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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid Leukemia; 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: aldesleukin; Drug: decitabine; Biological: natural killer cell therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (decitabine, allogeneic NK cells, aldesleukin); 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.	Other: laboratory biomarker analysis; Correlative studies; Biological: aldesleukin; Given SC; Other Names: Proleukin; IL-2; recombinant human interleukin-2; recombinant interleukin-2; Drug: decitabine; 20 mg/m2 Given IV (intravenous) for 5 days over 60 minutes; Other Names: DAC; 5-aza-dCyd; 5AZA; Biological: natural killer cell therapy; Undergo infusion of allogeneic NK cells on day 0

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sumithira Vasu

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2015
• Primary Completion (Actual): December 6, 2017
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: August 20, 2014
• First Submitted That Met QC Criteria: December 10, 2014
• First Posted (Estimate): December 15, 2014

Study Record Updates

• Last Update Posted (Actual): March 9, 2020
• Last Update Submitted That Met QC Criteria: March 5, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: AML; acute myeloid leukemia; decitabine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Aldesleukin; Decitabine; Azacitidine; Interleukin-2
• Other Study ID Numbers: OSU-14040; NCI-2014-01489 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No