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Evaluate the safety of natural killer (NK) cell infusion using CD56 monoclonal antibody selected with Miltenyi Biotec system following nonmyeloablative stem cell transplantation (SCT) from matched donors. This pilot study will evaluate toxicity including mortality, occurrence of acute graft versus host disease and other severe toxicity.
The use of non-selected donor lymphocyte infusions (DLIs) (to help early immune recovery and induce antitumor response) following nonmyeloablative allogeneic stem cell transplantation (ASCT) is also complicated by the risk of acute graft versus host disease (aGVHD) with 30-40% of patients experiencing grade III-IV aGVHD. Data suggests that the use of natural killer (NK) cells (instead of nonselected DLIs) in this setting may mediate a graft versus tumor (GVT) effect independently of aGVHD.
This pilot study is designed to evaluate the efficacy and toxicity of donor natural killer (NK) cell selection and infusion following nonmyeloablative allogeneic stem cell transplantation (ASCT) from matched donors.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NK Cell Infusion | Experimental | Natural Killer (NK) Cell infusion using CD56 monoclonal antibody |
|
| Donor Apheresis | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NK Cell infusion using CD56 monoclonal antibody | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Toxicity | 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. | 5 months |
| Measure | Description | Time Frame |
|---|---|---|
| Efficacy - Progression Free Survival | Evaluate efficacy of natural killer (NK) cell infusions in terms of progression free survival (PFS) in number of months without disease progression. | 3 years |
| Efficacy - Overall Survival |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David Rizzieri, MD | Duke Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University Health System | Durham | North Carolina | 27710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20188202 | Result | Rizzieri DA, Storms R, Chen DF, Long G, Yang Y, Nikcevich DA, Gasparetto C, Horwitz M, Chute J, Sullivan K, Hennig T, Misra D, Apple C, Baker M, Morris A, Green PG, Hasselblad V, Chao NJ. Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2010 Aug;16(8):1107-14. doi: 10.1016/j.bbmt.2010.02.018. Epub 2010 Feb 24. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | NK Cell Infusion | 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. |
| FG001 | Donor Apheresis | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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.
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| ID | Title | Description |
|---|---|---|
| BG000 | NK Cell Infusion | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Toxicity | 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. | Participants who completed cell infusion. | Posted | Number | participants | 5 months |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | NK Cell Infusion | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Skin GVHD | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Non-systematic Assessment | Acute Graft Versus Host Disease |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Rizzieri, MD | Duke University Medical Center | 919-668-1040 | david.rizzieri@duke.edu |
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| ID | Term |
|---|---|
| D008223 | Lymphoma |
| ID | Term |
|---|---|
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
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|
|
| Donor Apheresis | Procedure | 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. |
|
Evaluate efficacy of natural killer (NK) cell infusions in terms of overall survival (OS).
| 8 years |
| Efficacy - Disease Progression | Evaluate efficacy of natural killer (NK) cell infusions in terms of number of patients with disease progression. | 3 years |
| Adverse Event |
|
| Lack of Efficacy |
|
| Lab can't accommodate |
|
| BG001 | Donor Apheresis | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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. |
|
|
| Secondary | Efficacy - Progression Free Survival | Evaluate efficacy of natural killer (NK) cell infusions in terms of progression free survival (PFS) in number of months without disease progression. | Participants who completed cell infusion. | Posted | Mean | Full Range | months | 3 years |
|
|
|
| Secondary | Efficacy - Overall Survival | Evaluate efficacy of natural killer (NK) cell infusions in terms of overall survival (OS). | Participants who completed infusion. 9 patients were still alive at the time of this analysis. | Posted | Mean | Full Range | months alive post-infusion | 8 years |
|
|
|
| Secondary | Efficacy - Disease Progression | Evaluate efficacy of natural killer (NK) cell infusions in terms of number of patients with disease progression. | Participants who completed cell infusion. | Posted | Number | participants | 3 years |
|
|
|
| 4 |
| 21 |
| 13 |
| 21 |
|
| Hemorrhage / Bleeding | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Cardiac Left Ventricular Function | Cardiac disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Infection with normal ANC or Grade 1 or 2 neutrophils | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hemoglobin | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Hemolytic anemia | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Anorexia | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Ascites | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Gastritis | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Febrile Neutropenia | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
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| Infection - NOS | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment | Mycobacterium in sputum culture |
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| Infection with grade 3 or 4 neutrophils | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment | Parainfluenza; C-Diff; Varicella Zoster Virus; Cytomegalovirus; Gram negative bacteremia - Klebsiella |
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| Infection - normal ANC - grade 1 or 2 neutrophils | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment | Cytomegalovirus; Citrobacter; Fungal |
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| Infection without Febrile Neutropenia | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment | Polyoma Cystitis |
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| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Hypocalcemia | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Acute Interstitial Nephritis | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Creatinine | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Memory impairment | Nervous system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Pancytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Basal Cell Skin Cancer | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Fever | General disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Syncope | Nervous system disorders | CTCAE (3.0) | Non-systematic Assessment | Fainting or Falling Down |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Cystitis | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment | Hematuria |
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| Protenuria | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Urinary frequency/urgency | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment | Nocturia |
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| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |