Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hodgkin's Lymphoma, Leukemia, Lymphoid Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes, Myeloma, Non Hodgkin Lymphoma, Recurrent Acute Myeloid Leukemia, Adult, Recurrent Chronic Lymphocytic Leukemia, Recurrent Chronic Myelogenous Leukemia, Recurrent Hodgkin Lymphoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Plasma Cell Myeloma
Conditions
Keywords
Donor Type (Matched Related Donor or Matched Unrelated Donor)
Brief summary
Determine the relapse-free, donor lymphocyte infusion (DLI)-free survival in patients receiving the investigational regimen.This is a randomized phase II clinical trial, comparing two different dosing schedules of mycophenolate mofetil for graft versus host disease (GVHD) prevention following allogeneic stem cell transplantation. Risk for relapse, GVHD and non-relapse mortality will be assessed. Adaptive randomization between two study arms will be performed based on T cell counts at day 60.
Detailed description
In this study, the investigators will utilize a regimen combining low dose total body irradiation and rabbit ATG to facilitate stem cell transplantation (SCT) with human leukocyte antigen (HLA) matched related and unrelated donors. Based on the hypothesis that early treatment interventions have significant late effects in allogeneic SCT, a simple intervention, varying the duration of intense immunosuppression following SCT, will be investigated in this study. This may allow more robust recovery of donor immune system cells in the first two months following transplantation and eventually result in lower risk of cancer relapse, while maintaining effective graft versus host disease (GVHD) control. Patients will be randomly assigned to receive GVHD prevention therapy using one of two different immunosuppressive regimens with tacrolimus & mycophenolate mofetil (MMF). Patients assigned to the investigational group will receive MMF for 15 days following SCT with growth factor support using granulocyte macrophage colony stimulating factor (GM-CSF) beginning on post-transplant day 4. Patients randomized to the standard treatment group will receive MMF for 30 days following SCT with cytokine support using granulocyte colony stimulating factor (G-CSF) beginning on post-transplant day 4. If one of these treatment groups demonstrates an improvement in donor immune cell recovery, there may be a slow increase in the likelihood of patients being assigned to that more successful treatment group. Eventually the two groups will be compared with respect to the likelihood of either relapse or GVHD developing.
Interventions
DRUGmycophenolate mofetil
Given PO, by mouth, orally or IV, intravenous medication administration.
BIOLOGICALSargramostim
GM-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-15 cohort will receive sargramostim (GM-CSF) 250 mcg/m2/day beginning on post-transplant day 4 and continuing until neutrophil engraftment. Patients receiving GM-CSF will also receive inhaled corticosteroids, fluticasone (Flovent) 2 puffs twice daily, starting on post-transplant day 4 and stopping after cessation of GM-CSF, to diminish the risk of pneumonitis. Note: At investigator discretion, patients in the MMF-15 cohort who have preexisting pulmonary risk factors, will be permitted to receive G-CSF.
BIOLOGICALFilgrastim
G-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-30 cohort will receive filgrastim (G-CSF) 5 mcg/kg/day beginning on post-transplant day 4 and continuing until neutrophil engraftment.
Sponsors
Massey Cancer Center
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Any of the following high risk or recurrent hematological malignancies: * Hodgkin lymphoma (HL) * Non-Hodgkin lymphoma (NHL) * Chronic lymphocytic leukemia (CLL) * Multiple myeloma (MM) * Acute myelogenous leukemia (AML) * Acute lymphocytic leukemia (ALL) * Chronic myelogenous leukemia (CML) * Myelodysplastic syndrome (MDS) \*Note: Determination that the malignancy is high risk will be made by the investigator. * Investigator determination that the patient is an appropriate candidate for reduced intensity allogeneic SCT with the standard Massey Cancer Center-Virginia Commonwealth Health System Bone Marrow Transplant Massey Cancer Center Virginia Commonwealth University Health System Bone Marrow Transplant (MCC-VCUHS BMT) Program regimen employed in this trial * Patients with or without previous myeloablative autologous transplant * HLA-matched stem cell donor, either related (6/6 or 5/6 loci matched) or unrelated (8/8 or 7/8 loci matched) \*Note: Unrelated donors must be matched at HLA-A, -B, -C, and -DRB1 loci. However, a single locus mismatch will be acceptable in the event a more closely matched donor is not available. * Age ≥ 40 to \< 75 years; patients 18 to 39 years of age will be eligible only if the investigator has determined that the patient has comorbidity(ies) precluding conventional allogeneic transplantation with full intensity myeloablative conditioning * Karnofsky Performance Status of 70-100% * Negative serology for HIV * Women who are not postmenopausal or have not undergone hysterectomy must have a documented negative serum pregnancy test per standard MCC-VCUHS BMT Program guidelines * Ability to understand and the willingness to sign a written informed consent document \*Note: The consent form must be signed and dated prior to initiation of SCT preparative treatments.
Exclusion criteria
* Previous therapeutic radiation therapy (RT) that exceeds critical structure tolerance doses as determined by a radiation oncologist * Uncontrolled viral, fungal, or bacterial infection * Active meningeal or central nervous system disease * Previous therapy with rabbit anti-thymocyte globulin (ATG); previous treatment with equine ATG is allowed if more than 3 months ago \*Note: Previous myeloablative autologous transplant is permitted but not required. * Pregnancy or breastfeeding * Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | Up to 2 years following stem cell transplant | The primary outcome in this study is event-free survival, where the conditional events are the occurrence of relapse DLI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Probability of Overall Survival (OS) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) | Randomization up to 2 years | Overall survival (days to event or survival: time-to-event; survival: categorical) |
| Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Acute Graft Vs Host Disease (GVHD) | 60 Days following stem cell transplant | The number of patients diagnosed with acute acute GVHD between patients randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort) |
| Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Chronic Graft vs Host Disease (GVHD) | 60 Days following stem cell transplant | The differences in the rates of chronic GVHD between patients randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort) |
| Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Opportunistic Infections | 60 Days following stem cell transplant | The number of patients diagnosed with an opportunistic infections. |
| The Difference Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Day 60 Donor-derived (dd) Cluster of Differentiation (CD)3 10E3per microL Counts. | 60 Days Following Stem Cell Transplant | Day 60 donor-derived (dd) cluster of differentiation (CD)3 counts measured by 10E3per microL. |
| Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort)Diagnosed With Differences in the Rates of Engraftment Syndrome. | 60 Days Following Stem Cell Transplant | Number of patients diagnosed with engraftment syndrome. |
| Differences in the Rates of Achieving Donor Chimerisms (the Percentage of DNA in the Sample Which Comes From the Donor) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 100 Days following Stem Cell Transplant | Number of patients that achieved donor chimerisms by day 100. |
| Differences in the Rates of T-cell Recovery Kinetics Following Stem Cell Transplantation (SCT) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 100 Days Following Stem Cell Transplantation | Number of T Cells 10E3 per microL per arm indicating rates of T-cell recovery by Day 100 following SCT. |
| Determine the Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Diagnosis of Engraftment Loss. | 60 Days Following Stem Cell Transplant | Number of patients with engraftment loss. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (MMF-15, Sargramostim) Patients receive mycophenolate mofetil (MMF) PO or IV BID on days 0-15 and sargramostim SC from post-transplant day 4 until neutrophil engraftment.
mycophenolate mofetil: Given PO, by mouth, orally or IV, intravenous medication administration.
Sargramostim: GM-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-15 cohort will receive sargramostim (GM-CSF) 250 mcg/m2/day beginning on post-transplant day 4 and continuing until neutrophil engraftment.
Patients receiving GM-CSF will also receive inhaled corticosteroids, fluticasone (Flovent) 2 puffs twice daily, starting on post-transplant day 4 and stopping after cessation of GM-CSF, to diminish the risk of pneumonitis.
Note: At investigator discretion, patients in the MMF-15 cohort who have preexisting pulmonary risk factors, will be permitted to receive G-CSF. | 15 |
| Arm II (MMF-30, Filgrastim) Patients receive mycophenolate mofetil PO or IV BID on days 0-30 and filgrastim GCSF from post-transplant day 4 until neutrophil engraftment.
mycophenolate mofetil: Given PO, by mouth, orally or IV, intravenous medication administration.
Filgrastim: G-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-30 cohort will receive filgrastim (G-CSF) 5 mcg/kg/day beginning on post-transplant day 4 and continuing until neutrophil engraftment. | 11 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Relapse | 1 | 1 |
Baseline characteristics
| Characteristic | Arm I (MMF-15, Sargramostim) | Arm II (MMF-30, Filgrastim) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 9 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 10 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment United States | 15 Participants | 11 Participants | 26 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 15 | 6 / 11 |
| other Total, other adverse events | 15 / 15 | 10 / 11 |
| serious Total, serious adverse events | 15 / 15 | 11 / 11 |
Outcome results
Primary
The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort).
The primary outcome in this study is event-free survival, where the conditional events are the occurrence of relapse DLI.
Time frame: Up to 2 years following stem cell transplant
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (MMF-15, Sargramostim) | The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | Event Free Survival Yes | 7 Participants |
| Arm I (MMF-15, Sargramostim) | The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | Event Free Survival No | 8 Participants |
| Arm II (MMF-30, Filgrastim) | The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | Event Free Survival Yes | 4 Participants |
| Arm II (MMF-30, Filgrastim) | The Number of Patients With Relapse-free/Donor Lymphocyte Infusion(DLI)-Free Survival Rates Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | Event Free Survival No | 7 Participants |
Secondary
Determine the Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Diagnosis of Engraftment Loss.
Number of patients with engraftment loss.
Time frame: 60 Days Following Stem Cell Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Determine the Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Diagnosis of Engraftment Loss. | 0 Participants |
| Arm II (MMF-30, Filgrastim) | Determine the Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Diagnosis of Engraftment Loss. | 1 Participants |
Secondary
Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Chronic Graft vs Host Disease (GVHD)
The differences in the rates of chronic GVHD between patients randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort)
Time frame: 60 Days following stem cell transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Chronic Graft vs Host Disease (GVHD) | 9 Participants |
| Arm II (MMF-30, Filgrastim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Chronic Graft vs Host Disease (GVHD) | 7 Participants |
Secondary
Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort)Diagnosed With Differences in the Rates of Engraftment Syndrome.
Number of patients diagnosed with engraftment syndrome.
Time frame: 60 Days Following Stem Cell Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort)Diagnosed With Differences in the Rates of Engraftment Syndrome. | 0 Participants |
| Arm II (MMF-30, Filgrastim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort)Diagnosed With Differences in the Rates of Engraftment Syndrome. | 0 Participants |
Secondary
Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Opportunistic Infections
The number of patients diagnosed with an opportunistic infections.
Time frame: 60 Days following stem cell transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Opportunistic Infections | 7 Participants |
| Arm II (MMF-30, Filgrastim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Diagnosed With Opportunistic Infections | 9 Participants |
Secondary
Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Acute Graft Vs Host Disease (GVHD)
The number of patients diagnosed with acute acute GVHD between patients randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort)
Time frame: 60 Days following stem cell transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Acute Graft Vs Host Disease (GVHD) | 4 Participants |
| Arm II (MMF-30, Filgrastim) | Differences Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) With Acute Graft Vs Host Disease (GVHD) | 8 Participants |
Secondary
Differences in the Rates of Achieving Donor Chimerisms (the Percentage of DNA in the Sample Which Comes From the Donor) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort).
Number of patients that achieved donor chimerisms by day 100.
Time frame: 100 Days following Stem Cell Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences in the Rates of Achieving Donor Chimerisms (the Percentage of DNA in the Sample Which Comes From the Donor) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 15 Participants |
| Arm II (MMF-30, Filgrastim) | Differences in the Rates of Achieving Donor Chimerisms (the Percentage of DNA in the Sample Which Comes From the Donor) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 11 Participants |
Secondary
Differences in the Rates of T-cell Recovery Kinetics Following Stem Cell Transplantation (SCT) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort).
Number of T Cells 10E3 per microL per arm indicating rates of T-cell recovery by Day 100 following SCT.
Time frame: 100 Days Following Stem Cell Transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (MMF-15, Sargramostim) | Differences in the Rates of T-cell Recovery Kinetics Following Stem Cell Transplantation (SCT) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 313.6 10^3 *cells* per microliter | Standard Deviation 56.5 |
| Arm II (MMF-30, Filgrastim) | Differences in the Rates of T-cell Recovery Kinetics Following Stem Cell Transplantation (SCT) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort). | 222.2 10^3 *cells* per microliter | Standard Deviation 81.3 |
Secondary
The Difference Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Day 60 Donor-derived (dd) Cluster of Differentiation (CD)3 10E3per microL Counts.
Day 60 donor-derived (dd) cluster of differentiation (CD)3 counts measured by 10E3per microL.
Time frame: 60 Days Following Stem Cell Transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (MMF-15, Sargramostim) | The Difference Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Day 60 Donor-derived (dd) Cluster of Differentiation (CD)3 10E3per microL Counts. | 383.0 10^3 *cells* per microliter | Standard Error 539 |
| Arm II (MMF-30, Filgrastim) | The Difference Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) Day 60 Donor-derived (dd) Cluster of Differentiation (CD)3 10E3per microL Counts. | 254.1 10^3 *cells* per microliter | Standard Error 375 |
Secondary
The Probability of Overall Survival (OS) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort)
Overall survival (days to event or survival: time-to-event; survival: categorical)
Time frame: Randomization up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (MMF-15, Sargramostim) | The Probability of Overall Survival (OS) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) | 0.78 Probablility of 2 year survival |
| Arm II (MMF-30, Filgrastim) | The Probability of Overall Survival (OS) Between Patients Randomized to MMF-30 (Control Cohort) and MMF-15 (Investigational Cohort) | 0.5 Probablility of 2 year survival |