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Haploidentical Natural Killer Cells to Treat Refractory or Relapsed Acute Myelogenous Leukemia (AML)

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ClinicalTrials.gov Identifier: NCT01106950
Recruitment Status : Terminated (study drug (Ontak) no longer available)
First Posted : April 20, 2010
Results First Posted : June 26, 2013
Last Update Posted : December 28, 2017
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Leukemia, Myelogenous, Acute
Interventions Biological: Natural Killer Cells
Drug: Fludarabine
Drug: Cyclophosphamide
Drug: Denileukin diftitox
Procedure: Donor lymphapheresis
Drug: IL-2
Enrollment 15
Recruitment Details Study entry was open to patients 2 years and older regardless of gender, race, or ethnic background.
Pre-assignment Details Seventeen patients were enrolled, however, 2 patients did not receive Ontak (study drug) and were not included in the analysis.
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description Patients with acute myeloid leukemia (AML) are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Period Title: Overall Study
Started 15
Completed 15
Not Completed 0
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description Patients are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Baseline Participants 15
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
<=18 years
4
  26.7%
Between 18 and 65 years
8
  53.3%
>=65 years
3
  20.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants
44  (23.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
Female
6
  40.0%
Male
9
  60.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 15 participants
15
1.Primary Outcome
Title Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion
Hide Description The primary objective of this study was to estimate the incidence of in vivo expansion of natural killer (NK) cells 14 days after infusion of an allogeneic donor product enriched for NK progenitors. Successful in vivo donor NK cell expansion was defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/ul in the patient's peripheral blood 14 days after infusion.
Time Frame Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description:
Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Percentage of patients
27
2.Secondary Outcome
Title Percent of Patients With Complete Remission of Disease
Hide Description Disease response was defined as complete remission (disease response) by morphologic criteria including <5% blasts in a moderately cellular or cellular marrow. Complete remission was also correlated with NK cell expansion in vivo, IL-15 levels and donor/recipient KIR B genotyping, and Treg depletion.
Time Frame At least 4 weeks after last dose (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description:
Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Percentage of patients
53
3.Secondary Outcome
Title Percent of Patients With Disease Free Survival
Hide Description Number of patients alive and disease free at 6 months. The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.
Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description:
Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Percentage of patients
33
4.Secondary Outcome
Title Percent of Patients With Incidence of Relapse
Hide Description Number of patients who have had a relapse(the return of disease after its apparent recovery/cessation) after obtaining a complete remission of their disease.
Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description:
Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Percentage of patients
53
5.Secondary Outcome
Title Number of Patients With Treatment-Related Death
Hide Description Number of patients who died within the first 100 days of treatment due to toxicity.
Time Frame Day 100
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients
Hide Arm/Group Description:
Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Percentage of patients
13
6.Secondary Outcome
Title Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion
Hide Description Association between in vivo natural killer (NK) cell expansion and complete response without platelet recovery (CRp) with donor killer immunoglobulin-like (KIR) genotype and Treg depletion. In vivo donor NK cell expansion was correlated with regulatory T-cell (Treg) depletion as detected on flow cytometry.
Time Frame Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Evaluable (Treated) Patients (Expansion=No) Evaluable (Treated) Patients (Expansion=Yes)
Hide Arm/Group Description:
KIR matched: Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
KIR mismatched: Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Number of Participants Analyzed 7 8
Measure Type: Number
Unit of Measure: Percentage of patients
43 13
Time Frame [Not Specified]
Adverse Event Reporting Description Due to chemotherapy as prep for the NK cell infusion, it is expected that all patients will experience severe depression of their blood counts and other related toxicities. Adverse event (AE) collection will focus on targeted AEs and unexpected AEs at specific time points in relation to the NK cell infusion and IL-2 injections.
 
Arm/Group Title Treated Patients
Hide Arm/Group Description Patients with acute myeloid leukemia (AML) are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
All-Cause Mortality
Treated Patients
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Treated Patients
Affected / at Risk (%) # Events
Total   12/15 (80.00%)    
Blood and lymphatic system disorders   
Blood disorder  1  5/15 (33.33%)  5
Bone marrow hypocellular  1  1/15 (6.67%)  1
Hematologic toxicity - ANC<500  1  1/15 (6.67%)  1
febrile neutropenia  1 [1]  3/15 (20.00%)  3
Cardiac disorders   
Atrial fibrillation  1  1/15 (6.67%)  1
Left ventricular systolic dysfunction  1  1/15 (6.67%)  1
Gastrointestinal disorders   
Typhilitis  1  1/15 (6.67%)  1
Infections and infestations   
Lung Infection  1 [2]  1/15 (6.67%)  1
Encephalitis infection  1 [3]  1/15 (6.67%)  1
Infections and infestations- other  1 [4]  1/15 (6.67%)  1
Sepsis  1  2/15 (13.33%)  2
Nervous system disorders   
Intracranial hemorrhage  1 [5]  1/15 (6.67%)  1
Renal and urinary disorders   
Acute kidney injury  1  3/15 (20.00%)  3
Respiratory, thoracic and mediastinal disorders   
Adult respiratory distress syndrome  1  1/15 (6.67%)  1
Pleural hemorrhage  1  1/15 (6.67%)  1
Pneumonitis  1  1/15 (6.67%)  1
dyspnea  1 [6]  1/15 (6.67%)  1
Respiratory failure  1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders   
Infusion related reaction  1  1/15 (6.67%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
[1]
Grade 3
[2]
Fungal pneumonia
[3]
CMV encephalitis and viremia
[4]
HHV6 positive bone marrow and blood cultures
[5]
Possible fungal emboli
[6]
Grade 2
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Treated Patients
Affected / at Risk (%) # Events
Total   15/15 (100.00%)    
Blood and lymphatic system disorders   
Edema - grade 1  1  15/15 (100.00%)  113
Edema - grade 2  1  9/15 (60.00%)  36
Edema - grade 3  1  7/15 (46.67%)  28
Edema - grade 4  1  3/15 (20.00%)  8
Bruising - grade 2  1  1/15 (6.67%)  1
Blood disorder - grade 3  1  1/15 (6.67%)  1
Febrile neutropenia - grade 3  1  1/15 (6.67%)  1
Cardiac disorders   
Hypertension - grade 1  1  14/15 (93.33%)  58
Hypertension - grade 2  1  9/15 (60.00%)  42
Hypertension - grade 3  1  13/15 (86.67%)  63
Hypertension - grade 4  1  8/15 (53.33%)  20
Hypotension - grade 1  1  15/15 (100.00%)  142
Hypotension - grade 2  1  7/15 (46.67%)  20
Hypotension - grade 3  1  6/15 (40.00%)  7
Hypotension - grade 4  1  4/15 (26.67%)  12
Heart failure - grade 4  1  1/15 (6.67%)  1
Left ventricular systolic dysfunction - grade 3  1  1/15 (6.67%)  1
Endocrine disorders   
Increased creatinine - grade 2  1  1/15 (6.67%)  1
Increased creatinine - grade 3  1  1/15 (6.67%)  1
Gastrointestinal disorders   
Abdominal distension - grade 2  1  1/15 (6.67%)  1
Emesis - grade 3  1  1/15 (6.67%)  1
General disorders   
Gum/jaw pain - grade 2  1  4/15 (26.67%)  5
Headache - grade 1  1  2/15 (13.33%)  2
Fever - grade 1  1  15/15 (100.00%)  107
Fever - grade 2  1  4/15 (26.67%)  4
Fever - grade 3  1  3/15 (20.00%)  5
Fever - grade 4  1  15/15 (100.00%)  62
Chest pain - grade 3  1  1/15 (6.67%)  1
Headache - grade 2  1  1/15 (6.67%)  1
Headache - grade 4  1  1/15 (6.67%)  1
Immune system disorders   
Autoimmune disorder - grade 1  1  15/15 (100.00%)  146
Autoimmune disorder - grade 2  1  2/15 (13.33%)  2
Autoimmune disorder - grade 3  1  9/15 (60.00%)  12
Autoimmune disorder - grade 4  1  1/15 (6.67%)  1
Investigations   
Infusion related reaction - grade 1  1  15/15 (100.00%)  156
Infusion related reaction - grade 2  1  3/15 (20.00%)  4
Infusion related reaction - grade 3  1  4/15 (26.67%)  4
Nervous system disorders   
Confusion - grade 4  1  1/15 (6.67%)  2
Chills - grade 1  1  15/15 (100.00%)  130
Chills - grade 2  1  14/15 (93.33%)  23
Chills - grade 3  1  13/15 (86.67%)  28
Confusion - grade 3  1  1/15 (6.67%)  1
Renal and urinary disorders   
Acute kidney injury - grade 1  1  2/15 (13.33%)  2
Acute kidney injury - grade 2  1  2/15 (13.33%)  2
Acute kidney injury - grade 3  1  2/15 (13.33%)  2
Respiratory, thoracic and mediastinal disorders   
Diffuse alveolar hemorrhage - grade 5  1  5/15 (33.33%)  5
Dyspnea - grade 1  1  15/15 (100.00%)  133
Dyspnea - grade 2  1  7/15 (46.67%)  10
Dyspnea - grade 3  1  7/15 (46.67%)  15
Dyspnea - grade 4  1  5/15 (33.33%)  10
Dyspnea - grade 5  1  4/15 (26.67%)  15
Hypoxia - grade 1  1  15/15 (100.00%)  147
Hypoxia - grade 3  1  5/15 (33.33%)  10
Hypoxia - grade 4  1  10/15 (66.67%)  20
Hypoxia - grade 5  1  4/15 (26.67%)  4
Pneumonitis/pulmonary infiltrates - grade 1  1  15/15 (100.00%)  164
Pneumonitis/pulmonary infiltrates - grade 3  1  6/15 (40.00%)  12
Pneumonitis/pulmonary infiltrates - grade 4  1  1/15 (6.67%)  2
Pneumonitis/pulmonary infiltrates - grade 5  1  2/15 (13.33%)  4
Adult respiratory distress syndrome - grade 4  1  1/15 (6.67%)  1
Pneumonitis/pulmonary infiltrates - grade 2  1  1/15 (6.67%)  1
Pneumonitis - grade 4  1  1/15 (6.67%)  1
Lung infection - grade 4  1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders   
Rash/desquamation - grade 1  1  15/15 (100.00%)  152
Rash/desquamation - grade 2  1  4/15 (26.67%)  9
Rash/desquamation - grade 3  1  4/15 (26.67%)  7
Rash/desquamation - grade 4  1  1/15 (6.67%)  13
Vascular disorders   
Intracranial hemorrhage - grade 2  1  1/15 (6.67%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Jeffrey S. Miller, M.D.
Organization: Masonic Cancer Center, University of Minnesota
Phone: 612-625-7409
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01106950     History of Changes
Other Study ID Numbers: 2010LS010
MT2010-02 ( Other Identifier: Blood and Marrow Transplantation Program )
1003M79954 ( Other Identifier: IRB, University of Minnesota )
First Submitted: April 19, 2010
First Posted: April 20, 2010
Results First Submitted: May 6, 2013
Results First Posted: June 26, 2013
Last Update Posted: December 28, 2017