Cancer
Conditions
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
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.
Interventions
DRUGmycophenolate mofetil
Given orally
DRUGplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Martin, Paul
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cure of Chronic GVHD Without Resorting to Secondary Systemic Therapy | 2 years | Withdrawal of all systemic immunosuppressive treatment after resolution of chronic GVHD, before death or onset of recurrent malignancy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Open Label Systemic Treatment Because of Inadequate Response to Primary Therapy | 2 years | 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 | within 4 years | Development of bronchiolitis obliterans during treatment |
| Recurrent Malignancy | within 4 years | Development of recurrent malignancy after enrollment in the study |
| Non-relapse Mortality | within 4 years | Death without prior development of recurrent malignancy |
| Definitive Absence of Efficacy Success | 2 years | Administration of secondary systemic therapy for chronic GVHD, death during primary therapy, or onset of recurrent malignancy or bronchiolitis obliterans during primary therapy |
| Death | within 4 years | Death from any cause after enrollment in the study |
| Withdrawal of Prednisone | within 4 years | Withdrawal of treatment with prednisone after improvement or resolution of chronic GVHD |
| End of Systemic Treatment | within 4 years | Withdrawal of all immunosuppressive treatment without recurrent malignancy |
| Death or Recurrent Malignancy | within 4 years | Death due to any cause or development of recurrent malignancy at any time after enrollment |
Countries
Canada, United States
Participant flow
Recruitment details
Clinic patients were recruited from May 2004 through June 2008.
Participants by arm
| Arm | Count |
|---|---|
| Mycophenolate Mofetil Patients receive oral mycophenolate mofetil 1000 mg twice daily. | 74 |
| Placebo Patients receive oral placebo twice daily | 77 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Termination of trial | 18 | 24 |
Baseline characteristics
| Characteristic | Mycophenolate Mofetil | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 71 Participants | 139 Participants |
| Age Continuous | 48.3 years STANDARD_DEVIATION 13.3 | 47.9 years STANDARD_DEVIATION 13.3 | 48.1 years STANDARD_DEVIATION 13.3 |
| Region of Enrollment Canada | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 73 participants | 75 participants | 148 participants |
| Sex: Female, Male Female | 33 Participants | 37 Participants | 70 Participants |
| Sex: Female, Male Male | 41 Participants | 40 Participants | 81 Participants |
Outcome results
Primary
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
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Cure of Chronic GVHD Without Resorting to Secondary Systemic Therapy | 11 participants |
| Placebo | Cure of Chronic GVHD Without Resorting to Secondary Systemic Therapy | 10 participants |
p-value: 0.2295% CI: [0.7, 3.7]Regression, Cox
Secondary
Bronchiolitis Obliterans
Development of bronchiolitis obliterans during treatment
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Bronchiolitis Obliterans | 5 participants |
| Placebo | Bronchiolitis Obliterans | 4 participants |
p-value: 0.4895% CI: [0.4, 6]Regression, Cox
Secondary
Death
Death from any cause after enrollment in the study
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Death | 19 participants |
| Placebo | Death | 10 participants |
p-value: 0.195% CI: [0.9, 4.3]Regression, Cox
Secondary
Death or Recurrent Malignancy
Death due to any cause or development of recurrent malignancy at any time after enrollment
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Death or Recurrent Malignancy | 25 participants |
| Placebo | Death or Recurrent Malignancy | 15 participants |
p-value: 0.1495% CI: [0.9, 3.2]Regression, Cox
Secondary
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
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Definitive Absence of Efficacy Success | 45 participants |
| Placebo | Definitive Absence of Efficacy Success | 40 participants |
p-value: 0.0395% CI: [1.1, 2.6]Regression, Cox
Secondary
End of Systemic Treatment
Withdrawal of all immunosuppressive treatment without recurrent malignancy
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | End of Systemic Treatment | 15 participants |
| Placebo | End of Systemic Treatment | 15 participants |
p-value: 0.2895% CI: [0.7, 3.2]Regression, Cox
Secondary
Non-relapse Mortality
Death without prior development of recurrent malignancy
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Non-relapse Mortality | 8 participants |
| Placebo | Non-relapse Mortality | 5 participants |
p-value: 0.4195% CI: [0.5, 5]Regression, Cox
Secondary
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
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Open Label Systemic Treatment Because of Inadequate Response to Primary Therapy | 24 participants |
| Placebo | Open Label Systemic Treatment Because of Inadequate Response to Primary Therapy | 25 participants |
p-value: 0.5595% CI: [0.7, 2.1]Regression, Cox
Secondary
Recurrent Malignancy
Development of recurrent malignancy after enrollment in the study
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Recurrent Malignancy | 17 participants |
| Placebo | Recurrent Malignancy | 10 participants |
p-value: 0.1795% CI: [0.8, 3.9]Regression, Cox
Secondary
Withdrawal of Prednisone
Withdrawal of treatment with prednisone after improvement or resolution of chronic GVHD
Time frame: within 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mycophenolate Mofetil | Withdrawal of Prednisone | 30 participants |
| Placebo | Withdrawal of Prednisone | 33 participants |
p-value: 0.3495% CI: [0.08, 2.1]Regression, Cox