Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

• Infections [ Time Frame: Day of transplant up to one year ] [ Designated as safety issue: Yes ]
• Overall Survival [ Time Frame: Day of transplant up to one year ] [ Designated as safety issue: Yes ]
• Pharmacokinetics of visilizumab [ Time Frame: Day of transplant up to one year ] [ Designated as safety issue: Yes ]

The purpose of this study is to test if a new drug named visilizumab is able to decrease the severity of graft-versus-host disease in patients treated with a mismatched donor. In this study we will use visilizumab in combination with tacrolimus and methotrexate that is the "study treatment".

This protocol is a two stage, controlled, phase II study, to assess safety and compare the grade of acute graft-versus-host disease (GVHD) with visilizumab or thymoglobulin (ATG) in combination with tacrolimus + methotrexate in patients at high risk of GVHD after transplant from unrelated donors mismatched for 1-2 alleles of any type at HLA A, B, C and DRB1.

The study design includes two stages. The first stage of the trial will enroll 15 patients on a single arm to be treated with "study treatment" (visilizumab, tacrolimus and methotrexate) to assess for treatment safety and exclude intolerable GVHD. The second stage of the trial includes a random control group of patients treated with the current "standard treatment" (ATG, tacrolimus, and methotrexate) or "study treatment". The purpose of this comparison is to determine if the "study treatment" visilizumab causes less severe side effects and if it is more potent in reducing graft-versus-host disease symptoms than the "standard treatment".

In addition, immunological studies will be conducted to test the pharmacokinetics, immunogenicity, and pharmacodynamics of visilizumab or ATG administered for GVHD prophylaxis after hematopoietic cell transplantation.

• Drug: Visilizumab
  3 mg/m3, IV (in the vein) on day 0, prior to hematopoietic cell infusion (transplant)
• Drug: Tacrolimus
  0.02 mg/kg/24h (based on ideal body weight) continuous infusion (over 24 hours) beginning on day 4 after transplant up to approximately day 180 after transplant. Switch to oral tacrolimus as able. Dose adjusted based on levels. In the absence of GVHD, the dose will be tapered beginning 100 days after transplant
• Drug: Methotrexate
  15 mg/m2 IV on Day 1 after transplant; 10 mg/m2 IV on Days 3, 6 and 11 after transplant
• Drug: Antithymocyte globulin (ATG)
  1 mg/kg IV over 6 hours on Day 3 before transplant; 3.25 mg/kg IV over 4 hours on days 2 and 1 before transplant.
  Other Name: Thymoglobulin-ATG
• Drug: Tacrolimus
  0.03 mg/kg/24h (based on ideal body weight) continuous infusion (over 24 hours) beginning on day 3 before transplant up to approximately day 180 after transplant. Switch to oral tacrolimus as able. Dose adjusted based on levels. In the absence of GVHD, the dose will be tapered beginning 100 days after transplant.

• Experimental: Study Treatment
  Visilizumab, Tacrolimus and Methotrexate
  Interventions:

  • Drug: Visilizumab
  • Drug: Tacrolimus
  • Drug: Methotrexate
• Active Comparator: Standard Treatment
  Antithymocyte-globulin (ATG), Tacrolimus and Methotrexate
  Interventions:

  • Drug: Antithymocyte globulin (ATG)
  • Drug: Tacrolimus
  • Drug: Methotrexate

Inclusion Criteria:

• One of the following diagnoses with histological confirmation by the Pathology Department at H. Lee Moffitt Cancer Center:
• Acute Lymphocytic Leukemia (ALL) in complete remission (CR) 1 with t(9:22) or t(4:11), or any ALL beyond CR1
• Acute Myelogenous Leukemia (AML) with high risk cytogenetics in CR1 as defined by Bloomfield any AML beyond CR1
• Myelodysplastic Syndrome (MDS) with IPSS score > 1
• Chronic myelomonocytic leukemia (CMML)
• Chronic Myelogenous Leukemia (CML) with Imatinib-refractory chronic phase, or beyond chronic phase by morphology or cytogenetics
• Myelofibrosis
• Severe aplastic anemia
• Chemosensitive Non-Hodgkin's lymphoma and hodgkin's disease that are not candidate to autologous transplant due to prior autologous transplantation
• Multiple Myeloma patient not candidate for autologous stem cell transplantation
• Karnofsky performance status ≥ 70% (adult)
• Normal organ and marrow function as defined below:
• Hepatic: Total bilirubin must be less than or equal to 2mg/dL (Gilbert and other syndromes with increased indirect bilirubin are allowed); serum transaminases must be less than two times the upper limit of normal
• Pulmonary: DLCO (corrected for Hgb), FEV1, FVC must be greater than 50% predicted
• Cardiac: Left ventricular ejection fraction at rest must be greater than 50%
• Renal: Creatinine clearance (measured or calculated) must be equal or greater than 50 ml/min/1.73m2

Exclusion Criteria:

• Anti thymocyte globulin (ATG) or anti T cell therapy in prior 45 days
• Splenectomized patients;
• A positive pregnancy test administered to all females of childbearing potential prior to allogeneic stem cell transplant
• Inability to comply with follow up as determined by the patient's physician
• HIV-I/II infection prior to HSC transplantation, confirmed by NAT
• Uncontrolled bacterial or fungal infection
• History of documented invasive aspergillosis or CMV pneumonia
• Presence of any of the following comorbid conditions:
• History of myocardial infarction
• Congestive heart failure (even if symptomatically controlled)
• Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency)
• Untreated thoracic or abdominal aneurysm (6cm or more)
• History of any cerebrovascular accident including transient ischemic attacks
• Dementia
• History of peptic ulcer disease requiring treatment
• Connective tissue/rheumatologic disorders
• Diabetes unless being managed with dietary changes only
• Hemiplegia/paraplegia
• History of solid tumor excluding skin or cervical carcinoma after curative resection