Ustekinumab for the Prevention of Acute Graft-versus-Host Disease After Unrelated Donor Hematopoietic Cell Transplant

Study Overview
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Brief Summary
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This phase II trial studies how well ustekinumab works in preventing acute graft-versus-host disease after unrelated donor hematopoietic cell transplant. Sometimes the transplanted cells from a donor can attack the body's normal tissues (called graft-versus-host disease). Giving ustekinumab after the transplant may help prevent acute graft-versus-host disease by controlling the body's immune response.

Detailed Description
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OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive ustekinumab intravenously (IV). Beginning 8 weeks after receiving IV ustekinumab, patients receive ustekinumab subcutaneously (SC) on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse or unacceptable toxicity. NOTE: HCT infusion takes place on day 0. ARM II: Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive a placebo IV. Beginning 8 weeks after IV placebo, patients receive a placebo SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence grade III-IV acute GVHD, of disease relapse, or unacceptable toxicity. NOTE: HCT infusion takes place on day 0. After completion of study, patients are followed up at 6, 9, 12, 18, and 24 months post-HCT.

Official Title
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Randomized, Placebo-Controlled, Phase II Trial Examining Ustekinumab for Prevention of Graft Vs. Host Disease After Allogeneic Hematopoietic Cell Transplantation

Conditions
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Hematologic and Lymphocytic Disorder, Hematopoietic and Lymphoid System Neoplasm

Intervention / Treatment
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* Drug: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Biological: Ustekinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 70 Signed informed consent. Hematologic malignancy or disorder requiring allogeneic hematopoietic cell transplantation Adequate vital organ function: Left ventricular ejection fraction (LVEF) ≥ 50% Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 50% of predicted values on pulmonary function tests Transaminases (aspartate aminotransferase [AST], aspartate aminotransferase [ALT]) < 3 times upper limit of normal values Creatinine clearance ≥ 50 cc/min. Performance status: Karnofsky Performance Status Score ≥ 70%. HCT donor is at least 8/8 (matched at HLA-A, -B, -C, -DRB1) matched with the recipient PBSC (peripheral blood mobilized stem cells) as graft source Fully myeloablative, reduced-toxicity ablative, or reduced-intensity conditioning regimens. If melphalan is part of the conditioning regimen, dose must be at least 75mg/m^2 Exclusion Criteria: Active infection not controlled with appropriate antimicrobial therapy Human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection Anti-thymocyte globulin (ATG) as part of the conditioning regimen or GVHD prophylaxis Pregnant or nursing women Subjects of childbearing age unwilling to use an effective birth control method or refrain from sexual intercourse until 15 weeks after last dose of study drug Non-myeloablative conditioning regimens or conditioning regimens that use less than 75mg/m^2 of melphalan Prior allogeneic transplant Non-malignant blood disorders (e.g. sickle cell disease, aplastic anemia) Positive screening test for tuberculosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ustekinumab)<br>Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive ustekinumab IV. Beginning 8 weeks after receiving IV ustekinumab, patients receive ustekinumab SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse or unacceptable toxicity. NOTE: HCT infusion takes place on day 0. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Ustekinumab<br>* Given IV and SC<br>* Other names: Stelara;|
| Placebo Comparator: Arm II (placebo)<br>Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive a placebo IV. Beginning 8 weeks after IV placebo, patients receive a placebo SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse, or unacceptable toxicity. NOTE: HCT infusion takes place on day 0. | Drug: Placebo Administration<br>* Given IV and SC<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade II-IV acute graft versus host disease (GVHD) survival | Will be treated as a binary outcome, and the Cochran-Mantel-Haenszel test will be used to compare the two groups based on the stratification factors. | At 6 months post-hematopoietic cell transplantation (HCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of grade II-IV and grade III-IV acute GVHD |  | At 100 days post-HCT | 
| Cumulative incidence of grade II-IV and grade III-IV acute GVHD |  | At 6 months post-HCT | 
| Acute GVHD organ staging, overall grading, and classification | Minnesota risk criteria will be used to assess organ involvement, individual organ staging, and overall acute GVHD grade. Risk classification will be performed per MacMillan et al. | From time of HCT, assessed up to day 100 post-HCT | 
| Incidence of overall chronic GVHD | Will be assessed at serial study visits, and scored according to National Institutes of Health Consensus criteria. | From time of HCT, assessed up to 2 years post-HCT | 
| Incidence of moderate-severe chronic GVHD | Will be assessed at serial study visits, and scored according to National Institutes of Health Consensus criteria. | From time of HCT, assessed up to 2 years post-HCT | 
| Incidence of post-HCT relapse | Relapse is defined as hematologic relapse or any unplanned intervention (including withdrawal of immune suppression) to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes. | From time of HCT, assessed up to 2 years post-HCT | 
| Incidence of non-relapse mortality | Non-relapse mortality indicates death with primary malignancy that served as HCT indication in remission. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes. | From time of HCT, assessed up to 2 years post-HCT | 
| Relapse-free survival | Relapse is defined as hematologic relapse or any unplanned intervention (including withdrawal of immune suppression) to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes. | From time of HCT, assessed up to 2 years post-HCT | 
| Overall survival | Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes. | From time of HCT, assessed up to 2 years post-HCT |