Graft-vs-Host Disease
Conditions
Keywords
GVHD, Stem cell transplantation, Sirolimus
Brief summary
This trial will test the hypothesis that the combination of sirolimus, mycophenolate mofetil, and bortezomib will be effective in preventing both acute and chronic GVHD after reduced intensity allogeneic stem cell transplantation.
Detailed description
The combination of tacrolimus and methotrexate is standard therapy for prevention of GVHD, however, our recent experience has demonstrated that the substitution of sirolimus for methotrexate provides superior GVHD control with reduced transplant-related toxicity. One limitation to the use of calcineurin inhibitors in GVHD prevention is the disruption in Treg function and proliferation. Based on our evolving understanding of the role of Treg in the development of chronic GVHD, we propose a GVHD prophylactic regimen that is effective in prevention of acute GVHD, but by virtue of the maintenance of Treg activity may be able to prevent chronic GVHD. We hypothesize that the substitution of mycophenolate mofetil for tacrolimus as well as the addition of bortezomib may provide similar protection against acute GVHD and prevent chronic GVHD while minimizing renal toxicity after transplantation.
Interventions
DRUGSirolimus
DRUGMycophenolate mofetil
DRUGBortezomib
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
PDL BioPharma, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with hematologic malignancies, who are at high risk of complications after conventional myeloablative transplantation 2. Patients must have a 6/6 matched, related donor. Matching at HLA Class II will be based on PCR of sequence specific primers (SSP). Among family member transplants, serologic matching at Class I is sufficient 3. Patient age greater than 18 4. Performance status 0-2 5. Life expectancy of \> 100 days without transplantation 6. Written informed consent must be obtained in all cases from the patient
Exclusion criteria
1. Pregnancy 2. Prior Allogeneic Stem Cell Transplantation from any donor 3. Evidence of HIV infection or active Hepatitis B or C infection 4. Heart failure uncontrolled by medications 5. Total bilirubin \> 2.0 mg/dl that is due to hepatocellular dysfunction 6. AST \> 90 7. Cholesterol \> 300 mg/dl or Triglycerides \> 400 mg/dl while adequately treated 8. Uncontrolled bacterial, viral or fungal infection 9. Requirement for voriconazole at the time of hospital admission
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies | 150 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Renal Insufficiency | 1 year | Renal function will be measured weekly after transplant for 4 weeks, at 8 weeks and then at 3 month intervals from transplantation. Sentinel renal events such as the occurrence of thrombotic microangiopathy will be noted. The rationale for the substitution of mycophenolate mofetil for tacrolimus is to continue to prevent acute GVHD, but minimize renal toxicity after transplantation. We will thus monitor renal toxicity closely in this study. In our previous experience, the rate of grade III-V renal toxicity by day 100 after transplantation was about 10%. Here, grade III is defined as a creatinine level between 3.1 to 6 times the normal level, grade IV is defined as a creatinine level 6 times or more the normal level, and grade V is defined as a fatality due to renal toxicity. |
| To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | 1 year | This outcome measure was presented as a comparison between incidence of Grade 0-I aGVHD and Grade II-IV aGVHD across 5 time points (Weeks 1,2,3,8, and 12). |
| Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant | 30 days | Engraftment of donor cells by week 4 after transplantation. Assessment of donor stem cell engraftment will include donor-host hematopoietic chimerism analyses at 4 weeks and every 3 months after transplantation. Chimerism measured from peripheral blood or from bone marrow. |
| Incidence of Chronic GVHD | 1 year | Chronic GVHD will be graded according to the modified Seattle criteria. Chronic GVHD divided into limited and extensive and evaluated across the following systems: skin, cutaneous structures, liver, mouth, eyes, esophagus, intestines, lung, musculoskeletal, serous, nervous, urologic, vagina, hematopoietic, and immune. Localized skin involvement with or without hepatic dysfunction is classified as limited disease. Generalized skin involvement or limited disease plus eye involvement, oral involvement, hepatic dysfunction with abnormal liver histology, or involvement of any other target organ was classified as extensive disease. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-33. |
| Overall Survival | 1 year | — |
| Incidence of 100 Day Mortality | 100 days | — |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at Dana Farber Cancer Institute. The first participant was enrolled in November 2007. Enrollment was halted May 2008 due to an unacceptable rate of acute GVHD. The study reopened in November 2012 with addition of bortezomib. The last participant enrolled May 2013. The study was permanently closed to accural August 2013.
Participants by arm
| Arm | Count |
|---|---|
| Siro/MMF Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis
Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); | 13 |
| Siro/MMF/Bort Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis
Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) \*added with study reopening in 2012 | 2 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Alternative treatment for GVHD | 1 | 0 |
| Overall Study | Death | 5 | 2 |
| Overall Study | Relapse | 3 | 0 |
Baseline characteristics
| Characteristic | Siro/MMF | Siro/MMF/Bort | 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 | 11 Participants | 0 Participants | 11 Participants |
| Region of Enrollment United States | 13 participants | 2 participants | 15 participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 15 |
| serious Total, serious adverse events | 8 / 15 |
Outcome results
Primary
To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies
Time frame: 150 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies | 77 percentage of participants |
| Siro/MMF/Bort | To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies | 100 percentage of participants |
Secondary
Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant
Engraftment of donor cells by week 4 after transplantation. Assessment of donor stem cell engraftment will include donor-host hematopoietic chimerism analyses at 4 weeks and every 3 months after transplantation. Chimerism measured from peripheral blood or from bone marrow.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant | 9 participants |
| Siro/MMF/Bort | Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant | 2 participants |
Secondary
Incidence of 100 Day Mortality
Time frame: 100 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | Incidence of 100 Day Mortality | 31 percentage of participants |
| Siro/MMF/Bort | Incidence of 100 Day Mortality | 0 percentage of participants |
Secondary
Incidence of Chronic GVHD
Chronic GVHD will be graded according to the modified Seattle criteria. Chronic GVHD divided into limited and extensive and evaluated across the following systems: skin, cutaneous structures, liver, mouth, eyes, esophagus, intestines, lung, musculoskeletal, serous, nervous, urologic, vagina, hematopoietic, and immune. Localized skin involvement with or without hepatic dysfunction is classified as limited disease. Generalized skin involvement or limited disease plus eye involvement, oral involvement, hepatic dysfunction with abnormal liver histology, or involvement of any other target organ was classified as extensive disease. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-33.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | Incidence of Chronic GVHD | 15 percentage of participants |
| Siro/MMF/Bort | Incidence of Chronic GVHD | 50 percentage of participants |
Secondary
Overall Survival
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | Overall Survival | 39 percentage of participants |
| Siro/MMF/Bort | Overall Survival | 0 percentage of participants |
Secondary
The Rate of Renal Insufficiency
Renal function will be measured weekly after transplant for 4 weeks, at 8 weeks and then at 3 month intervals from transplantation. Sentinel renal events such as the occurrence of thrombotic microangiopathy will be noted. The rationale for the substitution of mycophenolate mofetil for tacrolimus is to continue to prevent acute GVHD, but minimize renal toxicity after transplantation. We will thus monitor renal toxicity closely in this study. In our previous experience, the rate of grade III-V renal toxicity by day 100 after transplantation was about 10%. Here, grade III is defined as a creatinine level between 3.1 to 6 times the normal level, grade IV is defined as a creatinine level 6 times or more the normal level, and grade V is defined as a fatality due to renal toxicity.
Time frame: 1 year
Population: One patient experienced grade 5 renal toxicity
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siro/MMF | The Rate of Renal Insufficiency | 1 participants |
| Siro/MMF/Bort | The Rate of Renal Insufficiency | 0 participants |
Secondary
To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence
This outcome measure was presented as a comparison between incidence of Grade 0-I aGVHD and Grade II-IV aGVHD across 5 time points (Weeks 1,2,3,8, and 12).
Time frame: 1 year
Population: In the Siro/MMF group, the overall number of participants analyzed was 13, however, the number of participants with the MMF level data available varies at each time point. For the Siro/MMF/Bort group, no data were analyzed due to no data available for this Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 1 MMF level (0-I aGVHD), n=3 | 2.43 ng/mL | Standard Deviation 1.19 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 1 MMF level (II-IV aGVHD), n=8 | 2.70 ng/mL | Standard Deviation 1.25 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 2 MMF level (0-I aGVHD), n=3 | 3.40 ng/mL | Standard Deviation 1.37 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 2 MMF level (II-IV aGVHD), n=6 | 3.07 ng/mL | Standard Deviation 2.25 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 3 MMF level (0-I aGVHD), n=3 | 2.57 ng/mL | Standard Deviation 1.35 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 3 MMF level (II-IV aGVHD), n=6 | 2.85 ng/mL | Standard Deviation 2.09 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 8 MMF level (0-I aGVHD), n=3 | 2.37 ng/mL | Standard Deviation 0.75 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 8 MMF level (II-IV aGVHD), n=4 | 2.13 ng/mL | Standard Deviation 1.18 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 12 MMF level (0-I aGVHD), n=2 | 1.75 ng/mL | Standard Deviation 0.07 |
| Siro/MMF | To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence | Week 12 MMF level (II-IV aGVHD), n=4 | 2.20 ng/mL | Standard Deviation 1.19 |
Comparison: Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 1.p-value: 0.77t-test, 2 sided
Comparison: Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 2.p-value: 0.59t-test, 2 sided
Comparison: Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 3.p-value: 0.92t-test, 2 sided
Comparison: Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 8.p-value: 0.63t-test, 2 sided
Comparison: Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 12.p-value: 0.79t-test, 2 sided