Graft-versus-Host Disease, Immune System Disorders
Conditions
Keywords
GVHD
Brief summary
The study is a Phase III, randomized double blind, placebo controlled, and trial evaluating the addition of Mycophenolate mofetil (MMF) vs. placebo to systemic corticosteroids as initial therapy for acute Graft Vs Host Disease (GVHD). The primary endpoint will be GVHD free survival at Day 56 post randomization.
Detailed description
Corticosteroids have been used as primary therapy for acute GVHD for many years. Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid therapy for previously untreated patients with acute GVHD. BMT CTN study 0302 (NCT00224874)was a randomized Phase II study evaluating etanercept, mycophenolate mofetil, denileukin diftitox or pentostatin in addition to corticosteroids. The results of that study suggested that mycophenolate mofetil produced the highest rates of CR at Day 28 and overall survival, supporting its evaluation in a Phase III study. Day 56 GVHD-free survival for the four treatment arms (all combining corticosteroids with one of the four study drugs) ranged from 39-71% across the four study arms.
Interventions
DRUGMycophenolate Mofetil
Oral dosing should be delivered in 250 mg units. For those \< 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period. * Patients who weight \> 60 kg should receive MMF 1 gm PO/IV every 8 hours. * Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours. * Patients who weight \<40 kg should receive 20 mg/kg IV or PO every 8 hours.
DRUGPlacebo
Oral dosing should be delivered in 250 mg units blinded placebo. For those \< 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period. * Patients who weight \> 60 kg should receive placebo 1 gm PO/IV every 8 hours. * Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours. * Patients who weight \<40 kg should receive 20 mg/kg IV or PO every 8 hours.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Acute GVHD developing after allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells or cord blood. Recipients of non-myeloablative and myeloablative transplants are eligible. * Acute GVHD after planned donor lymphocyte infusion or planned T cell add back are eligible. * De novo acute GVHD requiring systemic therapy. GVHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a context in which acute GVHD is likely to occur and where other etiologies such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out. Note that patients with stage I and II skin only (overall grade I) or isolated upper gastrointestinal (GI) involvement are eligible if the treating physician deems that systemic high-dose corticosteroid treatment is indicated. * The patient must have had no previous systemic immune suppressive therapy for treatment of acute GVHD except for a maximum 72 hours of prior corticosteroid therapy at \>0.5mg/kg methylprednisolone or equivalent after the onset of acute GVHD. * Clinical status at enrollment to allow tapering of steroids to not less than 0.25 mg/kg/day prednisone (0.2 mg/kg/day methylprednisolone) at Day 28 of therapy. * Absolute neutrophil count (ANC) greater than 500/µL. * Written informed consent and/or assent from patient, parent or guardian. * Documentation that the assent document and education materials have been provided to, and reviewed with, patients between the ages of 7 and 17. * Patients of all ages are eligible. * Biopsy confirmation of GVHD is recommended, but not required. Enrollment should not be delayed for biopsy or pathology results unless these are to be used to decide about whether to treat for GVHD.
Exclusion criteria
* Patients receiving mycophenolate mofetil or mycophenolic acid (Myfortic) within seven days of screening for enrollment. * Patients with uncontrolled infections will be excluded. If a bacterial or viral infection is present, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. If a fungal infection is present, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. * Relapsed/persistent malignancy requiring rapid immune suppression withdrawal. * Patients with GVHD after an unplanned Donor Lymphocyte Infusion (DLI), i.e., DLI that was not part of their original transplant therapy plan, or DLI given for treatment of persistent or recurrent malignancy after transplantation. * Patients unlikely to be available at the transplantation center on Day 28 and 56 of therapy. * A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation. * Patients receiving other drugs for the treatment of GVHD. * Patients receiving methylprednisolone \> 0.5 mg/kg/day (or 0.6 mg/kg/day prednisone) within 7 days before the onset of acute GVHD. If steroid therapy has been administered for treatment of a non-GVHD related condition and tapered to ≤ 0.5 mg/kg/day methylprednisolone (0.6 mg/kg/day prednisone) for seven or more days before the onset of acute GVHD, the patient is eligible. * Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study. Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding, therefore breast feeding patients are not eligible. * Adults unable to provide informed consent. * Patients on dialysis. * Patients with severe hepatic Veno-Occlusive Disease (VOD) or sinusoidal obstruction syndrome who in the judgement of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment. * Patients with a history of intolerance/allergy to MMF.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GVHD-free Survival | Day 56 | Success is defined as alive and free of GVHD at day 56 after randomization, all others are considered to be a study failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of GVHD Flares Requiring Increased Therapy | Day 90 | Flares are defined as any progression of acute GVHD after an initial response (i.e., earlier CR or PR) that requires re-escalation of steroid dosing, or initiation of additional topical or systemic therapy. |
| Incidence of Discontinuation of Immune Suppression Without Flare | Day 56, Day 180 and Day 360 post-treatment | — |
| Cumulative Steroid Dose | Days 28 and 56 | The cumulative steroid dose for each patient will be calculated by adding the doses (end of each week's dose) for each of the first four weeks of treatment, divided by the number of days of survival during this interval. The cumulative steroid dose was calculated for all patients per treatment arm and compared. |
| Incidence of Topical/Non-absorbable Therapy | Day 56 | — |
| Overall GVHD-free Survival Post-randomization | Months 6 and 12 | — |
| Incidence of Chronic GVHD | 12 months post-randomization | — |
| Percentage of Surviving Participants With Complete Response (CR) | Days 14, 28, and 56 | CR is defined as a score of 0 for the GVHD grading in all evaluable organs. |
| Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma | 12 months | — |
| Incidence of Cytomegalovirus (CMV) Reactivation | Year 1 | — |
| Cumulative Incidence of a Severe/Life-threatening/Fatal Infections | Year 1 | — |
| Disease-Free Survival (DFS) Post-Randomization | Year 1 | DFS includes death or progression/relapse of malignancy |
| Treatment Related Mortality (TRM) | Year 1 | — |
| Change in Patient Reported Outcomes From Enrollment to Day 56 | Day 56 | — |
| Incidence of Systemic Infections | 6 Months | Number of participants that experienced at least one infection. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from February 17, 2010 to November 11, 2011 from 36 different transplant centers.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Corticosteroids with placebo | 119 |
| Mycophenolate Mofetil Corticosteroids with Mycophenolate Mofetil | 116 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Determined to be ineligible | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Mycophenolate Mofetil | Total |
|---|---|---|---|
| Age, Customized Median Age | 52.9 years | 54 years | 53.8 years |
| Cutaneous involvement at onset Erythroderma and Bullae Formation/Desquamation | 4 participants | 1 participants | 5 participants |
| Cutaneous involvement at onset Generalized Erythroderma | 44 participants | 46 participants | 90 participants |
| Cutaneous involvement at onset Maculopapular Rash, 25-50% of Body Surface | 21 participants | 27 participants | 48 participants |
| Cutaneous involvement at onset Maculopapular Rash, <25% of Body Surface | 14 participants | 11 participants | 25 participants |
| Cutaneous involvement at onset No Rash | 36 participants | 31 participants | 67 participants |
| Grade of acute Graft-Vs-Host-Disease (GVHD) at Diagnosis Grade I | 16 participants | 11 participants | 27 participants |
| Grade of acute Graft-Vs-Host-Disease (GVHD) at Diagnosis Grade II | 62 participants | 68 participants | 130 participants |
| Grade of acute Graft-Vs-Host-Disease (GVHD) at Diagnosis Grade III | 34 participants | 30 participants | 64 participants |
| Grade of acute Graft-Vs-Host-Disease (GVHD) at Diagnosis Grade IV | 7 participants | 7 participants | 14 participants |
| Graft Source Bone marrow | 16 participants | 23 participants | 39 participants |
| Graft Source Cord blood | 1 participants | 2 participants | 3 participants |
| Graft Source Peripheral blood stem cell | 102 participants | 91 participants | 193 participants |
| Liver Abnormalities at Diagnosis Bilirubin >15 mg/dL | 0 participants | 1 participants | 1 participants |
| Liver Abnormalities at Diagnosis Bilirubin 2-3 mg/dL | 5 participants | 1 participants | 6 participants |
| Liver Abnormalities at Diagnosis Bilirubin <2 mg/dL | 110 participants | 106 participants | 216 participants |
| Liver Abnormalities at Diagnosis Bilirubin 3.1-6 mg/dL | 4 participants | 6 participants | 10 participants |
| Liver Abnormalities at Diagnosis Bilirubin 6.1-15 mg/dL | 0 participants | 2 participants | 2 participants |
| Lower GI Abnormalities at Diagnosis Diarrhea >1000 but ≤ 1500 mL/day | 9 participants | 8 participants | 17 participants |
| Lower GI Abnormalities at Diagnosis Diarrhea >1500 mL/day | 11 participants | 7 participants | 18 participants |
| Lower GI Abnormalities at Diagnosis Diarrhea >500 but ≤ 1000 mL/day | 14 participants | 21 participants | 35 participants |
| Lower GI Abnormalities at Diagnosis Diarrhea Less ≤ 500 mL/day | 19 participants | 21 participants | 40 participants |
| Lower GI Abnormalities at Diagnosis No Diarrhea | 66 participants | 57 participants | 123 participants |
| Lower GI Abnormalities at Diagnosis Stool with Frank Blood or Melena | 0 participants | 2 participants | 2 participants |
| Myeloablative Conditioning | 74 participants | 74 participants | 148 participants |
| Primary Disease Acute lymphoblastic leukemia | 14 participants | 16 participants | 30 participants |
| Primary Disease Acute myeloid leukemia | 47 participants | 41 participants | 88 participants |
| Primary Disease Chronic myeloid leukemia | 5 participants | 3 participants | 8 participants |
| Primary Disease Lymphoma | 17 participants | 17 participants | 34 participants |
| Primary Disease Myelodysplastic syndrome | 17 participants | 20 participants | 37 participants |
| Primary Disease Other | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 41 Participants | 45 Participants | 86 Participants |
| Sex: Female, Male Male | 78 Participants | 71 Participants | 149 Participants |
| Unrelated Donor | 72 participants | 66 participants | 138 participants |
| Upper GI Abnormalities at Diagnosis No Protracted Nausea and Vomiting | 82 participants | 85 participants | 167 participants |
| Upper GI Abnormalities at Diagnosis Persistent Nausea, Vomiting or Anorexia | 37 participants | 31 participants | 68 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 119 | 0 / 116 |
| serious Total, serious adverse events | 13 / 119 | 13 / 116 |
Outcome results
Primary
GVHD-free Survival
Success is defined as alive and free of GVHD at day 56 after randomization, all others are considered to be a study failure.
Time frame: Day 56
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | GVHD-free Survival | GVHD free | 60 participants |
| Placebo | GVHD-free Survival | Study Failure | 59 participants |
| Mycophenolate Mofetil | GVHD-free Survival | GVHD free | 69 participants |
| Mycophenolate Mofetil | GVHD-free Survival | Study Failure | 47 participants |
Secondary
Change in Patient Reported Outcomes From Enrollment to Day 56
Time frame: Day 56
Population: No data collected
Secondary
Cumulative Incidence of a Severe/Life-threatening/Fatal Infections
Time frame: Year 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cumulative Incidence of a Severe/Life-threatening/Fatal Infections | 42.9 percentage of participants |
| Mycophenolate Mofetil | Cumulative Incidence of a Severe/Life-threatening/Fatal Infections | 44.5 percentage of participants |
Secondary
Cumulative Steroid Dose
The cumulative steroid dose for each patient will be calculated by adding the doses (end of each week's dose) for each of the first four weeks of treatment, divided by the number of days of survival during this interval. The cumulative steroid dose was calculated for all patients per treatment arm and compared.
Time frame: Days 28 and 56
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Cumulative Steroid Dose | Day 28 | 0.63 mg/kg |
| Placebo | Cumulative Steroid Dose | Day 56 | 0.20 mg/kg |
| Mycophenolate Mofetil | Cumulative Steroid Dose | Day 28 | 0.60 mg/kg |
| Mycophenolate Mofetil | Cumulative Steroid Dose | Day 56 | 0.17 mg/kg |
Secondary
Disease-Free Survival (DFS) Post-Randomization
DFS includes death or progression/relapse of malignancy
Time frame: Year 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Disease-Free Survival (DFS) Post-Randomization | 63 percentage of participants |
| Mycophenolate Mofetil | Disease-Free Survival (DFS) Post-Randomization | 53.9 percentage of participants |
Secondary
Incidence of Chronic GVHD
Time frame: 12 months post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of Chronic GVHD | 43.3 percentage of participants |
| Mycophenolate Mofetil | Incidence of Chronic GVHD | 41.5 percentage of participants |
Secondary
Incidence of Cytomegalovirus (CMV) Reactivation
Time frame: Year 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of Cytomegalovirus (CMV) Reactivation | 39 percentage of participants |
| Mycophenolate Mofetil | Incidence of Cytomegalovirus (CMV) Reactivation | 44 percentage of participants |
Secondary
Incidence of Discontinuation of Immune Suppression Without Flare
Time frame: Day 56, Day 180 and Day 360 post-treatment
Population: No data collected
Secondary
Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma | 4 participants |
| Mycophenolate Mofetil | Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma | 6 participants |
Secondary
Incidence of GVHD Flares Requiring Increased Therapy
Flares are defined as any progression of acute GVHD after an initial response (i.e., earlier CR or PR) that requires re-escalation of steroid dosing, or initiation of additional topical or systemic therapy.
Time frame: Day 90
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of GVHD Flares Requiring Increased Therapy | 16 participants |
| Mycophenolate Mofetil | Incidence of GVHD Flares Requiring Increased Therapy | 8 participants |
Secondary
Incidence of Systemic Infections
Number of participants that experienced at least one infection.
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of Systemic Infections | 77 participants |
| Mycophenolate Mofetil | Incidence of Systemic Infections | 81 participants |
Secondary
Incidence of Topical/Non-absorbable Therapy
Time frame: Day 56
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of Topical/Non-absorbable Therapy | 81 participants |
| Mycophenolate Mofetil | Incidence of Topical/Non-absorbable Therapy | 77 participants |
Secondary
Overall GVHD-free Survival Post-randomization
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Overall GVHD-free Survival Post-randomization | 6 Months | 73.4 percentage of participants |
| Placebo | Overall GVHD-free Survival Post-randomization | 12 Months | 64.7 percentage of participants |
| Mycophenolate Mofetil | Overall GVHD-free Survival Post-randomization | 6 Months | 72.0 percentage of participants |
| Mycophenolate Mofetil | Overall GVHD-free Survival Post-randomization | 12 Months | 57.8 percentage of participants |
Secondary
Percentage of Surviving Participants With Complete Response (CR)
CR is defined as a score of 0 for the GVHD grading in all evaluable organs.
Time frame: Days 14, 28, and 56
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Surviving Participants With Complete Response (CR) | Day 14 | 49.6 percentage of participants |
| Placebo | Percentage of Surviving Participants With Complete Response (CR) | Day 28 | 44.5 percentage of participants |
| Placebo | Percentage of Surviving Participants With Complete Response (CR) | Day 56 | 53.8 percentage of participants |
| Mycophenolate Mofetil | Percentage of Surviving Participants With Complete Response (CR) | Day 14 | 44 percentage of participants |
| Mycophenolate Mofetil | Percentage of Surviving Participants With Complete Response (CR) | Day 28 | 46.6 percentage of participants |
| Mycophenolate Mofetil | Percentage of Surviving Participants With Complete Response (CR) | Day 56 | 60.3 percentage of participants |
Secondary
Treatment Related Mortality (TRM)
Time frame: Year 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Treatment Related Mortality (TRM) | 21.5 percentage of participants |
| Mycophenolate Mofetil | Treatment Related Mortality (TRM) | 21.8 percentage of participants |