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Safety Trial of NK DLI From 6/6 HLA Matched Family Member Following Nonmyeloablative ASCT

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ClinicalTrials.gov Identifier: NCT00586690
Recruitment Status : Completed
First Posted : January 4, 2008
Results First Posted : June 2, 2014
Last Update Posted : February 8, 2017
Sponsor:
Information provided by (Responsible Party):
David Rizzieri, MD, Duke University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphoma
Interventions Device: NK Cell infusion using CD56 monoclonal antibody
Procedure: Donor Apheresis
Enrollment 47
Recruitment Details Twenty five participants were recruited through the Adult Bone Marrow Transplant Program at Duke University Medical Center. Recruitment began in May, 2005 and ended in April, 2010. Patients who met the eligibility criteria were approached about the study and informed consent was conducted for those who agreed.
Pre-assignment Details Prior to initiating therapy, donors and subjects will have complete history, physical exam, routine laboratory tests, and/or radiographic tests. Recipients may have Bone marrow aspirate/biopsy repeated to check for prior abnormalities. If disease progression present, patient didn't continue with treatment.
Arm/Group Title NK Cell Infusion Donor Apheresis
Hide Arm/Group Description NK Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion. Patients will be evaluated for toxicity and response until 20 weeks after the last NK Infusion. Leukapheresis was repeated daily up to 3 days until the target dose of cells was reached (preferably without donor receiving growth factors). When possible, cells were transfused immediately after collection and processing. If collections occurred during initial mobilization at the time of stem cell transplant, the donor was off growth factor for >24 hours. These collections, which are extra cells collected from the donor following initial collections for transplant were sufficient for the natural killer cells used in the trial. The cells were NK selected using a CD56 antibody (CliniMACS CD56 Reagent), CliniMACSplus instrument and CliniMACS tubing set provided by Miltenyi Biotec using the company protocol (Miltenyi Biotec Inc, Auburn, California). Pre and post processing cell count, viability, Hematopoietic Progenitor Cell Assay (HPCA) and flow analysis were done.
Period Title: Overall Study
Started 21 [1] 22
Completed 5 22
Not Completed 16 0
Reason Not Completed
Death             2             0
Disease Progression             10             0
Adverse Event             1             0
Lack of Efficacy             2             0
Lab can't accommodate             1             0
[1]
Four consented subjects were screen failures.
Arm/Group Title NK Cell Infusion Donor Apheresis Total
Hide Arm/Group Description Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion. Apheresis repeated daily up to 3 days until target dose of cells reached (preferably without donor receiving growth factors). Cells were transfused immediately after collection and processing. If collections occurred during initial mobilization at the time of stem cell transplant, the donor was off growth factor for >24 hours. These extra cell collections from the donor were sufficient for the natural killer cells used in the trial. The cells were NK selected using a CD56 antibody (CliniMACS CD56 Reagent), CliniMACSplus instrument and CliniMACS tubing set provided by Miltenyi Biotec using the company protocol (Miltenyi Biotec Inc, Auburn, California). Pre and post processing cell count, viability, Hematopoietic Progenitor Cell Assay (HPCA) and flow analysis were done. Total of all reporting groups
Overall Number of Baseline Participants 25 22 47
Hide Baseline Analysis Population Description
Eligible adult patients were those who engrafted following a fludarabine based T cell depleted non-myeloablative allogeneic transplant regimen with alemtuzumab. Donors were the same HLA 6/6 matched family member used for the allogeneic transplantation.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 22 participants 47 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
21
  84.0%
18
  81.8%
39
  83.0%
>=65 years
4
  16.0%
4
  18.2%
8
  17.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 22 participants 47 participants
Female
9
  36.0%
8
  36.4%
17
  36.2%
Male
16
  64.0%
14
  63.6%
30
  63.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 22 participants 47 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   4.0%
1
   4.5%
2
   4.3%
White
24
  96.0%
21
  95.5%
45
  95.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 22 participants 47 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
25
 100.0%
22
 100.0%
47
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 25 participants 22 participants 47 participants
25 22 47
1.Primary Outcome
Title Toxicity
Hide Description Evaluate the toxicity post-infusion including mortality, occurrence of acute graft versus host disease (GVHD) and other severe toxicity until a minimum of 8 weeks following the last infusion, then at least monthly for 3 additional months. Unacceptable toxicity was defined as grade ≥ III aGVHD of the gut or liver or Grade 4 aGVHD of the skin lasting > 7 days; other Grade 4 toxicity from the procedure in the major organs that lasted > 5 days; or treatment-related mortality (TRM). Though these infusions are provided early following transplantation and severe toxicity could still have occurred due to the primary transplant procedure, for this study any aGVHD or other toxicities occurring after the first day of infusion of the natural killer (NK) cell enriched Donor Lymphocyte Infusions (DLIs) is considered here as study related.
Time Frame 5 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed cell infusion.
Arm/Group Title NK Cell Infusion
Hide Arm/Group Description:

Natural Killer (NK) Cell infusion using CD56 monoclonal antibody:

The cells from leukapheresis will be NK cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion.

Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: participants
Death 1
GvHD 8
2.Secondary Outcome
Title Efficacy - Progression Free Survival
Hide Description Evaluate efficacy of natural killer (NK) cell infusions in terms of progression free survival (PFS) in number of months without disease progression.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed cell infusion.
Arm/Group Title NK Cell Infusion
Hide Arm/Group Description:
Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion.
Overall Number of Participants Analyzed 21
Mean (Full Range)
Unit of Measure: months
12
(3 to 33)
3.Secondary Outcome
Title Efficacy - Overall Survival
Hide Description Evaluate efficacy of natural killer (NK) cell infusions in terms of overall survival (OS).
Time Frame 8 years
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed infusion. 9 patients were still alive at the time of this analysis.
Arm/Group Title NK Cell Infusion
Hide Arm/Group Description:
Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion.
Overall Number of Participants Analyzed 21
Mean (Full Range)
Unit of Measure: months alive post-infusion
31
(2 to 92)
4.Secondary Outcome
Title Efficacy - Disease Progression
Hide Description Evaluate efficacy of natural killer (NK) cell infusions in terms of number of patients with disease progression.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed cell infusion.
Arm/Group Title NK Cell Infusion
Hide Arm/Group Description:
Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion.
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: participants
10
Time Frame Each patient will be followed for toxicity until 8 weeks post-infusion or 5 months after the last natural killer cell infusion (NKI), whichever comes first. All adverse events will be recorded from the 1st day of infusion until the subject is off study.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title NK Cell Infusion
Hide Arm/Group Description Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion.
All-Cause Mortality
NK Cell Infusion
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
NK Cell Infusion
Affected / at Risk (%) # Events
Total   4/21 (19.05%)    
Blood and lymphatic system disorders   
Hemorrhage / Bleeding * 1  1/21 (4.76%)  1
Thrombocytopenia * 1  1/21 (4.76%)  1
Cardiac disorders   
Cardiac Left Ventricular Function * 1  1/21 (4.76%)  1
Infections and infestations   
Infection with normal ANC or Grade 1 or 2 neutrophils * 1  2/21 (9.52%)  2
Respiratory, thoracic and mediastinal disorders   
Dyspnea * 1  1/21 (4.76%)  1
Hypoxia * 1  1/21 (4.76%)  1
Skin and subcutaneous tissue disorders   
Skin GVHD * 1 [1]  1/21 (4.76%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Acute Graft Versus Host Disease
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
NK Cell Infusion
Affected / at Risk (%) # Events
Total   13/21 (61.90%)    
Blood and lymphatic system disorders   
Thrombocytopenia * 1  2/21 (9.52%)  3
Hemoglobin * 1  1/21 (4.76%)  1
Hemolytic anemia * 1  2/21 (9.52%)  2
Pancytopenia * 1  1/21 (4.76%)  1
Neutropenia * 1  1/21 (4.76%)  1
Gastrointestinal disorders   
Anorexia * 1  1/21 (4.76%)  1
Ascites * 1  1/21 (4.76%)  1
Diarrhea * 1  1/21 (4.76%)  3
Gastritis * 1  2/21 (9.52%)  2
Vomiting * 1  3/21 (14.29%)  3
General disorders   
Fever * 1  1/21 (4.76%)  1
Infections and infestations   
Febrile Neutropenia * 1  2/21 (9.52%)  2
Infection - NOS * 1 [1]  1/21 (4.76%)  1
Infection with grade 3 or 4 neutrophils * 1 [2]  6/21 (28.57%)  7
Infection - normal ANC - grade 1 or 2 neutrophils * 1 [3]  5/21 (23.81%)  7
Infection without Febrile Neutropenia * 1 [4]  1/21 (4.76%)  1
Metabolism and nutrition disorders   
Hypoalbuminemia * 1  1/21 (4.76%)  2
Hypocalcemia * 1  1/21 (4.76%)  1
Acute Interstitial Nephritis * 1  1/21 (4.76%)  2
Creatinine * 1  1/21 (4.76%)  1
Nervous system disorders   
Memory impairment * 1  1/21 (4.76%)  1
Syncope * 1 [5]  2/21 (9.52%)  2
Renal and urinary disorders   
Cystitis * 1 [6]  1/21 (4.76%)  1
Protenuria * 1  1/21 (4.76%)  1
Urinary frequency/urgency * 1 [7]  1/21 (4.76%)  1
Respiratory, thoracic and mediastinal disorders   
Hypoxia * 1  1/21 (4.76%)  1
Pneumonitis * 1  1/21 (4.76%)  1
Skin and subcutaneous tissue disorders   
Basal Cell Skin Cancer * 1  1/21 (4.76%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Mycobacterium in sputum culture
[2]
Parainfluenza; C-Diff; Varicella Zoster Virus; Cytomegalovirus; Gram negative bacteremia - Klebsiella
[3]
Cytomegalovirus; Citrobacter; Fungal
[4]
Polyoma Cystitis
[5]
Fainting or Falling Down
[6]
Hematuria
[7]
Nocturia
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: David Rizzieri, MD
Organization: Duke University Medical Center
Phone: 919-668-1040
EMail: david.rizzieri@duke.edu
Layout table for additonal information
Responsible Party: David Rizzieri, MD, Duke University
ClinicalTrials.gov Identifier: NCT00586690    
Other Study ID Numbers: Pro00005124
First Submitted: December 21, 2007
First Posted: January 4, 2008
Results First Submitted: February 5, 2014
Results First Posted: June 2, 2014
Last Update Posted: February 8, 2017