Sirolimus, Tacrolimus, and Methotrexate in Preventing Acute Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplantation

Study Overview
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Brief Summary
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RATIONALE: Sirolimus, tacrolimus, and methotrexate may be effective in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation. PURPOSE: This phase I/II trial is studying the side effects of sirolimus when given together with tacrolimus and methotrexate and to see how well they work in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation for hematologic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the safety and efficacy of sirolimus when administered with tacrolimus and methotrexate for the prevention of acute graft-versus-host disease (GVHD) in patients with hematological malignancies undergoing hematopoietic stem cell transplantation from unrelated donors. Secondary Determine the absorption and pharmacokinetics of sirolimus in patients treated with this regimen. Correlate sirolimus blood concentration with prevention of GVHD or toxicity in patients treated with this regimen. Determine the severity of post-transplantation mucositis in patients treated with this regimen. OUTLINE: This is a nonrandomized, open-label, pilot study. Patients receive oral sirolimus once daily on days -3 to 175 and tacrolimus IV continuously beginning on day -3 and continuing until the patient is able to tolerate food and then orally twice daily until day 175. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Treatment continues in the absence of acute graft-vs-host disease or unacceptable toxicity. Patients are followed for 5 years. PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 3 years.

Official Title
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A Phase I/II Study of Sirolimus in Addition to Tacrolimus and Methotrexate for the Prevention of Acute-Graft-Versus-Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation From Unrelated Donors

Conditions
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Chronic Myeloproliferative Disorders, Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Drug: methotrexate
* Drug: sirolimus
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of hematological malignancy No chronic phase chronic myelogenous leukemia, de novo acute leukemia in first remission, or myelodysplastic syndromes with refractory anemia Scheduled for hematopoietic stem cell transplantation from unrelated donors Currently receiving conditioning regimen comprising cyclosporine and total body radiotherapy (1,200 to 1,350 cGy) or busulfan and cyclosporine Donor must be typed to the highest level of resolution One single non-serologic disparity for A, B, or C alleles allowed provided the disparity is within the third or fourth digit of the allele No mismatch at DRB1 or DQB1 PATIENT CHARACTERISTICS: Age Per primary treatment protocol Performance status Not specified Life expectancy Not specified Hematopoietic Not specified Hepatic SGOT and SGPT ≤ 2.0 times upper limit of normal Bilirubin normal Hepatitis B and C virus negative Renal Creatinine clearance ≥ 70 mL/min Cardiovascular No cardiac insufficiency requiring treatment No coronary artery disease Pulmonary No acute pulmonary infection by chest x-ray No severe hypoxemia with pO_2 < 70 mm Hg AND DLCO < 70% of predicted No mild hypoxemia with pO_2 < 80 mm Hg AND DLCO < 60% of predicted Other Not pregnant or nursing Negative pregnancy test HIV negative No active systemic infection No known hypersensitivity to macrolide antibiotics (e.g., erythromycin, azithromycin, or clarithromycin) No prior intolerance or unresponsiveness to sirolimus PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No concurrent T-cell depleted transplantations Chemotherapy See Disease Characteristics Endocrine therapy Not specified Radiotherapy See Disease Characteristics Surgery Not specified Other No concurrent grapefruit juice No concurrent voriconazole
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: methotrexate|nan|
|Drug: sirolimus|nan|
|Drug: tacrolimus|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease, accelerated phase chronic myelogenous leukemia, atypical chronic myeloid leukemia, blastic phase chronic myelogenous leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, previously treated myelodysplastic syndromes, recurrent adult acute lymphoblastic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, de novo myelodysplastic syndromes, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, recurrent adult acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory hairy cell leukemia, refractory multiple myeloma, relapsing chronic myelogenous leukemia, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, noncontiguous stage II adult Burkitt lymphoma, stage III adult Burkitt lymphoma, stage IV 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, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, childhood chronic myelogenous leukemia, recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, recurrent childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, untreated childhood acute lymphoblastic leukemia, untreated childhood acute myeloid leukemia and other myeloid malignancies, recurrent/refractory childhood Hodgkin lymphoma, juvenile myelomonocytic leukemia, splenic marginal zone lymphoma, untreated adult acute lymphoblastic leukemia, untreated adult acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory cytopenia with multilineage dysplasia, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent marginal zone lymphoma