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

Study Overview
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Brief Summary
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The purpose of this study was to test whether a new drug named visilizumab would decrease the severity of graft-versus-host disease in patients treated with a mismatched donor. Investigators planned to use visilizumab in combination with tacrolimus and methotrexate as the study treatment.

Detailed Description
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The protocol plan was a two stage, controlled, phase II study to assess safety and compare the grade of acute graft-versus-host disease (GVHD) with visilizumab, or Anti-thymocyte Globulin (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 human leukocyte antigen (HLA) A, B, C and DRB1. The study design included two stages. The first stage of the trial was to 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 was to include a random control group of patients treated with the current standard treatment (ATG, tacrolimus, and methotrexate) or study treatment. The purpose of this comparison was 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.

Official Title
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A Phase II Study of Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: Visilizumab
* Drug: Tacrolimus
* Drug: Methotrexate
* Drug: Antithymocyte globulin (ATG)
* Drug: Tacrolimus
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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 1 (CR1) 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 International Prognostic Scoring System (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: diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hgb), forced expiratory volume-one second (FEV1), forced vital capacity (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/1.73m^2 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 hematopoietic stem cell (HSC) transplantation, confirmed by nucleic acid test (NAT) Uncontrolled bacterial or fungal infection History of documented invasive aspergillosis or cytomegalovirus (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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Study Stage: Study Treatment<br>Visilizumab, Tacrolimus and Methotrexate. | Drug: Visilizumab<br>* 3 mg/m^3, IV (in the vein) on day 0, prior to hematopoietic cell infusion (transplant).<br>Drug: Tacrolimus<br>* 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 to be tapered beginning 100 days after transplant.<br>Drug: Methotrexate<br>* 15 mg/m^2 intravenously (IV) on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.<br>|
| Active Comparator: Second Study Stage: Standard Treatment<br>Second Stage: Antithymocyte-globulin (ATG), Tacrolimus and Methotrexate. The study was closed during first stage and did not proceed to the second stage comparison to ATG in combination with tacrolimus/methotrexate as originally planned. | Drug: Antithymocyte globulin (ATG)<br>* 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.<br>* Other names: Thymoglobulin-ATG;Drug: Tacrolimus<br>* 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 to be tapered beginning 100 days after transplant.<br>Drug: Methotrexate<br>* 15 mg/m^2 IV on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days | Cumulative Incidence of Grade II-IV Acute GVHD Score at 100 Days. Investigators had planned to assess whether the grade of acute GVHD was decreased by visilizumab in combination with tacrolimus/methotrexate compared to standard treatment with thymoglobulin/tacrolimus/methotrexate after transplantation from unrelated mismatched donors, from day of transplant up to one year. Study was closed during the first treatment stage and did not proceed to the second stage treatment comparison to ATG in combination with tacrolimus/methotrexate as originally planned. Overall GVHD Grade: From Filipovich AH, Weisdorf D, Pavletic S, etal: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 11:945-955 (2005). Grade I: Skin Stage 1-2, Liver Stage 0, Gut State 0; Grade II: Skin Stage 3 or, Liver Stage 1 or, Gut Stage 1; Grade II | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Epstein-Barr Virus (EBV) Reactivation | Number of participants who reactivated EBV. Patients had their plasma tested once weekly using the TaqMan polymerase chain reaction (PCR) for quantitative determination of EBV-DNA for 6 weeks. Plasma levels > 1000 copies per ml plasma were scored as positive. | 3 months | 
| Incidence of Rituximab Response to Reactivated EBV Without PTLD | Participants who developed plasma EBV-DNA of >1000 copies/mL on any tests received rituximab. Incidence of Rituximab Response: Reactivated EBV participants whose plasma titers cleared after rituximab, without post-transplant lymphoproliferative disorder (PTLD). | 100 days | 
| Overall Survival (OS) | Median OS in days. Survival was measured from the time of transplant to the time of death. | At 2 years and 5 years | 
| Pharmacodynamics of Visilizumab - Test 1 | Mean Cmax (±SD) | At 1 - 2 hours | 
| Pharmacodynamics of Visilizumab - Test 2 | Mean terminal half-life (±SD) | Up to 205 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allogeneic transplant, graft versus host disease, GVHD, GVHD prevention, unrelated donors, mismatched unrelated donors, hematological malignancies, Leukemia, Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Aplastic Anemia, Multiple Myeloma