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Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation

Primary Purpose

Graft-vs-Host Disease

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Mycophenolate mofetil
Bortezomib
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Graft-vs-Host Disease focused on measuring GVHD, Stem cell transplantation, Sirolimus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Siro/MMF

Siro/MMF/Bort

Arm Description

Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF)

Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *added with study reopening in 2012

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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.
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).
Incidence of 100 Day Mortality
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.
Overall Survival

Full Information

First Posted
October 23, 2007
Last Updated
October 20, 2014
Sponsor
Dana-Farber Cancer Institute
Collaborators
Wyeth is now a wholly owned subsidiary of Pfizer, PDL BioPharma, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00548717
Brief Title
Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation
Official Title
Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease Prophylaxis After Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
October 2014
Overall Recruitment Status
Terminated
Why Stopped
First two patients enrolled after trial reopened, developed grade III-IV acute GVHD and subsequently passed away.
Study Start Date
October 2007 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Wyeth is now a wholly owned subsidiary of Pfizer, PDL BioPharma, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft-vs-Host Disease
Keywords
GVHD, Stem cell transplantation, Sirolimus

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Siro/MMF
Arm Type
Experimental
Arm Description
Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF)
Arm Title
Siro/MMF/Bort
Arm Type
Experimental
Arm Description
Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *added with study reopening in 2012
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
Cellcept
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant
Description
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
Title
The Rate of Renal Insufficiency
Description
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
Title
To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence
Description
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
Title
Incidence of 100 Day Mortality
Time Frame
100 days
Title
Incidence of Chronic GVHD
Description
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
Title
Overall Survival
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with hematologic malignancies, who are at high risk of complications after conventional myeloablative transplantation 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 Patient age greater than 18 Performance status 0-2 Life expectancy of > 100 days without transplantation Written informed consent must be obtained in all cases from the patient Exclusion Criteria: Pregnancy Prior Allogeneic Stem Cell Transplantation from any donor Evidence of HIV infection or active Hepatitis B or C infection Heart failure uncontrolled by medications Total bilirubin > 2.0 mg/dl that is due to hepatocellular dysfunction AST > 90 Cholesterol > 300 mg/dl or Triglycerides > 400 mg/dl while adequately treated Uncontrolled bacterial, viral or fungal infection Requirement for voriconazole at the time of hospital admission
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Corey Cutler, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation

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