A Study of Tacrolimus/Methotrexate and Tocilizumab to Prevent Acute Graft-Versus-Host Disease (AGVD) After Allogeneic Hematopoietic Stem Cell Transplant

Study Overview
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Brief Summary
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This is a phase II open label trial designed to evaluate the efficacy of Tac/MTX/Toc in preventing graft versus host disease (GVHD). Outcomes of patients on this clinical trial will be compared to those of contemporary controls from the CIBMTR.

Detailed Description
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This is a Phase II open label trial designed to evaluate the efficacy of Tacrolimus (Tac), Methotrexate (MTX) and Tocilizumab (Toc) (combined Tac/MTX/Toc) in preventing graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation compared to a contemporary control cohort selected from the Center for International Bone Marrow Transplant Research (CIBMTR) that is treated with standard methotrexate and tacrolimus for GVHD prevention. The control group of patients will satisfy similar eligibility requirements as the patients enrolled in the clinical trial and they will be matched for relevant clinical variables (age, sex, conditioning regimen, disease, graft source, etc). Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 post transplant. Methotrexate will be dosed at 15 mg/m^2 Day +1 and 10mg/m^2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1. Ancillary Study: The ancillary study will evaluate whether tocilizumab is effective at positively impacting mood, fatigue, sleep, and pain in a group of individuals undergoing allogeneic hematopoietic stem cell transplantation as compared to individuals not receiving tocilizumab. We will also assess whether tocilizumab alters gene expression and Rap1 prenylation in a manner that may reduce further progression or relapse of cancer after transplant.

Official Title
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Phase II Open-Label Trial of Tacrolimus/Methotrexate and Tocilizumab for the Prevention of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Methotrexate
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative disease and myelodysplasia with less than 5% of blasts in the bone marrow Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, Non-Hodgkin Lymphoma or Hodgkin Disease with chemosensitive disease at time of transplant Planned conditioning regimens including combination of busulfan and fludarabine or busulfan and cyclophosphamide Transplantation with T-cell-replete grafts Bone marrow or mobilized peripheral blood cell grafts Patients must have either a sibling donor (6/6 match at human leukocyte antigens (HLA-A, -B and -DRB1) or a unrelated donor (8/8 match at HLA-A, -B, -C and -DRB1) Cardiac function: Ejection fraction at rest >45% for myeloablative conditioning or >40% for reduced intensity conditioning Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight) Pulmonary function: Diffusing Capacity of Lung for Carbon Monoxide (DLCO) ≥40% (adjusted for hemoglobin) and FEV1≥50% Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) < 2.5x the upper normal limit Signed informed consent Exclusion Criteria: Prior allogeneic hematopoietic cell transplant (HCT) Karnofsky Performance Score <70% Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression of infectious disease or no clinical improvement) at time of enrollment Prior intolerance or allergy to Tocilizumab Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody at time of conditioning regimen History of diverticulitis, Crohn's disease or ulcerative colitis History of demyelinating disorder Pregnant and lactating women Patients with a history of rheumatologic disorders who have previously received Tocilizumab Eligibility for the Control Arm Patients in the control arm will be identified from patients reported to the CIBMTR from U.S centers. Control patients will be required to satisfy similar eligibility requirements as patients being enrolled in the clinical trial. Patients will need to fulfill the same inclusion criteria for the clinical trial according to Section 2.4.1, plus the following: Receive Tac/MTX as the sole GVHD prophylaxis approach Receive the same regimens as specified in Table 2.5 Year of transplant from 2010 to 2013 Exclusion criteria for the controls: 1. Karnofsky Performance Score < 70% Data for all eligible patients will be used to constitute the control database for this study

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus, Methotrexate and Tocilizumab (Tac/MTX/Toc)<br>Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 posttransplant. Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1 | Drug: Tacrolimus<br>* Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 posttransplant.<br>* Other names: FK506;Drug: Methotrexate<br>* Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m^2 Days +3, +6 and +11.<br>* Other names: Trexall;Drug: Tocilizumab<br>* Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1.<br>* Other names: Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Not Experiencing Grade II-IV Acute Graph Versus Host Disease (aGVHD) | This measure is the number of subjects who did not experience grade II-IV aGVHD at or before day 180 comparing recipients of tacrolimus (Tac), methotrexate (MTX), and tocilizumab (Toc) to a contemporary control population abstracted from a database maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR). The staging of aGVHD was according to the criteria of Przepiorka, et al., 1995 which assigns a score to the clinical status of multiple organ systems aggregated to determine the clinical stage. A higher stage indicates more severe aGVHD symptoms and poorer clinical outcome. | Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score of Depressive Symptoms Using General Depressive Subscale of the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument | The measure of depressive symptoms will be determined from the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions (see Watson, 2007). The General Depression subscale of the IDAS and includes a subset of 20 five-item Likert-style questions (1= Not at All to 5-= Extremely) with a scoring range of 20-100. Higher scores indicate more severe symptoms. | Baseline, Day 28, Day 100 and Day 180 | 
| Score of Anxiety Symptoms Using the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument | Levels of anxiety symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. (see Watson, 2007). Anxiety will be assessed combining two domain categories of the IDAS (panic and traumatic intrusions). There are seven 5-item, Likert-style questions responding symptom severity during the past 2 weeks, including today ... ranging from 'Not at all' to 'Extremely.' Scores range from 0 to 28 with higher scores indicating worse symptoms. | Baseline, Day 28, Day 100 and Day 180 | 
| Score of Fatigue Symptoms Using the Fatigue Symptom Inventory (FSI) Instrument | Levels of fatigue symptoms will be measured using the Fatigue Symptom Inventory instrument. The FSI comprises 13 eleven-item Likert-style questions ranging from 0 = Not at all fatigued to 10 -Extreme fatigue. The FSI score is the average of the individual question scores. The range of scores is 0 to 10 with higher scores indicate greater fatigue (Hann, 1998). | Baseline, Day 28, Day 100 and Day 180 | 
| Score of Sleep Symptoms Using the Pittsburgh Sleep Quality Index (PSQI) Instrument | Levels of sleep symptoms will be measured using the Pittsburgh Sleep Quality Index instrument. The PSQI contains 19 four-item Likert-style questions conducted over a 30-day period and 5 questions rated by the bed partner or roommate. Responses range from 0 = Not in the past month to 3 = Three or more times a week. The bed partner/roommate questions were not assessed. The 19 self-rated questions are grouped into seven component domains including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. See Buysse (1989), for the scoring schema of the component domains. The PSQI score is the sum of the seven component scores and ranges from 0 to 21. Higher scores indicate poorer sleep quality. | Baseline, Day 28, Day 100 and Day 180 | 
| Score of Pain Symptoms Using the Brief Pain Inventory (BPI) Instrument (Interference) | Levels of interference in activities due to pain symptoms will be measured using the Brief Pain Inventory (BPI) instrument. The BPI Interference scale is a mean of 7 eleven-item Likert-style questions with a range of 0-10 (0 = Does not interfere to 10 = Completely interferes). Higher scores indicate greater interference in daily activities due to pain symptoms (see Cleeland 1994). | Baseline, Day 28, Day 100 and Day 180 |