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

Phase 2

Terminated

Conditions: Graft Versus Host Disease

Interventions: Drug: Visilizumab
Drug: Antithymocyte globulin (ATG)
Drug: Tacrolimus
Drug: Methotrexate

Registration Number: NCT00720629

Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary: 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: 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".

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
First Study Stage: Study Treatment	Visilizumab	Visilizumab, Tacrolimus and Methotrexate.
First Study Stage: Study Treatment	Methotrexate	Visilizumab, Tacrolimus and Methotrexate.
Second Study Stage: Standard Treatment	Antithymocyte globulin (ATG)	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.
First Study Stage: Study Treatment	Tacrolimus	Visilizumab, Tacrolimus and Methotrexate.
Second Study Stage: Standard Treatment	Methotrexate	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.
Second Study Stage: Standard Treatment	Tacrolimus	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days	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

Secondary Outcome Measures

Name	Time	Method
Pharmacodynamics of Visilizumab - Test 2	Up to 205 hours	Mean terminal half-life (±SD)
Incidence of Epstein-Barr Virus (EBV) Reactivation	3 months	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.
Incidence of Rituximab Response to Reactivated EBV Without PTLD	100 days	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).
Overall Survival (OS)	At 2 years and 5 years	Median OS in days. Survival was measured from the time of transplant to the time of death.
Pharmacodynamics of Visilizumab - Test 1	At 1 - 2 hours	Mean Cmax (±SD)