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First two patients enrolled after trial reopened, developed grade III-IV acute GVHD and subsequently passed away.
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| Name | Class |
|---|---|
| Wyeth is now a wholly owned subsidiary of Pfizer | INDUSTRY |
| PDL BioPharma, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Siro/MMF | Experimental | Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) |
|
| Siro/MMF/Bort | Experimental | Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *added with study reopening in 2012 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus | Drug |
|
| |
| Mycophenolate mofetil |
| Measure | Description | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 30 days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Corey Cutler, MD | Dana-Farber Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dana-Farber Cancer Institute | Boston | Massachusetts | 02115 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Siro/MMF | Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin) Mycophenolate Mofetil (MMF) |
| FG001 | Siro/MMF/Bort | Sirolimus, Mycophenolate Mofetil, and Bortezomib for GVHD prophylaxis Sirolimus (Rapamycin) Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *Bortezomib added when study reopened in November 2012 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Drug |
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| Bortezomib | Drug |
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| 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. | 1 year |
| 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). | 1 year |
| Incidence of 100 Day Mortality | 100 days |
| 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. | 1 year |
| Overall Survival | 1 year |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Siro/MMF | Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); |
| BG001 | Siro/MMF/Bort | Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Number | percentage of participants | 150 days |
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| 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. | Posted | Number | participants | 30 days |
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| 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. | One patient experienced grade 5 renal toxicity | Posted | Number | participants | 1 year |
| |||||||||||||||||||||||||||||||
| 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). | 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. | Posted | Mean | Standard Deviation | ng/mL | 1 year |
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| Secondary | Incidence of 100 Day Mortality | Posted | Number | percentage of participants | 100 days |
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| 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. | Posted | Number | percentage of participants | 1 year |
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| Secondary | Overall Survival | Posted | Number | percentage of participants | 1 year |
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Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during the study. All SAEs and grade 3 or higher treatment and/or transplant related toxicities (AEs) are recorded.
It is not simple to segregate prophylactic regimen related from transplant related toxicities. We thus report transplant and/or regimen related toxicities combined and do not segregate toxicities by regimen. Moreover, since only 2 patients received Siro/MMF/Bort, comparison of toxicites between the two regimens is infeasible.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Siro/MMF (+/- Bortezomib) | Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis (+/- Bortezomib) Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012 | 8 | 15 | 11 | 15 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders |
| |||
| Multi-organ Failure | General disorders |
| |||
| GVHD | Immune system disorders |
| |||
| HHV6 encephalitis | Infections and infestations |
| |||
| Temporary blindness | Eye disorders |
| |||
| Sepsis | Infections and infestations |
| |||
| Pneumonia | Infections and infestations |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Documented infection | Infections and infestations |
| |||
| Suspected Undocumented infection | Infections and infestations |
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| Cholecystitis | Hepatobiliary disorders |
| |||
| Dehydration | Gastrointestinal disorders |
| |||
| Diarrhea | Gastrointestinal disorders | w/o prior colostomy |
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| Encephalopathy | Nervous system disorders |
| |||
| Hyperglycemia | Metabolism and nutrition disorders |
| |||
| Hyponatremia | Metabolism and nutrition disorders |
| |||
| Necrosis-small bowel NOS | Gastrointestinal disorders |
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| Pneumonitis/pulmonary infiltrates | Respiratory, thoracic and mediastinal disorders |
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| Thrombotic microangiopathy | Blood and lymphatic system disorders |
| |||
| Renal Toxicity | Renal and urinary disorders |
| |||
| Neurologic Toxicity | Nervous system disorders |
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Early termination leading to small numbers of subjects analyzed. Results are reported for transparency only, and should not be used to extrapolate significant conclusions.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Corey Cutler | Dana Farber Cancer Institute | 617-632-3470 | Corey_Cutler@dfci.harvard.edu |
| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D009173 | Mycophenolic Acid |
| D000069286 | Bortezomib |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D001897 | Boronic Acids |
| D000148 | Acids, Noncarboxylic |
| D000143 | Acids |
| D007287 | Inorganic Chemicals |
| D001896 | Boron Compounds |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| >=65 years |
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| Male |
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| Participants |
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| Participants |
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