Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)
Condition: Acute Leukemia; Chronic Myelogenous Leukemia; Myelodysplasia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Hodgkin's Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after
      allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if
      any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free
      survival at one year after transplant compared to the current standard prophylaxis regimen.
    

Detailed description: 
      GVHD is a complication that can occur after a bone marrow or stem cell transplant. The
      transplant recipient's body is attacked by the newly introduced cells. Only about 40% of
      patients with acute GVHD have durable responses when treated with corticosteroid therapy. A
      strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an
      effective approach to improve survival after allogeneic transplantation.

      GVHD incidence can be decreased with various treatment plans. Early transplants were done
      using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later
      shown to work better than methotrexate. Then doctors discovered that the combined use of
      cyclosporine and methotrexate worked even better than either agent alone. More recently,
      other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic
      agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been
      conducted to compare available treatment combinations for related and unrelated donors. The
      combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis.

      However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current
      clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and
      bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and
      tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II
      clinical trial will compare each intervention arm with a Tac/MTX control.

      This study will enroll people who have a cancer of the blood or lymph glands and a stem cell
      transplant is a treatment option. The study will take at least two years and will include 270
      participants - 90 participants in each of three treatment groups. The purpose of this study
      is to compare three combinations of medications to see whether one or more of them are better
      than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.
    

Intervention name(s): Tacrolimus (ARM with Methotrexate); Tacrolimus (ARM with MMF and Cyclophosphamide); Methotrexate (ARM with Maraviroc); Methotrexate (ARM with Bortezomib); Maraviroc; Bortezomib; Mycophenolate mofetil; Cyclophosphamide
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels. The dose should be adjusted accordingly to maintain a suggested level of 5-15 ng/mL. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.; Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. Serum levels of tacrolimus will be measured at Day 7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.; Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of maraviroc. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.; Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of bortezomib. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.; Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to hematopoietic stem cell infusion, and continue until Day 30 post HSCT. If the patient requires a two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day.; Bortezomib will be administered at the dose of 1.3 mg/m2 based upon actual body weight (ABW) as an approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous administration of bortezomib is not allowed on this protocol.; MMF will be given at a dose of 15 mg/kg three times a day (TID) based upon ABW with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day 5 and discontinue after the last dose on Day 35, or may be continued if active GVHD is present.; Hydration prior to cyclophosphamide may be given according to institutional standards.
Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide.
Cyclophosphamide [50 mg/kg ideal body weight (IBW); if ABW < IBW, use ABW] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the HSCT) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
Other intervention name(s): Prograf®; FK506; Prograf®; FK506; MTX; MTX; Selzentry®; Velcade®; Cellcept®; Cytoxan®
Intervention MeSH terms: Mycophenolic Acid; Maraviroc; Cyclophosphamide; Methotrexate; Bortezomib; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Acute Lymphoblastic Leukemia/Lymphoma; Acute Myelogenous Leukemia; Mantel-Cell Lymphoma; Hematopoietic Transplant; GVHD Prophylaxis