Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant

Study Overview
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Brief Summary
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RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, and antithymocyte globulin before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with tacrolimus and antithymocyte globulin and to see how well it works in preventing graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem cell transplant.

Detailed Description
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OBJECTIVES: Primary To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis. To determine the safety of this regimen in these patients at 6 months after PBSCT. Secondary To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen. To determine the length of hospital stay of these patients within 100 days after PBSCT. To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen. To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen. To determine the incidence of chronic GVHD in patients treated with this regimen. To determine the overall and disease-free survival of these patients at 2 years after PBSCT. To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT. To conduct immunocorrelative studies prior to and at various time points after PBSCT. OUTLINE: Conditioning regimen: Patients receive 1 of 6 conditioning regimens (standard of care treatment) between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity. Regimen I: Patients receive fludarabine phosphate IV and busulfan IV. Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV. Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV. Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV. Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV. Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI. Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0. Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1. Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution. After completion of study therapy, patients are followed periodically for up to 2 years.

Official Title
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A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin®, as Graft-versus-Host- Disease Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

Conditions
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Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Intervention / Treatment
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* Biological: rituximab
* Drug: busulfan
* Drug: carmustine
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: etoposide
* Drug: fludarabine phosphate
* Drug: melphalan
* Radiation: total body irradiation (TBI)
* Drug: anti-thymocyte globulin IV


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of a hematological malignancy, including any of the following: Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR) Hodgkin lymphoma in CR or PR Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria: In CR Not in CR and meets the following criteria: Bone marrow blast < 20% within 4 weeks of transplantation Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy Myelodysplastic syndromes, treated or untreated Chronic myeloid leukemia in chronic phase or accelerated phase Multiple myeloma in CR or PR Chronic lymphocytic leukemia in second or greater CR or PR Myelofibrosis or other myeloproliferative disorders meeting the following criteria: Bone marrow blasts < 20% within 4 weeks of transplantation Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy Patients with ascites not allowed No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc) Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician High resolution molecular HLA typing is required for HLA class I and II No more than one antigen or allele mismatch No documented uncontrolled CNS disease PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-2 Karnofsky PS 60-100% Creatinine clearance > 50 mL/min Bilirubin < 3 times upper limit of normal (ULN) ALT and AST < 3 times ULN LVEF > 50% FVC, FEV_1, or DLCO > 50% predicted Patients on home oxygen not allowed Able to cooperate with oral medication intake HIV negative No active hepatitis B or hepatitis C No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy or chemotherapy + total body irradiation<br>Standard of care (SOC) chemotherapy or ( SOC) chemotherapy + total body irradiation (TBI) of one of the following regimens: Regimen I: Patients receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV. Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV;anti-thymocyte globulin IV. Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV; anti-thymocyte globulin IV. Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV. Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV; anti-thymocyte globulin IV. Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI; anti-thymocyte globulin IV. | Biological: rituximab<br>* Given IV<br>* Other names: Zytux;Drug: busulfan<br>* Given IV<br>* Other names: Myleran;Drug: carmustine<br>* Given IV<br>* Other names: Gliadel;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Neosar;Drug: cytarabine<br>* Given IV<br>* Other names: Depocyt;Drug: etoposide<br>* Given IV<br>* Other names: Toposar;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara®;Drug: melphalan<br>* Given IV<br>* Other names: Alkeran;Radiation: total body irradiation (TBI)<br>* Given once or twice daily<br>* Other names: radiotherapy;Drug: anti-thymocyte globulin IV<br>* Given IV<br>* Other names: Thymoglobulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute Graft-versus-host Disease (GVHD) |  | Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria | 
| Severity of Acute Graft-versus-host Disease (GVHD) |  | Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria | 
| Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment. |  | Within 6 months after PBSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Chronic GVHD. |  | Within 2 years after PBSCT | 
| Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] ) |  | post transplant, up to 4 weeks | 
| Overall Survival. |  | At 2 years after PBSCT | 
| Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders) |  | Within 6 months after PBSCT | 
| Karnofsky Performance Status Performance Status | 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead | At 90 days after PBSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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 Hodgkin lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, 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 small lymphocytic lymphoma, 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 Hodgkin lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, 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 small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone 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, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), chronic phase chronic myelogenous leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, primary myelofibrosis, atypical chronic myeloid leukemia, BCR-ABL negative, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia