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Sponsor/ PI leaving institution, no plans to continue this research at this time
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The purpose of this study is to determine the ability of a donor lymphocyte infusion (DLI) given with methotrexate to hasten immune recovery without causing severe graft-versus-host disease (GVHD) in recipients who have had a T-cell depleted transplant.
Studies have shown that giving donor T cells after a mismatched T cell-depleted stem cell transplant can speed up recovery of T cells in the patient. This approach can cause severe graft versus host disease (GVHD). The purpose of this study is to determine whether giving a donor lymphocyte infusion (DLI) with methotrexate can accelerate immune recovery in recipients of T cell-depleted stem cell transplants. Thirty days after a T-cell depleted transplant, patients will be given a DLI. They will be monitored for immune recovery as measured by CD4 count and for GVHD toxicity.
Patients will be separated into six cohorts based on dose of DLI received: 3 x 10^4, 4 x 10^4, 5 x 10^4, 6 X 10^4, 8 x 10^4, and 10 X10^4 cells/ kg of body weight. A minimum of 3 patients will be tested at each dose starting with the lowest dose. Dose escalation will continue until the dose associated with CD4 count >100 at Day +120 after transplant without significant GVHD is determined. All patients will receive thirteen doses of methotrexate after the DLI to prevent GVHD. Patients will be followed for 2 years for outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Infusion of donor lymphocytes | Experimental | Patients will receive an infusion of donor lymphocyte after T-cell depleted transplant. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Infusion of donor lymphocytes | Biological | A donor lymphocyte infusion will be given to provide T cells. There will be a dose escalation: 3 x 10^4, 4 x 10^4, 5 x 10^4, 6 X 10^4, 8 x 10^4, and 10 X10^4 cells/kg body weight. At least three patients will be assessed at each dose to determine safety before dose is increased. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Immune Recovery Following Transplantation | Immune recovery was measured by CD4+ cells > 100/μL by Day 120 following transplantation | 120 days after transplant |
| Incidence and Severity of GVHD | Patients were evaluated for acute GVHD due to prophylactic DLI between the day of prophylactic DLI infusion and Day +180 after transplant. GVHD was graded using standard criteria. | 180 days after transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Subjects were actively monitored for adenovirus, cytomegalovirus (CMV), human herpes virus 6 (HHV6), and Epstein-Barr virus (EBV) as part of standard post-transplant care. All infections were collected from date of DLI until 1 year after transplant. | 1 year |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrew Gilman, MD | Department of Pediatrics, Levine Children's Hospital, Carolinas Healthcare System | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Levine Children's Hospital, Carolinas Medical Center | Charlotte | North Carolina | 28203 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29047161 | Derived | Gilman AL, Leung W, Cowan MJ, Cannon M, Epstein S, Barnhart C, Shah K, Hyland M, Fukes T, Ivanova A. Donor lymphocyte infusion and methotrexate for immune recovery after T-cell depleted haploidentical transplantation. Am J Hematol. 2018 Feb;93(2):169-178. doi: 10.1002/ajh.24949. Epub 2017 Nov 17. |
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Subjects were enrolled to two cohorts based on donor type, Mismatched Related Donor (MMRD) and Matched Unrelated Donor (MUD).
Patients who received a CD34+ selected peripheral blood stem cell (PBSC) transplant on the companion study, LCH BMT 09-01, at Levine Children's Hospital between December 2009 and June 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Day +1, +3, +10, +17, and +24 |
| FG001 | MMRD: 3 x 10^4/kg DLI + MTX to Day +52 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
| FG002 | MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 4 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
| FG003 | MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 4 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45, +52, +59, +66, +73, and +80 |
| FG004 | MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 5 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45, +52, +59, +66, +73, and +80 |
| FG005 | MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Matched Unrelated Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Day +1, +3, +10, +17, and +24 |
| FG006 | MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Matched Unrelated Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Infusion of Donor Lymphocytes | Patients will receive an infusion of donor lymphocyte after T-cell depleted transplant. Infusion of donor lymphocytes: A donor lymphocyte infusion will be given to provide T cells. There will be a dose escalation: 3 x 10^4, 4 x 10^4, 5 x 10^4, 6 X 10^4, 8 x 10^4, and 10 X10^4 cells/kg body weight. At least three patients will be assessed at each dose to determine safety before dose is increased. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| 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 | Number of Participants With Immune Recovery Following Transplantation | Immune recovery was measured by CD4+ cells > 100/μL by Day 120 following transplantation | Patients who received subsequent therapy, such as therapeutic DLI (eg. for treatment of viral infection or relapse), chemotherapy, or a PBSC infusion were considered not evaluable as this could interfere with response assessments. | Posted | Count of Participants | Participants | 120 days after transplant |
|
From the time of donor lymphocyte infusion (DLI) up to one year after transplant.
Infections that met the definition of a Serious Adverse Event are reported as the type of infection, when the cause of infection was known.
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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 | Infusion of Donor Lymphocytes | Patients will receive an infusion of donor lymphocyte after T-cell depleted transplant. Infusion of donor lymphocytes: A donor lymphocyte infusion will be given to provide T cells. There will be a dose escalation: 3 x 10^4, 4 x 10^4, 5 x 10^4, 6 X 10^4, 8 x 10^4, and 10 X10^4 cells/kg body weight. At least three patients will be assessed at each dose to determine safety before dose is increased. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders | CTCAE (3.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neutropenia | Investigations | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Andrew Gilman | PRA Health Sciences | 704-615-2744 | gilmanandy@prahs.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 14, 2014 | Jul 31, 2017 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 14, 2014 | Jul 31, 2017 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D007153 | Immunologic Deficiency Syndromes |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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|
| Death |
|
| participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
| OG002 | MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 4 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
| OG003 | MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 4 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45, +52, +59, +66, +73, and +80 |
| OG004 | MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Mismatched Related Donor: Donor Lymphocyte Infusion (DLI) 5 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45, +52, +59, +66, +73, and +80 |
| OG005 | MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Matched Unrelated Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Day +1, +3, +10, +17, and +24 |
| OG006 | MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Matched Unrelated Donor: Donor Lymphocyte Infusion (DLI) 3 x 10^4 cells/kg followed by methotrexate (MTX) 10 mg/m2 on Days +1, +3, +10, +17, and +24, 7.5 mg/m2 on Days +31 and +38, 5 mg/m2 on days +45 and +52 |
|
|
|
| Primary | Incidence and Severity of GVHD | Patients were evaluated for acute GVHD due to prophylactic DLI between the day of prophylactic DLI infusion and Day +180 after transplant. GVHD was graded using standard criteria. | Patients that had not had grade II-IV acute GVHD following prophylactic DLI but received therapeutic DLI (eg. for treatment of viral infection or relapse), chemotherapy, or a PBSC infusion prior to Day +180 were considered not evaluable because these therapies may cause or prevent GVHD and affect the determination of this endpoint. | Posted | Count of Participants | Participants | 180 days after transplant |
|
|
|
|
| Secondary | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Subjects were actively monitored for adenovirus, cytomegalovirus (CMV), human herpes virus 6 (HHV6), and Epstein-Barr virus (EBV) as part of standard post-transplant care. All infections were collected from date of DLI until 1 year after transplant. | Patients who relapsed and received subsequent chemotherapy were no longer followed for infections as these therapies increase the risk of infections. | Posted | Number | participants | 1 year |
|
|
|
| 12 |
| 38 |
| 32 |
| 38 |
| 27 |
| 38 |
| HHV-6 reactivation | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Graft vs Host disease | Immune system disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| EBV-related lymphoproliferative disease | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Relapse | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (3.0) | Non-systematic Assessment |
|
| CMV reactivation | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection w/ unknown absolute neutrophil count (ANC) | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Thrombotic Microangiopathy | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| ALT/ AST elevated | Investigations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection- eye NOS | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Pulmonary/ Upper Respiratory- other | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment | Blood tinged sputum following fungal pneumonia |
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| BK virus/ hemorrhagic cystitis | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
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| Hypertension | Vascular disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Pericardial effusion | Cardiac disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Renal failure | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Seizure | Nervous system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Infection- select | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment | viral upper respiratory infection |
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| Platelet count decreased | Investigations | CTCAE (3.0) | Non-systematic Assessment |
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| Leukopenia | Investigations | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
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| Relapse | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (3.0) | Non-systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Rash | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Thrombotic microangiopathy | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Thrombotic microangiopathy | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
| ALT elevated | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
| Hemorrage, GU- urinary NOS | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment | Hemorrhagic cystitis |
|
| Hypertension | Vascular disorders | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
| Hypokalemia | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
| Pain | General disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Renal/ Genitorurinary NOS | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Seizures | Nervous system disorders | CTCAE (3.0) | Non-systematic Assessment | grade 3 |
|
| Lymphopenia | Investigations | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Non-systematic Assessment | grade 4 |
|
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| Grade II GVHD |
|
| Grade III/IV GVHD |
|
| Title | Measurements |
|---|---|
|
| Clostridium difficile colitis |
|
| Sinusitis |
|
| CMV reactivation, no disease |
|
| Galactomannan positive |
|
| BK virus, no disease |
|
| BK virus, hemorrhagic cystitis |
|
| EBV-related lymphoproliferative disease |
|
| Bacteremia, gram negative |
|
| Herpes simplex virus |
|
| Bacteremia, gram positive |
|
| Acute otitis media |
|
| Candidiasis (non-invasive) |
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| Pneumonia |
|
| Infection with normal ANC - grade 3 |
|
| Adenovirus disease |
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| EBV reactivation, no disease |
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| Varicella |
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| Nocardia |
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| Pneumonia- fungal |
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| Methicillin-resistant staphylococcus aureus (MRSA) |
|
| Norovirus |
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| Parvovirus B19 (low level) |
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| Rotavirus |
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| Sapovirus |
|
| Possible respiratory fungal infection (rhizomucor) |
|