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

Study Overview
=================
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.

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

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Drug: mycophenolate mofetil
* Drug: placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 4 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mycophenolate mofetil<br>Patients receive oral mycophenolate mofetil twice daily. | Drug: mycophenolate mofetil<br>* Given orally<br>* Other names: CellCept;|
| Placebo Comparator: Placebo<br>Patients receive oral placebo twice daily | Drug: placebo<br>* Given orally<br>* Other names: Control;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 2 years | 
| 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 | 2 years | 
| Bronchiolitis Obliterans | Development of bronchiolitis obliterans during treatment | within 4 years | 
| Recurrent Malignancy | Development of recurrent malignancy after enrollment in the study | within 4 years | 
| Non-relapse Mortality | Death without prior development of recurrent malignancy | within 4 years | 
| Death or Recurrent Malignancy | Death due to any cause or development of recurrent malignancy at any time after enrollment | within 4 years | 
| Death | Death from any cause after enrollment in the study | within 4 years | 
| Withdrawal of Prednisone | Withdrawal of treatment with prednisone after improvement or resolution of chronic GVHD | within 4 years | 
| End of Systemic Treatment | Withdrawal of all immunosuppressive treatment without recurrent malignancy | within 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IIIC breast cancer, splenic marginal zone lymphoma, stage IV breast cancer, 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, 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 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 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