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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

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ClinicalTrials.gov Identifier: NCT00548717
Recruitment Status : Terminated (First two patients enrolled after trial reopened, developed grade III-IV acute GVHD and subsequently passed away.)
First Posted : October 24, 2007
Results First Posted : October 21, 2014
Last Update Posted : October 21, 2014
Sponsor:
Collaborators:
Wyeth is now a wholly owned subsidiary of Pfizer
PDL BioPharma, Inc.
Information provided by (Responsible Party):
Corey S. Cutler, MD, MPH, Dana-Farber Cancer Institute

Study Description
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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.

Condition or disease Intervention/treatment Phase
Graft-vs-Host Disease Drug: Sirolimus Drug: Mycophenolate mofetil Drug: Bortezomib Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease Prophylaxis After Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation
Study Start Date : October 2007
Actual Primary Completion Date : September 2013
Actual Study Completion Date : September 2013

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U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Siro/MMF
Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF)
 Drug: Sirolimus
Other Name: Rapamycin
Drug: Mycophenolate mofetil
Other Name: Cellcept
Experimental: Siro/MMF/Bort
Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *added with study reopening in 2012
 Drug: Sirolimus
Other Name: Rapamycin
Drug: Mycophenolate mofetil
Other Name: Cellcept
Drug: Bortezomib
Other Name: Velcade


Outcome Measures
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Primary Outcome Measures :
  1. 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 Measures :
  1. Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant [ Time Frame: 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.

  2. The Rate of Renal Insufficiency [ Time Frame: 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.


  3. To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence [ Time Frame: 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).

  4. Incidence of 100 Day Mortality [ Time Frame: 100 days ]
  5. Incidence of Chronic GVHD [ Time Frame: 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.


  6. Overall Survival [ Time Frame: 1 year ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00548717


Locations
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Wyeth is now a wholly owned subsidiary of Pfizer
PDL BioPharma, Inc.
Investigators
Principal Investigator: Corey Cutler, MD Dana-Farber Cancer Institute
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party: Corey S. Cutler, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00548717     History of Changes
Other Study ID Numbers: DFCI 07-197
First Posted: October 24, 2007    Key Record Dates
Results First Posted: October 21, 2014
Last Update Posted: October 21, 2014
Last Verified: October 2014

Keywords provided by Corey S. Cutler, MD, MPH, Dana-Farber Cancer Institute:
GVHD
Stem cell transplantation
Sirolimus

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Bortezomib
Sirolimus
Everolimus
Mycophenolic Acid
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
 Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antitubercular
Antitubercular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action