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Mycophenolate Mofetil (MMF) for Treatment of Chronic Graft-versus-host Disease (GVHD)

Primary Purpose

Cancer

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
mycophenolate mofetil
placebo
Sponsored by
Martin, Paul
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cancer focused on measuring graft versus host disease, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, atypical chronic myeloid leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, disseminated neuroblastoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, juvenile myelomonocytic leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, poor prognosis metastatic gestational trophoblastic tumor, previously treated childhood rhabdomyosarcoma, previously treated myelodysplastic syndromes, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, splenic marginal zone lymphoma, stage I multiple myeloma, stage II multiple myeloma, stage II ovarian epithelial cancer, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III chronic lymphocytic leukemia, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III multiple myeloma, stage III ovarian epithelial cancer, stage III small lymphocytic lymphoma, stage III malignant testicular germ cell tumor, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV breast cancer, stage IV chronic lymphocytic leukemia, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV ovarian epithelial cancer, stage IV small lymphocytic lymphoma, childhood myelodysplastic syndromes

Eligibility Criteria

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

DISEASE CHARACTERISTICS: Newly diagnosed chronic-graft-versus host disease (GVHD) Systemic immunosuppressive treatment indicated AND no contraindication to treatment with mycophenolate mofetil Has undergone prior transplantation with any type of donor, hematopoietic stem cell graft, or conditioning regimen No clinical, laboratory, or image-based evidence known to be present at the time of enrollment and indicating a high probability of subsequent recurrent or progressive disease PATIENT CHARACTERISTICS: Age Any age Performance status Not specified Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Hepatic Not specified Renal Not specified Pulmonary No known bronchiolitis obliterans as a manifestation of chronic GVHD Immunologic No fungal infection without radiographic evidence of improvement during continued antifungal therapy No cytomegalovirus (CMV) pneumonia without major radiographic evidence of improvement No other CMV infection without reduction of antigenemia or viral load during continued antiviral therapy No active disseminated varicella zoster viral infection No known hypersensitivity or allergy to MMF Gastrointestinal Able to tolerate oral medication No lactose-intolerant children who are too young to swallow capsules No frank blood from the rectum No melena No known gastrointestinal ulceration Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Female patients must use 2 forms of contraception 4 weeks prior to, during, and for 6 weeks after completion of study treatment Not hospitalized at time of enrollment No rare, hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy Not specified Endocrine therapy Prior treatment with prednisone or equivalent allowed provided the dose was ≤ 1.0 mg/kg/day at the time of enrollment Concurrent systemic glucocorticoids allowed Radiotherapy Not specified Surgery Not specified Other Prior mycophenolate mofetil (MMF) for prevention or treatment of acute GVHD allowed provided MMF was discontinued at least 2 weeks before the diagnosis of chronic GVHD was made No prior systemic treatment for chronic GVHD No prior treatment for chronic GVHD Concurrent antacids allowed provided there is at least a 2-hour interval before and after administration of MMF No other concurrent systemic immunosuppressive treatment except cyclosporine, tacrolimus or sirolimus

Sites / Locations

  • City of Hope Comprehensive Cancer Center
  • Stanford Cancer Center
  • University of Florida Shands Cancer Center
  • University of Chicago Cancer Research Center
  • University of Michigan Comprehensive Cancer Center
  • Masonic Cancer Center at University of Minnesota
  • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Hackensack University Medical Center Cancer Center
  • Oregon Health and Science University Cancer Institute
  • Vanderbilt-Ingram Cancer Center
  • Baylor University Medical Center - Dallas
  • M. D. Anderson Cancer Center at University of Texas
  • Texas Transplant Institute
  • Fred Hutchinson Cancer Research Center
  • University of Washington School of Medicine
  • Princess Margaret Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Mycophenolate mofetil

Placebo

Arm Description

Patients receive oral mycophenolate mofetil twice daily.

Patients receive oral placebo twice daily

Outcomes

Primary Outcome Measures

Cure of Chronic GVHD Without Resorting to Secondary Systemic Therapy
Withdrawal of all systemic immunosuppressive treatment after resolution of chronic GVHD, before death or onset of recurrent malignancy

Secondary Outcome Measures

Definitive Absence of Efficacy Success
Administration of secondary systemic therapy for chronic GVHD, death during primary therapy, or onset of recurrent malignancy or bronchiolitis obliterans during primary therapy
Open Label Systemic Treatment Because of Inadequate Response to Primary Therapy
Administration of any systemic therapy other than the immunosuppressive agents used for initial treatment, because of persistent or progressive chronic graft-versus-host disease
Bronchiolitis Obliterans
Development of bronchiolitis obliterans during treatment
Recurrent Malignancy
Development of recurrent malignancy after enrollment in the study
Non-relapse Mortality
Death without prior development of recurrent malignancy
Death or Recurrent Malignancy
Death due to any cause or development of recurrent malignancy at any time after enrollment
Death
Death from any cause after enrollment in the study
Withdrawal of Prednisone
Withdrawal of treatment with prednisone after improvement or resolution of chronic GVHD
End of Systemic Treatment
Withdrawal of all immunosuppressive treatment without recurrent malignancy

Full Information

First Posted
August 4, 2004
Last Updated
May 1, 2013
Sponsor
Martin, Paul
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00089141
Brief Title
Mycophenolate Mofetil (MMF) for Treatment of Chronic Graft-versus-host Disease (GVHD)
Official Title
A Randomized Study to Evaluate The Efficacy of Mycophenolate Mofetil Added to The Systemic Immunosuppressive Regimen First Used For Treatment of Chronic Graft-Versus-Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2009
Overall Recruitment Status
Terminated
Why Stopped
Low probability of positive outcome
Study Start Date
May 2004 (undefined)
Primary Completion Date
July 2008 (Actual)
Study Completion Date
September 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Martin, Paul
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Mycophenolate mofetil added to immunosuppressive treatment regimens may be effective in treating newly diagnosed chronic graft-versus-host disease caused by stem cell transplantation. It is not yet known whether immunosuppressive treatment regimens are more effective with or without mycophenolate mofetil in treating chronic graft-versus-host disease. PURPOSE: This randomized phase III trial is studying whether the addition of mycophenolate mofetil improves the efficacy of immunosuppressive treatment regimens in patients with newly diagnosed chronic graft-versus-host disease.
Detailed Description
OBJECTIVES: Compare the efficacy of immunosuppressive treatment regimens with vs without mycophenolate mofetil in patients with newly diagnosed chronic graft-vs-host disease. Compare the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, double-blind, placebo-controlled, prospective, multicenter study. Patients are stratified according to organ involvement of chronic graft-versus-host disease (GVHD) (single organ vs multiple organs) and transplant center. Patients are randomized to 1 of 2 treatment arms. All patients receive usual therapy for chronic GVHD comprising oral prednisone twice daily and oral cyclosporine, oral tacrolimus or oral sirolimus twice daily until 2 weeks after the first evidence of improvement of symptoms of chronic GVHD. Arm I: Patients receive oral mycophenolate mofetil twice daily. Arm II: Patients receive oral placebo twice daily. In both arms administration of the study drug continues for 3 months after completion of prednisone and cyclosporine, tacrolimus or sirolimus in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and then every 3 months. Patients are followed every 3 months for 3-5 years. PROJECTED ACCRUAL: A total of 230 patients (115 per treatment arm) will be accrued for this study within 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer
Keywords
graft versus host disease, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, atypical chronic myeloid leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, disseminated neuroblastoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, juvenile myelomonocytic leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, poor prognosis metastatic gestational trophoblastic tumor, previously treated childhood rhabdomyosarcoma, previously treated myelodysplastic syndromes, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, splenic marginal zone lymphoma, stage I multiple myeloma, stage II multiple myeloma, stage II ovarian epithelial cancer, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III chronic lymphocytic leukemia, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III multiple myeloma, stage III ovarian epithelial cancer, stage III small lymphocytic lymphoma, stage III malignant testicular germ cell tumor, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV breast cancer, stage IV chronic lymphocytic leukemia, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV ovarian epithelial cancer, stage IV small lymphocytic lymphoma, childhood myelodysplastic syndromes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
151 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mycophenolate mofetil
Arm Type
Active Comparator
Arm Description
Patients receive oral mycophenolate mofetil twice daily.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients receive oral placebo twice daily
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
CellCept
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
placebo
Other Intervention Name(s)
Control
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Cure of Chronic GVHD Without Resorting to Secondary Systemic Therapy
Description
Withdrawal of all systemic immunosuppressive treatment after resolution of chronic GVHD, before death or onset of recurrent malignancy
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Definitive Absence of Efficacy Success
Description
Administration of secondary systemic therapy for chronic GVHD, death during primary therapy, or onset of recurrent malignancy or bronchiolitis obliterans during primary therapy
Time Frame
2 years
Title
Open Label Systemic Treatment Because of Inadequate Response to Primary Therapy
Description
Administration of any systemic therapy other than the immunosuppressive agents used for initial treatment, because of persistent or progressive chronic graft-versus-host disease
Time Frame
2 years
Title
Bronchiolitis Obliterans
Description
Development of bronchiolitis obliterans during treatment
Time Frame
within 4 years
Title
Recurrent Malignancy
Description
Development of recurrent malignancy after enrollment in the study
Time Frame
within 4 years
Title
Non-relapse Mortality
Description
Death without prior development of recurrent malignancy
Time Frame
within 4 years
Title
Death or Recurrent Malignancy
Description
Death due to any cause or development of recurrent malignancy at any time after enrollment
Time Frame
within 4 years
Title
Death
Description
Death from any cause after enrollment in the study
Time Frame
within 4 years
Title
Withdrawal of Prednisone
Description
Withdrawal of treatment with prednisone after improvement or resolution of chronic GVHD
Time Frame
within 4 years
Title
End of Systemic Treatment
Description
Withdrawal of all immunosuppressive treatment without recurrent malignancy
Time Frame
within 4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Newly diagnosed chronic-graft-versus host disease (GVHD) Systemic immunosuppressive treatment indicated AND no contraindication to treatment with mycophenolate mofetil Has undergone prior transplantation with any type of donor, hematopoietic stem cell graft, or conditioning regimen No clinical, laboratory, or image-based evidence known to be present at the time of enrollment and indicating a high probability of subsequent recurrent or progressive disease PATIENT CHARACTERISTICS: Age Any age Performance status Not specified Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Hepatic Not specified Renal Not specified Pulmonary No known bronchiolitis obliterans as a manifestation of chronic GVHD Immunologic No fungal infection without radiographic evidence of improvement during continued antifungal therapy No cytomegalovirus (CMV) pneumonia without major radiographic evidence of improvement No other CMV infection without reduction of antigenemia or viral load during continued antiviral therapy No active disseminated varicella zoster viral infection No known hypersensitivity or allergy to MMF Gastrointestinal Able to tolerate oral medication No lactose-intolerant children who are too young to swallow capsules No frank blood from the rectum No melena No known gastrointestinal ulceration Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Female patients must use 2 forms of contraception 4 weeks prior to, during, and for 6 weeks after completion of study treatment Not hospitalized at time of enrollment No rare, hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy Not specified Endocrine therapy Prior treatment with prednisone or equivalent allowed provided the dose was ≤ 1.0 mg/kg/day at the time of enrollment Concurrent systemic glucocorticoids allowed Radiotherapy Not specified Surgery Not specified Other Prior mycophenolate mofetil (MMF) for prevention or treatment of acute GVHD allowed provided MMF was discontinued at least 2 weeks before the diagnosis of chronic GVHD was made No prior systemic treatment for chronic GVHD No prior treatment for chronic GVHD Concurrent antacids allowed provided there is at least a 2-hour interval before and after administration of MMF No other concurrent systemic immunosuppressive treatment except cyclosporine, tacrolimus or sirolimus
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul J. Martin, MD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010-3000
Country
United States
Facility Name
Stanford Cancer Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305-5824
Country
United States
Facility Name
University of Florida Shands Cancer Center
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-100277
Country
United States
Facility Name
University of Chicago Cancer Research Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637-1470
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0942
Country
United States
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
UNMC Eppley Cancer Center at the University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-3330
Country
United States
Facility Name
Hackensack University Medical Center Cancer Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Oregon Health and Science University Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3098
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-6838
Country
United States
Facility Name
Baylor University Medical Center - Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
M. D. Anderson Cancer Center at University of Texas
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
Texas Transplant Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109-1024
Country
United States
Facility Name
University of Washington School of Medicine
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
19270260
Citation
Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, Fay JW, van Besien K, Gupta V, Kitko C, Johnston LJ, Maziarz RT, Arora M, Jacobson PA, Weisdorf D. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009 May 21;113(21):5074-82. doi: 10.1182/blood-2009-02-202937. Epub 2009 Mar 6.
Results Reference
result

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Mycophenolate Mofetil (MMF) for Treatment of Chronic Graft-versus-host Disease (GVHD)

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