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

Phase 2TerminatedNCT00548717

Dana-Farber Cancer Institute15 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Graft-vs-Host Disease

Interventions

SirolimusDRUG

Mycophenolate mofetilDRUG

BortezomibDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

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 Outcomes

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

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

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

Incidence of 100 Day Mortality

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.