Clinical trial NCT02206035: A Study of Tacrolimus/Methotrexate and Tocilizumab to Prevent Acute Graft-Versus-Host Disease (AGVD) After Allogeneic Hematopoietic Stem Cell Transplant
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hematopoietic Stem Cell Transplantation
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2014-08-01
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years
2. Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative disease and myelodysplasia with less than 5% of blasts in the bone marrow
3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, Non-Hodgkin Lymphoma or Hodgkin Disease with chemosensitive disease at time of transplant
4. Planned conditioning regimens including combination of busulfan and fludarabine or busulfan and cyclophosphamide
5. Transplantation with T-cell-replete grafts
6. Bone marrow or mobilized peripheral blood cell grafts
7. 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)
8. Cardiac function: Ejection fraction at rest \>45% for myeloablative conditioning or \>40% for reduced intensity conditioning
9. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
10. Pulmonary function: Diffusing Capacity of Lung for Carbon Monoxide (DLCO) ≥40% (adjusted for hemoglobin) and FEV1≥50%
11. 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
12. Signed informed consent

Exclusion Criteria:

1. Prior allogeneic hematopoietic cell transplant (HCT)
2. Karnofsky Performance Score \<70%
3. 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
4. Prior intolerance or allergy to Tocilizumab
5. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody at time of conditioning regimen
6. History of diverticulitis, Crohn's disease or ulcerative colitis
7. History of demyelinating disorder
8. Pregnant and lactating women
9. 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:

1. Receive Tac/MTX as the sole GVHD prophylaxis approach
2. Receive the same regimens as specified in Table 2.5
3. 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

Primary outcomes:
measure: Number of Subjects Not Experiencing Grade II-IV Acute Graph Versus Host Disease (aGVHD)
timeFrame: Day 180
Secondary outcomes:
measure: Score of Depressive Symptoms Using General Depressive Subscale of the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument
timeFrame: Baseline, Day 28, Day 100 and Day 180
measure: Score of Anxiety Symptoms Using the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument
timeFrame: Baseline, Day 28, Day 100 and Day 180
measure: Score of Fatigue Symptoms Using the Fatigue Symptom Inventory (FSI) Instrument
timeFrame: Baseline, Day 28, Day 100 and Day 180
measure: Score of Sleep Symptoms Using the Pittsburgh Sleep Quality Index (PSQI) Instrument
timeFrame: Baseline, Day 28, Day 100 and Day 180
measure: Score of Pain Symptoms Using the Brief Pain Inventory (BPI) Instrument (Interference)
timeFrame: Baseline, Day 28, Day 100 and Day 180
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: William Drobyski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Wisconsin
name: Marcelo Pasquini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Wisconsin
name: Jennifer Knight, MD
role: PRINCIPAL_INVESTIGATOR
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