Graft vs. Host Disease
Conditions
Keywords
Acute Graft vs. Host Disease (aGVHD), Graft vs. Host Disease (GVHD)
Brief summary
To determine whether treatment with ustekinumab will alter the ratio of T Regulatory Cell (Treg)/total cluster of differentiation 4 (CD4)+ cells in peripheral blood at day 30 post-hematopoietic cell transplantation (HCT).
Detailed description
This is a comparative study to assess the biologic and clinical activity of the agent ustekinumab when given in concert with our established regimen of SIR/TAC. Patients will be randomly assigned between the standard regimen of tacrolimus/sirolimus (TAC/SIR + placebo) vs. the investigational regimen of tacrolimus/sirolimus/ustekinumab (TAC/SIR/U) in a 1:1 scheme.
Interventions
DRUGUstekinumab
One subcutaneous injection administered on day -1 and repeated on day +20 after transplant
DRUGPlacebo
Subcutaneous injection of sterile saline (identical volume to that of ustekinumab) administered via the identical route and schedule as ustekinumab.
DRUGTacrolimus (TAC)
Administered starting day -3 according to Blood and Marrow Transplant (BMT) Program standard operating procedures. TAC levels to be monitored and maintained at a target range of 3-7 given concurrent administration with sirolimus. Specific dose adjustments within this therapeutic range to be determined by the treating physician.
DRUGSirolimus
Administered initially as an oral loading dose on day -1. Thereafter, SIR to be administered as an oral regimen daily. The dose for both loading and ongoing administration to be dictated by the standard operating procedures of the BMT program. SIR levels to be monitored according to standard procedures. Dose adjustments to be made according to drug levels, with target range of 5-14ng/mL (therapeutic range by Abbott Architect instrument at Moffitt).
Sponsors
Gateway for Cancer Research
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Hematologic disorder requiring allogeneic hematopoietic cell transplantation * Adequate vital organ function: * Left ventricular ejection fraction (LVEF) \>/= 45% by multigated acquisition (MUGA) scan * FEV1, FVC, and diffusing lung capacity oxygenation (DLCO) \>/= 50% of predicted values on pulmonary function tests * Transaminases (AST, ALT) \< 3 times upper limit of normal values * Creatinine clearance \>/= 50 cc/min. * Performance status: Karnofsky Performance Status Score \>/= 60%.
Exclusion criteria
* Active infection not controlled with appropriate antimicrobial therapy * HIV, hepatitis B, or hepatitis C infection * Sorror's co-morbidity factors with total score \> 3 * Important modification to co-morbidity index calculation: DLCO will not be included in assessment of pulmonary risk, excepting those with DLCO \< 50%, who will merit a score of 3 and thereby be excluded from the trial. * Anti-thymocyte globulin (ATG) as part of the conditioning regimen * Cyclophosphamide as part of the conditioning regimens
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| T Regulatory Cell (Treg)/Total Cluster of Differentiation 4 (CD4)+ Ratio | 30 days post transplant | Median Blood Treg/Total CD4+ Ratio at day 30 following hematopoietic cell transplantation (HCT). Comparison between study arms: Ustekinumab vs. Placebo. From NCI Dictionary: T reg - A type of immune cell that blocks the actions of some other types of lymphocytes, to keep the immune system from becoming over-active. T regs are being studied in the treatment of cancer. A T reg is a type of white blood cell and a type of lymphocyte. Also called regulatory T cell, suppressor T cell, and T-regulatory cell. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute Graft vs. Host Disease (AGVHD) | 100 days post transplant | Cumulative incidence of Grade II - IV AGVHD to be characterized weekly from day of transplant to day 100 using the 1995 updated grading scheme for Graft vs. Host Disease (GVHD) developed by Glucksberg, et al. |
Countries
United States
Participant flow
Recruitment details
54 participants (potential donors and recipients) were enrolled at Moffitt Cancer Center from 3/15/2013 through 5/22/2014.
Pre-assignment details
30 eligible recipients were randomly assigned 1:1 (Ustekinumab n=15, Placebo n=15) with stratification for donor type. Results Data pertains to recipients only.
Participants by arm
| Arm | Count |
|---|---|
| Ustekinumab Ustekinumab, Tacrolimus and Sirolimus. Ustekinumab: 45 mg for adults who weight 100 kg or less; 90 mg for adults who weight greater than 100 kg. Tacrolimus: Level determined according to Blood and Marrow Transplant (BMT) Program standard operating procedures. Sirolimus: The dose for both loading and ongoing administration to be dictated by the standard operating procedures of the BMT program. | 15 |
| Placebo Placebo, Tacrolimus, and Sirolimus. Placebo: Identical volume to that of ustekinumab. Tacrolimus: Level determined according to Blood and Marrow Transplant (BMT) Program standard operating procedures. Sirolimus: The dose for both loading and ongoing administration to be dictated by the standard operating procedures of the BMT program. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Ustekinumab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 11 Participants | 24 Participants |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 11 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 15 | 8 / 15 |
| serious Total, serious adverse events | 4 / 15 | 4 / 15 |
Outcome results
Primary
T Regulatory Cell (Treg)/Total Cluster of Differentiation 4 (CD4)+ Ratio
Median Blood Treg/Total CD4+ Ratio at day 30 following hematopoietic cell transplantation (HCT). Comparison between study arms: Ustekinumab vs. Placebo. From NCI Dictionary: T reg - A type of immune cell that blocks the actions of some other types of lymphocytes, to keep the immune system from becoming over-active. T regs are being studied in the treatment of cancer. A T reg is a type of white blood cell and a type of lymphocyte. Also called regulatory T cell, suppressor T cell, and T-regulatory cell.
Time frame: 30 days post transplant
Population: All participating recipients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ustekinumab | T Regulatory Cell (Treg)/Total Cluster of Differentiation 4 (CD4)+ Ratio | 13 ratio |
| Placebo | T Regulatory Cell (Treg)/Total Cluster of Differentiation 4 (CD4)+ Ratio | 11 ratio |
Secondary
Incidence of Acute Graft vs. Host Disease (AGVHD)
Cumulative incidence of Grade II - IV AGVHD to be characterized weekly from day of transplant to day 100 using the 1995 updated grading scheme for Graft vs. Host Disease (GVHD) developed by Glucksberg, et al.
Time frame: 100 days post transplant
Population: All participating recipients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ustekinumab | Incidence of Acute Graft vs. Host Disease (AGVHD) | 33.3 percentage of participants |
| Placebo | Incidence of Acute Graft vs. Host Disease (AGVHD) | 40.0 percentage of participants |