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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

This study has been terminated.
(First two patients enrolled after trial reopened, developed grade III-IV acute GVHD and subsequently passed away.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT00548717
First Posted: October 24, 2007
Last Update Posted: October 21, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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
October 23, 2007
October 24, 2007
September 29, 2014
October 21, 2014
October 21, 2014
October 2007
September 2013   (Final data collection date for primary outcome measure)
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 ]
To determine the rate of Grade II-IV acute GVHD when the combination of sirolimus and mycophenolate mofetil is used for GVHD prophylaxis after allogeneic stem cell transplantation in patients with hematologic malignancies. [ Time Frame: 100 days ]
Complete list of historical versions of study NCT00548717 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.

  • 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).
  • Incidence of 100 Day Mortality [ Time Frame: 100 days ]
  • 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.

  • Overall Survival [ Time Frame: 1 year ]
  • Donor stem cell engraftment, including donor-host hematopoietic chimerism studies post transplant. [ Time Frame: 1 year ]
  • The Rate of Renal Insufficiency [ Time Frame: 1 year ]
  • To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence [ Time Frame: 1 year ]
  • Incidence of 100 Day Mortality [ Time Frame: 100 days ]
  • Incidence of Chronic GVHD [ Time Frame: 1 year ]
  • Overall Survival [ Time Frame: 1 year ]
Not Provided
Not Provided
 
Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation
Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease Prophylaxis After Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation
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.
Interventional
Phase 2
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Graft-vs-Host Disease
  • Drug: Sirolimus
    Other Name: Rapamycin
  • Drug: Mycophenolate mofetil
    Other Name: Cellcept
  • Drug: Bortezomib
    Other Name: Velcade
  • Experimental: Siro/MMF
    Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF)
    Interventions:
    • Drug: Sirolimus
    • Drug: Mycophenolate mofetil
  • 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
    Interventions:
    • Drug: Sirolimus
    • Drug: Mycophenolate mofetil
    • Drug: Bortezomib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
15
September 2013
September 2013   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00548717
DFCI 07-197
Yes
Not Provided
Not Provided
Corey S. Cutler, MD, MPH, Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
  • Wyeth is now a wholly owned subsidiary of Pfizer
  • PDL BioPharma, Inc.
Principal Investigator: Corey Cutler, MD Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP