloid Leukemia (AML)

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: decitabine
* Biological: natural killer cell therapy
* Biological: aldesleukin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed or refractory AML Patients without a response after two cycles of decitabine Patients with primary refractory AML (persistent disease after standard induction with 7+3) or relapsed AML Patients who have relapsed post-allogeneic transplant Patients with secondary AML or therapy related disease (t-AML) are eligible; patients who received decitabine or 5-azacytidine as prior treatment for myelodysplastic syndrome (MDS) remain eligible Patients with central nervous system (CNS) leukemia are eligible as long as they have received treatment and most recent cerebrospinal fluid (CSF) analysis is negative for leukemia If the patient has co-morbid medical illness, life expectancy attributed to the comorbid illness must be greater than 6 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Total bilirubin < 2.0 mg/dL Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal Creatinine < 2.0 mg/dL New York Heart Association (NYHA) congestive heart failure (CHF) class II or better Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; if the patient does not agree, the patient is not eligible; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and willingness to sign the written informed consent document Human immunodeficiency virus (HIV) infection without acquired immune deficiency syndrome (AIDS)-defining criteria are eligible DONOR: Donors must be human leukocyte antigen (HLA)-haploidentical first-degree relatives of the patient; eligible donors include biological parents, siblings or half-siblings, or children DONOR: Donor must be in general good health and eligible for apheresis as determined by the medical provider DONOR: HLA-haploidentical donor/recipient match by at least class I serologic typing at the HLA-A and B loci DONOR: Willing and able to provide informed consent Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine that are not easily managed Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; as infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study Pregnant women or women who are breastfeeding are excluded from this study; confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women Patients with metastatic malignant solid tumors who received treatment in the past 6 months are excluded DONOR: Pregnancy DONOR: HIV

Ages Eligible for Study
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Minimum Age: 18 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 (decitabine, allogeneic NK cells, aldesleukin)<br>Patients receive decitabine IV over 60 minutes on days -4 to 0 and undergo infusion of allogeneic NK cells on day 0. Beginning 1 hour after infusion allogeneic NK cells, patients also receive aldesleukin SC every other day for 6 doses. | Drug: decitabine<br>* 20 mg/m2 Given IV (intravenous) for 5 days over 60 minutes<br>* Other names: DAC;Biological: natural killer cell therapy<br>* Undergo infusion of allogeneic NK cells on day 0<br>Biological: aldesleukin<br>* Given SC<br>* Other names: recombinant interleukin-2;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicities graded by using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 | Will be summarized descriptively. Infusion toxicity and tolerability will be summarized by frequencies of type of reaction and will be tabulated for each cohort of patients treated under a specific approach and manufacturing process. | Up to 28 days post NK infusion | 
| DLTs (dose limiting toxicites) defined by occurrence of life-threatening consequences within 4 hours of infusion graded using CTCAE version 4.0 | Infusion toxicity and tolerability will be summarized by frequencies of type of reaction and will be tabulated for each cohort of patients treated under a specific approach and manufacturing process. | Within 4 hours of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic response of these combinations of agents in patients ORR | Therapeutic response assessed using International Working Group criteria | Up to 30 days post-treatment | 
| Detect infused NK cells in vivo by donor-specific short tandem repeats in the Histocompatibility laboratory at Ohio state University. | Infused NK cells will be detected in vivo by donor-specific short tandem repeats in the Histocompatibility laboratory at Ohio state University. Prior to NK cell infusion, donor and recipient samples will be evaluate for unique short-tandem repeats. After the NK cell infusion, samples will be drawn at different time points( days 7, 14 and 21) to determine if circulating NK cells in the recipient are derived from the donor or recipient. | Up to 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, acute myeloid leukemia, decitabine