Graft Versus Host Disease
Conditions
Keywords
graft versus host disease, GVHD, allogeneic transplant, GVHD prevention, unrelated donors, mismatched unrelated donors, hematological malignancies, Leukemia, Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Aplastic Anemia, Multiple Myeloma
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.
Interventions
DRUGVisilizumab
3 mg/m\^3, IV (in the vein) on day 0, prior to hematopoietic cell infusion (transplant).
DRUGTacrolimus
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.
DRUGMethotrexate
15 mg/m\^2 intravenously (IV) on Day 1 after transplant; 10 mg/m\^2 IV on Days 3, 6 and 11 after transplant.
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.
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| Pharmacodynamics of Visilizumab - Test 2 | Up to 205 hours | Mean terminal half-life (±SD) |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center between February 2008 and April 2010.
Pre-assignment details
The study was closed during the single-arm, first stage and did not proceed to the second stage comparison to antithymocyte globulin (ATG) in combination with tacrolimus/methotrexate as originally planned.
Participants by arm
| Arm | Count |
|---|---|
| First Stage: Study Treatment Visilizumab, Tacrolimus and Methotrexate. All participants. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | First Stage: Study Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 36.5 years |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 8 |
| serious Total, serious adverse events | 8 / 8 |
Outcome results
Primary
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
Time frame: 100 days
Population: All participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Study Stage: Study Treatment | Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days | Grade II-IV Acute GVHD | 8 participants |
| First Study Stage: Study Treatment | Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days | Grade I-II Acute GVHD | 6 participants |
| First Study Stage: Study Treatment | Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days | Grade III-IV Acute GVHD | 2 participants |
Secondary
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.
Time frame: 3 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First Study Stage: Study Treatment | Incidence of Epstein-Barr Virus (EBV) Reactivation | 6 participants |
Secondary
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).
Time frame: 100 days
Population: Reactivated EBV participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First Study Stage: Study Treatment | Incidence of Rituximab Response to Reactivated EBV Without PTLD | 6 participants |
Secondary
Overall Survival (OS)
Median OS in days. Survival was measured from the time of transplant to the time of death.
Time frame: At 2 years and 5 years
Population: Participants who had died by Year 2 and additional participants who had died by Year 5.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First Study Stage: Study Treatment | Overall Survival (OS) | 197 days |
| 5 Year Analysis Group | Overall Survival (OS) | 1803 days |
Secondary
Pharmacodynamics of Visilizumab - Test 1
Mean Cmax (±SD)
Time frame: At 1 - 2 hours
Population: All participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| First Study Stage: Study Treatment | Pharmacodynamics of Visilizumab - Test 1 | 1564 ng/mL | Standard Deviation 428 |
Secondary
Pharmacodynamics of Visilizumab - Test 2
Mean terminal half-life (±SD)
Time frame: Up to 205 hours
Population: All participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| First Study Stage: Study Treatment | Pharmacodynamics of Visilizumab - Test 2 | 157 hours | Standard Deviation 48 |