Failure of Bone Marrow Graft
Conditions
Keywords
Plerixafor and Allogeneic Myeloablative Stem Cell Transplant
Brief summary
This phase I/II clinical trial will test the safety and the efficacy of post transplant administration of plerixafor in enhancing hematological recovery in humans. Patients who are appropriate candidates for myeloablative allogeneic stem cell transplantation from an HLA-matched sibling, matched unrelated donor or umbilical cord blood are eligible for enrollment. The investigators plan to enroll a total of 50 patients for this study (30 patients with HLA-matched sibling or matched unrelated donor transplant, and 20 patients with umbilical cord blood transplant). During phase I study, a small number of patients (3-6 patients from each group) will be enrolled to determine the safety of post transplant administration of plerixafor. Patients will receive plerixafor given at 240 µg/kg subcutaneously every other day beginning at day +2 after transplant until day +21 or engraftment. Limiting toxicities are defined as primary or secondary graft failure, plerixafor-related severe premature ventricular arrhythmia or death. If safety criteria are met from the investigators phase I study, the investigators will proceed with phase II study to determine the efficacy of post transplant administration of plerixafor in enhancing haematological recovery. The experimental aspect of this study is the use of plerixafor and all other aspects of care will be in line with the standard of care. Both Phase I and Phase II patients will be combined for efficacy analysis, and data collected from this study will be compared with the investigators historical control. The results from this study will set the stage and provide the justification for a larger phase 3 trial.
Detailed description
Recruitment to this trial will be stratified by donor type as HLA (human leukocyte antigen) matched sibling, matched unrelated donor or umbilical cord blood. Patients will be conditioned with a myeloablative regimen such as, but not limited to, total body irradiation and cyclophosphamide. The donor stem cell grafts will come from mobilized peripheral blood of 8/8 or 7/8 HLA-identical family members, 8/8 (HLA A, B, C, DRBeta1) allele-level matched unrelated donors, or dual umbilical cord blood grafts with at least 4 of 6 HLA matching at HLA A and B (low resolution) and DRBeta1 (at high resolution). The target CD34+ cell dose will be 5 X 10(6)/kg recipient ideal body weight. For HLA matched sibling or matched unrelated donor (MUD) transplants, all patients will receive a minimum of 2 X 10(6) CD 24+ cells/kg. For cord blood transplants, each unit will contain a minimum total nucleated cell count of of 1.5 X 10(7)/kg. Post-transplant GVHD (graft versus host disease) prophylaxis will be given per institutional standard.
Interventions
DRUGPlerixafor
Matched sibling or Dual Cord donor subjects will receive plerixafor at 240 ug/kg subcutaneously every other day beginning at day +2 after transplant until day +21 or engraftment occurs.
Sponsors
Genzyme, a Sanofi Company
Mitchell Horwitz, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 65 years. * 8/8 or 7/8 HLA-identical matched sibling OR Allele level 8/8 (HLA-A, B, C, DR Beta1)matched unrelated donor or 4/6 or better HLA matched cord blood. * Patients with high risk hematologic malignancies who are appropriate candidates for a myeloablative allogeneic stem cell transplantation. * Patients with a history of CNS disease must have been treated and have no active CNS disease at the time of protocol treatment. * ECOG performance status \< or equal to 2 * Patients must have adequate function of other organ systems as measured by: * Creatinine clearance (by Cockcroft Gault equation) \> or equal to 30ml/min. Hepatic transaminases (ALT/AST) \< or equal to 4 x normal, bilirubin \< or equal to 2.0 mg/dl. * Pulmonary function tests demonstrating FVC and FEV1 of \> or equal to 50% of predicted for age and DLCO \> or equal to 50% of predicted. * Ejection fraction of \> or equal to 45% by echocardiogram, radionuclide scan or cardiac MRI. * Patients must be HIV negative. * Patients must not be pregnant.
Exclusion criteria
* Patients with \> 5% blasts in bone marrow or peripheral circulation. * Uncontrolled infection. * Class III or IV angina as per NYHA criteria.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plerixafor-associated Adverse Events | 100 Days Post Transplant | — |
| Time to Neutrophil Recovery | 100 Days post Transplant | leukocytes \> 500/ul on 2 consecutive days |
| Time to Platelet Recovery | 100 Days Post Transplant | platelet \> 20,000/ul on 2 consecutive days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IL-12 at Day 30 | 30 days | IL-12 at day 30; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. |
| Participants Experiencing Grade II-IV Acute Graft Versus Host Disease | 100 days | We are reporting on the number of participants experiencing a grade II-IV acute graft versus host disease will be assessed weekly through Day 100 post transplant. Staging and grading of Acute GvHD is graded by pattern of organ involvement and clinical performance status using the Grading Index of Acute GvHD (Gluckman) and the Grading Index of Acute GVHD by the CIBMTR (Centers for International Blood and Marrow Transplant Research) |
| CD3+ Cell Count at Day 90 | 90 Days | Cell reconstitution - CD3+ cell count at day 90 post transplant. This is a marker for the function of your immune system. |
| CD4 Cell Count at Day 90 | 90 days | CD4 cell count at Day 90; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. |
| CD8 Cell Count at Day 90 | 90 days | CD8 cell count at Day 90; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). |
| NK Cell Count at Day 90 | 90 days | NK cell count at Day 90;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system. |
| B Cell Count at Day 90 | 90 days | B cell count at Day 90; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system. |
| IFN Gamma at Day 30 | 30 days | IFN gamma at day 30; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection. |
| TNF-alpha at Day 30 | 30 days | TNF-alpha at day 30; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells. |
| CD4 Cell Count at Day 30 | 30 days | CD4 cell count at Day 30; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. |
| CD4 Cell Count at Day 60 | 60 days | CD4 cell count at Day 60; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. |
| NK Cell Count at Day 60 | 60 days | NK cell count at Day 60;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system. |
| CD8 Cell Count at Day 60 | 60 days | CD8 cell count at Day 60; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). |
| NK Cell Count at Day 30 | 30 days | NK cell count at Day 30;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system. |
| B Cell Count at Day 30 | 30 days | B cell count at Day 30; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system. |
| B Cell Count at Day 60 | 60 days | B cell count at Day 60; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system. |
| IL-12 at Day 7 | 7 days | IL-12 at day 7; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. |
| IL-12 at Day 14 | 14 days | IL-12 at day 14; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. |
| IFN Gamma at Day 7 | 7 days | IFN gamma at day 7; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection. |
| IFN Gamma at Day 14 | 14 days | IFN gamma at day 14; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection. |
| TNF-alpha at Day 7 | 7 days | TNF-alpha at day 7; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells. |
| TNF-alpha at Day 14 | 14 days | TNF-alpha at day 14; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells. |
| CD8 Cell Count at Day 30 | 30 days | CD8 cell count at Day 30; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). |
| Transplant-related Mortality | 100 Days Post Transplant | — |
| Absolute Lymphocyte Count at Day 90 | 90 days | Cell reconstitution - absolute lymphocyte count at day 90 post transplant. |
Countries
United States
Participant flow
Recruitment details
Patients who are appropriate candidates for myeloablative allogeneic stem cell transplantation from an HLA-matched sibling, matched unrelated donor or umbilical cord blood are eligible for enrollment. The first subject was consented on 9/28/2011. The study closed to accrual on 5/27/2014.
Pre-assignment details
41 participants signed consent and 30 received transplant. 11 patients who signed consent were screen failures. Reasons patients did not receive transplant included lack of donor, insurance denial, too much disease, uncontrolled infection, class III or IV angina. 29 participants were used in results analysis because one participant withdrew.
Participants by arm
| Arm | Count |
|---|---|
| Transplant Recipients This arm includes transplant recipients from matched sibling donors and dual cord donors. Subjects will receive plerixafor at 240 ug/kg subcutaneously every other day beginning at day +2 after transplant until day +21 or engraftment occurs. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Transplant Recipients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 12 / 29 |
Outcome results
Primary
Plerixafor-associated Adverse Events
Time frame: 100 Days Post Transplant
Population: Out of the 30 transplant recipients, one participant withdrew and was therefore not analyzed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant Recipients | Plerixafor-associated Adverse Events | GI upset | 1 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | nausea | 1 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | diarrhea | 2 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | fatigue | 1 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | rash | 1 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | pneumonia | 3 number of adverse events |
| Transplant Recipients | Plerixafor-associated Adverse Events | bruising | 1 number of adverse events |
Primary
Time to Neutrophil Recovery
leukocytes \> 500/ul on 2 consecutive days
Time frame: 100 Days post Transplant
Population: Out of the 30 transplant recipients, one participant withdrew and was therefore not analyzed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | Time to Neutrophil Recovery | 17 days |
Primary
Time to Platelet Recovery
platelet \> 20,000/ul on 2 consecutive days
Time frame: 100 Days Post Transplant
Population: Out of the 30 transplant recipients, one participant withdrew and was therefore not analyzed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | Time to Platelet Recovery | 18 days |
Secondary
Absolute Lymphocyte Count at Day 90
Cell reconstitution - absolute lymphocyte count at day 90 post transplant.
Time frame: 90 days
Population: the population includes all participants for which we have data at day 90
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | Absolute Lymphocyte Count at Day 90 | 549 number of lymphocytes |
Secondary
B Cell Count at Day 30
B cell count at Day 30; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system.
Time frame: 30 days
Population: the population includes subjects for which we have data at Day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | B Cell Count at Day 30 | 6 number of B cells |
Secondary
B Cell Count at Day 60
B cell count at Day 60; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system.
Time frame: 60 days
Population: the population includes subjects for which we have data at Day 60.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | B Cell Count at Day 60 | 18 number of B cells |
Secondary
B Cell Count at Day 90
B cell count at Day 90; B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype and they function as part of the immune system.
Time frame: 90 days
Population: the population includes subjects for which we have data at Day 90.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | B Cell Count at Day 90 | 7 number of B cells |
Secondary
CD3+ Cell Count at Day 90
Cell reconstitution - CD3+ cell count at day 90 post transplant. This is a marker for the function of your immune system.
Time frame: 90 Days
Population: the population includes all participants for which we have data at day 90
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD3+ Cell Count at Day 90 | 655 number of CD3+ cells |
Secondary
CD4 Cell Count at Day 30
CD4 cell count at Day 30; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells.
Time frame: 30 days
Population: The population includes subjects for which we have data at day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD4 Cell Count at Day 30 | 252 number of CD4 cells |
Secondary
CD4 Cell Count at Day 60
CD4 cell count at Day 60; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells.
Time frame: 60 days
Population: The population includes subjects for which we have data at day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD4 Cell Count at Day 60 | 220 number of CD4 cells |
Secondary
CD4 Cell Count at Day 90
CD4 cell count at Day 90; CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells.
Time frame: 90 days
Population: The population includes subjects for which we have data at day 90.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD4 Cell Count at Day 90 | 180 number of CD4 cells |
Secondary
CD8 Cell Count at Day 30
CD8 cell count at Day 30; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR).
Time frame: 30 days
Population: the population includes subjects for which we have data at day 30
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD8 Cell Count at Day 30 | 255 number of CD8 cells |
Secondary
CD8 Cell Count at Day 60
CD8 cell count at Day 60; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR).
Time frame: 60 days
Population: the population includes subjects for which we have data at day 60
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD8 Cell Count at Day 60 | 199 number of CD8 cells |
Secondary
CD8 Cell Count at Day 90
CD8 cell count at Day 90; CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR).
Time frame: 90 days
Population: the population includes subjects for which we have data at day 90
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | CD8 Cell Count at Day 90 | 172 number of CD8 cells |
Secondary
IFN Gamma at Day 14
IFN gamma at day 14; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection.
Time frame: 14 days
Population: the population includes subject for which we have data at Day 14.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IFN Gamma at Day 14 | 20.0 pg/mL |
Secondary
IFN Gamma at Day 30
IFN gamma at day 30; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection.
Time frame: 30 days
Population: the population includes subject for which we have data at Day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IFN Gamma at Day 30 | 8.6 pg/mL |
Secondary
IFN Gamma at Day 7
IFN gamma at day 7; Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons which are important for immunity against infection.
Time frame: 7 days
Population: the population includes subject for which we have data at Day 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IFN Gamma at Day 7 | 3.9 pg/mL |
Secondary
IL-12 at Day 14
IL-12 at day 14; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation.
Time frame: 14 days
Population: the population includes all participants for which we have data at day 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IL-12 at Day 14 | 13.3 pg/mL |
Secondary
IL-12 at Day 30
IL-12 at day 30; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation.
Time frame: 30 days
Population: the population includes all participants for which we have data at day 30
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IL-12 at Day 30 | 40.7 pg/mL |
Secondary
IL-12 at Day 7
IL-12 at day 7; Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation.
Time frame: 7 days
Population: the population includes all participants for which we have data at day 7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | IL-12 at Day 7 | 8.4 pg/mL |
Secondary
NK Cell Count at Day 30
NK cell count at Day 30;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system.
Time frame: 30 days
Population: the population includes subjects for which we have data at Day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | NK Cell Count at Day 30 | 226 number of NK cells |
Secondary
NK Cell Count at Day 60
NK cell count at Day 60;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system.
Time frame: 60 days
Population: the population includes subjects for which we have data at Day 60.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | NK Cell Count at Day 60 | 221 number of NK cells |
Secondary
NK Cell Count at Day 90
NK cell count at Day 90;Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the immune system.
Time frame: 90 days
Population: the population includes subjects for which we have data at Day 90.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | NK Cell Count at Day 90 | 137 number of NK cells |
Secondary
Participants Experiencing Grade II-IV Acute Graft Versus Host Disease
We are reporting on the number of participants experiencing a grade II-IV acute graft versus host disease will be assessed weekly through Day 100 post transplant. Staging and grading of Acute GvHD is graded by pattern of organ involvement and clinical performance status using the Grading Index of Acute GvHD (Gluckman) and the Grading Index of Acute GVHD by the CIBMTR (Centers for International Blood and Marrow Transplant Research)
Time frame: 100 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant Recipients | Participants Experiencing Grade II-IV Acute Graft Versus Host Disease | Grade 2 | 5 participants |
| Transplant Recipients | Participants Experiencing Grade II-IV Acute Graft Versus Host Disease | Grade 3 | 5 participants |
Secondary
TNF-alpha at Day 14
TNF-alpha at day 14; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells.
Time frame: 14 days
Population: the population includes subject for which we have data at Day 14.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | TNF-alpha at Day 14 | 43.8 pg/mL |
Secondary
TNF-alpha at Day 30
TNF-alpha at day 30; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells.
Time frame: 30 days
Population: the population includes subject for which we have data at Day 30.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | TNF-alpha at Day 30 | 146.5 pg/mL |
Secondary
TNF-alpha at Day 7
TNF-alpha at day 7; Tumor necrosis factor is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The primary role of TNF is in the regulation of immune cells.
Time frame: 7 days
Population: the population includes subject for which we have data at Day 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transplant Recipients | TNF-alpha at Day 7 | 15.9 pg/mL |
Secondary
Transplant-related Mortality
Time frame: 100 Days Post Transplant
Population: Out of the 30 transplant recipients, one participant withdrew and was therefore not analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant Recipients | Transplant-related Mortality | 11 participants |