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:

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

ClinicalTrials.gov Identifier:

NCT00548717

First received: October 23, 2007

Last updated: October 20, 2014

Last verified: October 2014

History of Changes

Purpose

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	Intervention	Phase
Graft-vs-Host Disease	Drug: Sirolimus Drug: Mycophenolate mofetil Drug: Bortezomib	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

Drug Information available for: Mycophenolic acid Mycophenolate sodium Sirolimus Mycophenolate mofetil hydrochloride Mycophenolate mofetil Everolimus Temsirolimus Bortezomib

Genetic and Rare Diseases Information Center resources: Homologous Wasting Disease

U.S. FDA Resources

Further study details as provided by Dana-Farber Cancer Institute:

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 [ Time Frame: 150 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant [ Time Frame: 30 days ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: Yes ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Incidence of Chronic GVHD [ Time Frame: 1 year ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]


Enrollment:	15
Study Start Date:	October 2007
Study Completion Date:	September 2013
Primary Completion Date:	September 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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


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
Study First Received:	October 23, 2007
Results First Received:	September 29, 2014
Last Updated:	October 20, 2014
Health Authority:	United States: Institutional Review Board

Keywords provided by 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 Mycophenolate mofetil Antineoplastic Agents Anti-Bacterial Agents	Anti-Infective Agents Antibiotics, Antineoplastic Antifungal Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 23, 2016

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