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Cytokine-Induced Killer Cells after Donor Stem Cell Transplant in Treating Patients with Refractory or Relapsed Acute Myeloid Leukemia

Trial Status: Active

This phase II trial studies how well cytokine-induced killer cells after donor stem cell transplant work in treating patients with acute myeloid leukemia that has come back or has not responded to treatment. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cytokine-induced killer cells after the transplant may stop this from happening.

Inclusion Criteria

  • Refractory AML without complete remission (CR) after 2 or more cycles of induction therapy (primary induction failure), or AML relapsed after obtaining a CR and failed one or more cycles of re-induction therapy; standard dose 10-day decitabine (20 mg/m^2 daily IV x 10 days) or 7-day azacitidine (75-100 mg/m^2 daily SC/IV x 7 days) will be considered as one cycle of induction therapy
  • Deemed to be not otherwise eligible for a myeloablative hematopoietic cell transplant; high risk characteristics for a myeloablative transplant include age > 60 years and a HCT comorbidity index > 3
  • Available human leukocyte antigen (HLA)-haploidentical donor that meets the criteria
  • Patients with known central nervous system (CNS) involvement with AML are eligible provided that they have been treated and cerebrospinal fluid (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 performance status > 60%
  • Total bilirubin < 2 mg/dl
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 3.0 x institutional upper limit of normal (IULN)
  • Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 by Cockcroft-Gault formula
  • Oxygen saturation >= 90% on room air and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) of at least 40%
  • Ejection fraction >= 40%
  • Able to be off of corticosteroids (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) and any other immune suppressive medications beginning on day -3
  • 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 including throughout the initial evaluation period (100 days after CIML NK cell infusion)
  • Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)
  • DONOR: Related donor (parents, sibling, offspring, or offspring of sibling)
  • DONOR: HLA-haploidentical donor/recipient match by molecular typing at the HLA-A, HLA-B and HLA-DRB1 loci
  • DONOR: In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study
  • DONOR: Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria

  • Relapsed after allogeneic transplantation
  • Circulating blast count > 30,000/uL by morphology or flow cytometry (cyto-reductive therapies including leukapheresis or hydroxyurea are allowed)
  • Uncontrolled bacterial or viral infections, or known human immunodeficiency virus (HIV), hepatitis B or C infection
  • Presence of donor specific antibodies (DSA) with mean fluorescence intensity (MFI) of >= 5000 as assessed by the single antigen bead assay, < 6 weeks prior to starting transplant conditioning
  • Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (EKG) suggestive of acute ischemia or active conduction system abnormalities
  • New or progressive pulmonary infiltrates; progressive pulmonary infiltrate is defined as an increase of 20% or greater from prior radiologic exam; radiologic assessment methods may be computed tomography (CT) or posterioranterior (PA)/lateral (L) x-ray imaging; infiltrates attributed to infection must be stable or improving after 1 week of appropriate therapy, or 4 weeks for presumed or proven fungal infections to be eligible
  • Known hypersensitivity to one or more of the study agents
  • Received any investigational drugs within the 14 days prior to the first day of transplant conditioning
  • Pregnant and/or breastfeeding
  • DONOR: Positive for hepatitis, human T-lymphotropic virus (HTLV), or HIV infection
  • DONOR: Pregnant and/or breastfeeding

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE
Contact: Amanda Fishback Cashen
Phone: 314-454-8323

PRIMARY OBJECTIVE:

I. To determine the rate of leukemia free survival (LFS) at 1 year post-transplantation.

SECONDARY OBJECTIVES:

I. To determine the rate of LFS at 3 months post-transplantation.

II. To determine the complete remission (CR) rate at day 28 post-transplantation.

III. To determine the rate of overall survival (OS) at 1-year post-transplantation.

IV. To determine the incidence of relapse in patients who are found to be in CR on day 28 marrow post-transplant.

EXPLORATORY OBJECTIVES:

I. To determine the incidence of transplant related mortality (TRM) at day 100 post-transplantation.

II. To determine the incidence of transplant related mortality (TRM) at 6 months post-transplantation.

III. To determine the incidence of transplant related mortality (TRM) at 1 year post-transplantation.

IV. To determine the time to neutrophil engraftment.

V. To determine the time to platelet engraftment.

VI. To determine the engraftment rates at day 100 post-transplant by the donor/recipient STR (single tandem repeat) chimerism and or X/Y fluorescence in situ hybridization (FISH) in sex mismatched donor-recipient pairs.

VII. To determine the incidence and severity of acute graft versus host disease (GVHD) rates.

VIII. To determine the incidence and severity of chronic GVHD rates.

CORRELATIVE OBJECTIVES:

I. To evaluate the number, phenotype, and function of memory-like natural killer (NK) cells following adoptive transfer.

II. To assess serum cytokine levels, and superagonist interleukin-15:interleukin-15 receptor alphaSu/Fc fusion complex ALT-803 (ALT-803) levels, before and after cytokine-induced memory-like (CIML) NK cell infusion.

III. To assess functional responses and gene expression of memory-like NK cells and graft-derived NK cells to leukemia targets.

IV. To assess immune reconstitution following haploidentical (haplo)-hematopoietic cell transplantation (HCT) with same donor NK cell infusion.

V. To assess acute myeloid leukemia (AML) blasts and the bone marrow (BM) microenvironment pre-therapy and at first relapse to identify mechanisms of immunoevasion and assess association with AML mutations and clonal architecture.

VI. To determine the impact of KIR genotype and KIR ligand mismatches on the post-transplant outcomes.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to -2, cyclophosphamide IV over 60 minutes on days -6 to -5, and undergo total body irradiation (TBI) on day -1. Patients undergo HCT on day 0 and receive cyclophosphamide IV over 120 minutes on days 3-4. Patients then receive cytokine-induced killer cells IV on day 7. Beginning 4 hours after cytokine-induced killer cell infusion, patients receive ALT-803 subcutaneously (SC) on days 7, 28, 49, and 70. Patients also receive tacrolimus IV or orally (PO) on days 5-180 and mycophenolate mofetil IV or PO thrice daily (TID) on days 5-35 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for up to 48 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Amanda Fishback Cashen

  • Primary ID 201610088
  • Secondary IDs NCI-2016-01559
  • Clinicaltrials.gov ID NCT02782546