Graft vs Host Disease, Immune System Disorders
Conditions
Keywords
Acute Graft vs Host Disease, GVHD
Brief summary
The study is a randomized Phase II, four arm treatment trial. The primary purpose of the study is to define new agents with promising activity against acute graft-versus-host disease (GVHD) suitable for testing against corticosteroids alone in a subsequent Phase III trial.
Detailed description
BACKGROUND: Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell (HSC) transplantation. Acute GVHD produces significant morbidity and complicates patient management resulting in organ toxicity, frequent infections, malnutrition, and substantial delay in recovery from transplantation. Corticosteroids have been the primary therapy for acute GVHD for over three decades. Various additional immunosuppressive strategies have been tested as GVHD therapy but neither anti-thymocyte globulin (ATG), CD5-immunotoxins, IL-1 antagonists nor other agents have been demonstrably helpful in either control of GVHD symptoms or improvement in survival. Published response rates of complete response (CR) to acute GVHD therapy with corticosteroids range from 25-41%. These rates will be used as benchmarks for assessing efficacy of promising new agents. New immunosuppressive agents and strategies are required to improve the management of GVHD and decrease the toxicities of the immunosuppressive regimens. DESIGN NARRATIVE: In this trial, patients with newly diagnosed acute GVHD will be randomly assigned to receive corticosteroids plus one of four new agents (etanercept, MMF, denileukin diftitox \[Ontak\], and pentostatin). A control arm of only corticosteroids will not be employed. Each agent will be assessed for safety and efficacy (at least 35% complete remission \[CR\] rate at Day 28 of therapy can be expected from previously untreated patients).
Interventions
DRUGEtanercept
Etanercept \[25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in complete response by 4 weeks\].
DRUGMycophenolate Mofetil
Mycophenolate mofetil (MMF) \[20 mg/kg (maximum 1 gm) orally or intravenously twice daily; continue through prednisone taper, then taper MMF over 4 weeks\].
Denileukin Diftitox (ONTAK®) \[9 mcg/kg intravenously Days 1, 3, 5, 15, 17, 19\].
DRUGPentostatin
Pentostatin \[1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17
Sponsors
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Prior allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells, or cord blood * De novo acute GVHD diagnosed within 48 hours prior to enrollment; biopsy confirmation of GVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results; the patient must have had no previous systemic immune suppressive therapy given for treatment of acute GVHD except for a maximum 48 hours of prior corticosteroid therapy (at least 1 mg/kg/day methylprednisolone) * Patients that have undergone a scheduled donor lymphocyte infusion (DLI) as part of their original transplant therapy plan * Absolute neutrophil count (ANC) greater than 500/µL * Clinical status at enrollment to allow tapering of steroids to not less than 1 mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of therapy (e.g., persisting malignant disease suggesting the need for accelerated taper of immunosuppression) * Estimated creatinine clearance greater than 30 mL/minute * Assent and educational materials provided to, and reviewed with, patients under the age of 18
Exclusion criteria
* ONTAK, pentostatin, or etanercept given within 7 days of enrollment * Active uncontrolled infection * Patients that have undergone an unscheduled DLI, or DLI that was not part of their original transplant therapy plan * If any prior steroid therapy (for indication other than GVHD), treatment at doses of at least 0.5 mg/kg/day methylprednisolone within 7 days prior to onset of GVHD * Patients unlikely to be available at the transplant center on Day 28 and 56 of therapy * A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation (see Chapter 2 of the BMT CTN Manual of Procedures for details of de novo chronic GVHD) * Other investigational therapeutics for GVHD within 30 days, including agents used for GVHD prophylaxis * Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study * Adults unable to provide informed consent * Patients with a history of intolerance to any of the study drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Complete Response (CR) at Day 28 of Therapy | Measured at Day 28 | Complete response at day 28 after randomization. CR was defined as resolution of all signs and symptoms of Graft-Versus-Host Disease (GVHD) in all evaluable organs in comparison to Day 1 scoring. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Treatment Failure | Measured at Day 56 | — |
| Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 | Measured at Day 90 | Flares were defined as any increase in symptoms of or therapy for acute GVHD after an initial response (i.e., progression from an earlier CR or PR). |
| Number of Patients Discontinuing Immune Suppression Without Flare | Measured at Days 90, 180, and 270 post-treatment | Immunosuppression discontinuation was defined as the discontinuation of corticosteroids and all additional immunosuppressives, except cyclosporine or tacrolimus, for treatment of acute GVHD without subsequent flare by Day 90 post-initiation of therapy and later by discontinuation of all immunosuppressive medications, including cyclosporine or tacrolimus. |
| Number of Partial Response (PR), Mixed Response (MR), and Progression | Measured at Day 28 | Partial response, mixed response, and progression at Day 28 after randomization. Partial response was defined as improvement in one or more organs involved with Graft-Versus-Host Disease (GVHD) symptoms without progression in others. Mixed response was defined as improvement in one or more organs with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ. Progression was defined as deterioration in at least one organ without any improvement in others. |
| Number of Patients Surviving at 6 and 9 Months Post Randomization | Measured at 6 and 9 months | — |
| Cumulative Incidence of Systemic Infections | Measured at Day 270 | — |
| Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma | Measured at 9 months | — |
| Number of Patients With Chronic Graft-versus-host Disease (GVHD) | Measured at 9 months | Number of patients with limited and extensive chronic GVHD at 9 months |
Countries
United States
Participant flow
Recruitment details
Clinic patients were recruited from August 2005 through March 2008.
Participants by arm
| Arm | Count |
|---|---|
| Etanercept Patients received 25 mg Etanercept subcutaneously twice weekly for up to 4 weeks; discontinue if in Complete Response (CR) by 4 weeks | 46 |
| Mycophenolate Mofetil Patients received Mycophenolate Mofetil (MMF) 20 mg/kg (maximum 1 gm) per oral or intravenously twice daily; continue through prednisone taper, then taper MMF over 4 weeks | 45 |
| Denileukin Diftitox Patients received Denileukin Diftitox 9 mcg/kg intravenously over 1 hour on days 1, 3, 5, 15, 17, 19. | 47 |
| Pentostatin Patients received Pentostatin 1.5 mg/m2 intravenously daily on days 1-3 and 15-17. | 42 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Mycophenolate Mofetil | Total | Etanercept | Pentostatin | Denileukin Diftitox |
|---|---|---|---|---|---|
| Age, Continuous | 42 years | 50 years | 50 years | 53 years | 51 years |
| Conditioning Regimen Myeloablative | 37 participants | 117 participants | 29 participants | 26 participants | 25 participants |
| Conditioning Regimen Non-myeloablative | 8 participants | 61 participants | 17 participants | 15 participants | 21 participants |
| Conditioning Regimen Unknown | 0 participants | 2 participants | 0 participants | 1 participants | 1 participants |
| Donor Status Related | 24 participants | 83 participants | 21 participants | 17 participants | 21 participants |
| Donor Status Unknown | 0 participants | 3 participants | 1 participants | 1 participants | 1 participants |
| Donor Status Unrelated | 21 participants | 94 participants | 24 participants | 24 participants | 25 participants |
| Enrollment Acute GVHD Grade 0 | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants |
| Enrollment Acute GVHD Grade I | 3 participants | 23 participants | 8 participants | 4 participants | 8 participants |
| Enrollment Acute GVHD Grade II | 25 participants | 99 participants | 25 participants | 26 participants | 23 participants |
| Enrollment Acute GVHD Grade III | 16 participants | 54 participants | 12 participants | 11 participants | 15 participants |
| Enrollment Acute GVHD Grade IV | 1 participants | 3 participants | 0 participants | 1 participants | 1 participants |
| MMF Prophylaxis No | 45 participants | 136 participants | 32 participants | 28 participants | 31 participants |
| MMF Prophylaxis Yes | 0 participants | 44 participants | 14 participants | 14 participants | 16 participants |
| Organ Involvement at Randomization GI tract, lower | 18 participants | 61 participants | 12 participants | 17 participants | 14 participants |
| Organ Involvement at Randomization GI tract, upper | 12 participants | 49 participants | 10 participants | 13 participants | 14 participants |
| Organ Involvement at Randomization Liver | 7 participants | 25 participants | 6 participants | 5 participants | 7 participants |
| Organ Involvement at Randomization Skin | 35 participants | 140 participants | 36 participants | 34 participants | 35 participants |
| Primary Disease Acute Lymphoblastic Leukemia (ALL) | 9 participants | 26 participants | 6 participants | 7 participants | 4 participants |
| Primary Disease Acute Myeloid Leukemia (AML) / MDS | 21 participants | 89 participants | 24 participants | 20 participants | 24 participants |
| Primary Disease Chronic Myeloid Leukemia (CML) | 2 participants | 5 participants | 2 participants | 0 participants | 1 participants |
| Primary Disease Lymphoma | 6 participants | 25 participants | 5 participants | 6 participants | 8 participants |
| Primary Disease Other | 7 participants | 35 participants | 9 participants | 9 participants | 10 participants |
| Sex: Female, Male Female | 17 Participants | 67 Participants | 16 Participants | 15 Participants | 19 Participants |
| Sex: Female, Male Male | 28 Participants | 113 Participants | 30 Participants | 27 Participants | 28 Participants |
| Stem Cell Type Bone Marrow | 13 participants | 42 participants | 5 participants | 9 participants | 15 participants |
| Stem Cell Type Peripheral Blood | 29 participants | 111 participants | 36 participants | 27 participants | 19 participants |
| Stem Cell Type Umbilical Cord Blood | 3 participants | 25 participants | 5 participants | 5 participants | 12 participants |
| Stem Cell Type Unknown | 0 participants | 2 participants | 0 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 46 | 0 / 45 | 0 / 47 | 0 / 42 |
| serious Total, serious adverse events | 4 / 46 | 2 / 45 | 2 / 47 | 7 / 42 |
Outcome results
Primary
Number of Complete Response (CR) at Day 28 of Therapy
Complete response at day 28 after randomization. CR was defined as resolution of all signs and symptoms of Graft-Versus-Host Disease (GVHD) in all evaluable organs in comparison to Day 1 scoring.
Time frame: Measured at Day 28
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etanercept | Number of Complete Response (CR) at Day 28 of Therapy | 12 participants |
| Mycophenolate Mofetil | Number of Complete Response (CR) at Day 28 of Therapy | 27 participants |
| Denileukin Diftitox | Number of Complete Response (CR) at Day 28 of Therapy | 25 participants |
| Pentostatin | Number of Complete Response (CR) at Day 28 of Therapy | 16 participants |
Secondary
Cumulative Incidence of Systemic Infections
Time frame: Measured at Day 270
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etanercept | Cumulative Incidence of Systemic Infections | 47 percentage of participants |
| Mycophenolate Mofetil | Cumulative Incidence of Systemic Infections | 44 percentage of participants |
| Denileukin Diftitox | Cumulative Incidence of Systemic Infections | 62 percentage of participants |
| Pentostatin | Cumulative Incidence of Systemic Infections | 57 percentage of participants |
Secondary
Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
Time frame: Measured at 9 months
Population: No data collected
Secondary
Number of Partial Response (PR), Mixed Response (MR), and Progression
Partial response, mixed response, and progression at Day 28 after randomization. Partial response was defined as improvement in one or more organs involved with Graft-Versus-Host Disease (GVHD) symptoms without progression in others. Mixed response was defined as improvement in one or more organs with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ. Progression was defined as deterioration in at least one organ without any improvement in others.
Time frame: Measured at Day 28
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Etanercept | Number of Partial Response (PR), Mixed Response (MR), and Progression | Partial Response | 10 participants |
| Etanercept | Number of Partial Response (PR), Mixed Response (MR), and Progression | Progression | 7 participants |
| Etanercept | Number of Partial Response (PR), Mixed Response (MR), and Progression | Mixed Response | 3 participants |
| Mycophenolate Mofetil | Number of Partial Response (PR), Mixed Response (MR), and Progression | Partial Response | 8 participants |
| Mycophenolate Mofetil | Number of Partial Response (PR), Mixed Response (MR), and Progression | Progression | 1 participants |
| Mycophenolate Mofetil | Number of Partial Response (PR), Mixed Response (MR), and Progression | Mixed Response | 4 participants |
| Denileukin Diftitox | Number of Partial Response (PR), Mixed Response (MR), and Progression | Mixed Response | 0 participants |
| Denileukin Diftitox | Number of Partial Response (PR), Mixed Response (MR), and Progression | Partial Response | 3 participants |
| Denileukin Diftitox | Number of Partial Response (PR), Mixed Response (MR), and Progression | Progression | 3 participants |
| Pentostatin | Number of Partial Response (PR), Mixed Response (MR), and Progression | Partial Response | 10 participants |
| Pentostatin | Number of Partial Response (PR), Mixed Response (MR), and Progression | Progression | 4 participants |
| Pentostatin | Number of Partial Response (PR), Mixed Response (MR), and Progression | Mixed Response | 2 participants |
Secondary
Number of Patients Discontinuing Immune Suppression Without Flare
Immunosuppression discontinuation was defined as the discontinuation of corticosteroids and all additional immunosuppressives, except cyclosporine or tacrolimus, for treatment of acute GVHD without subsequent flare by Day 90 post-initiation of therapy and later by discontinuation of all immunosuppressive medications, including cyclosporine or tacrolimus.
Time frame: Measured at Days 90, 180, and 270 post-treatment
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Etanercept | Number of Patients Discontinuing Immune Suppression Without Flare | Day 90 | 7 participants |
| Etanercept | Number of Patients Discontinuing Immune Suppression Without Flare | Day 270 | 16 participants |
| Etanercept | Number of Patients Discontinuing Immune Suppression Without Flare | Day 180 | 12 participants |
| Mycophenolate Mofetil | Number of Patients Discontinuing Immune Suppression Without Flare | Day 90 | 4 participants |
| Mycophenolate Mofetil | Number of Patients Discontinuing Immune Suppression Without Flare | Day 270 | 17 participants |
| Mycophenolate Mofetil | Number of Patients Discontinuing Immune Suppression Without Flare | Day 180 | 13 participants |
| Denileukin Diftitox | Number of Patients Discontinuing Immune Suppression Without Flare | Day 180 | 8 participants |
| Denileukin Diftitox | Number of Patients Discontinuing Immune Suppression Without Flare | Day 90 | 5 participants |
| Denileukin Diftitox | Number of Patients Discontinuing Immune Suppression Without Flare | Day 270 | 10 participants |
| Pentostatin | Number of Patients Discontinuing Immune Suppression Without Flare | Day 90 | 2 participants |
| Pentostatin | Number of Patients Discontinuing Immune Suppression Without Flare | Day 270 | 10 participants |
| Pentostatin | Number of Patients Discontinuing Immune Suppression Without Flare | Day 180 | 8 participants |
Secondary
Number of Patients Surviving at 6 and 9 Months Post Randomization
Time frame: Measured at 6 and 9 months
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Etanercept | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 6 | 26 participants |
| Etanercept | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 9 | 22 participants |
| Mycophenolate Mofetil | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 9 | 29 participants |
| Mycophenolate Mofetil | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 6 | 32 participants |
| Denileukin Diftitox | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 6 | 28 participants |
| Denileukin Diftitox | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 9 | 24 participants |
| Pentostatin | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 6 | 24 participants |
| Pentostatin | Number of Patients Surviving at 6 and 9 Months Post Randomization | Month 9 | 21 participants |
Secondary
Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90
Flares were defined as any increase in symptoms of or therapy for acute GVHD after an initial response (i.e., progression from an earlier CR or PR).
Time frame: Measured at Day 90
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etanercept | Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 | 16 participants |
| Mycophenolate Mofetil | Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 | 12 participants |
| Denileukin Diftitox | Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 | 15 participants |
| Pentostatin | Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 | 15 participants |
Secondary
Number of Patients With Chronic Graft-versus-host Disease (GVHD)
Number of patients with limited and extensive chronic GVHD at 9 months
Time frame: Measured at 9 months
Population: All patients randomized were included in the analysis on an intent-to-treat basis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etanercept | Number of Patients With Chronic Graft-versus-host Disease (GVHD) | 11 participants |
| Mycophenolate Mofetil | Number of Patients With Chronic Graft-versus-host Disease (GVHD) | 19 participants |
| Denileukin Diftitox | Number of Patients With Chronic Graft-versus-host Disease (GVHD) | 15 participants |
| Pentostatin | Number of Patients With Chronic Graft-versus-host Disease (GVHD) | 12 participants |
Secondary
Proportion of Treatment Failure
Time frame: Measured at Day 56
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etanercept | Proportion of Treatment Failure | 24 percentage of participants |
| Mycophenolate Mofetil | Proportion of Treatment Failure | 9 percentage of participants |
| Denileukin Diftitox | Proportion of Treatment Failure | 26 percentage of participants |
| Pentostatin | Proportion of Treatment Failure | 29 percentage of participants |