Tocilizumab for Chronic Graft-versus-Host Disease Treatment

Study Overview
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Brief Summary
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This phase II trial studies how well tocilizumab works in treating chronic graft-versus-host disease (GVHD) in patients that have not responded to treatment after at least two prior therapies. Tocilizumab blocks a protein that stimulates the body's immune system. By blocking this protein, the investigators may reduce the symptoms of chronic GVHD.

Detailed Description
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PRIMARY OBJECTIVES: I. Efficacy will be determined by the proportion of patients with failure free survival (FFS) at 6 months. SECONDARY OBJECTIVES: I. Patients achieving a complete response (CR) or partial response (PR) at 6 months based on clinician judged response. II. Patients achieving a CR or PR by objective response measures at 6 months. III. Failure-free survival (FFS) at 1 year. IV. Change in steroid dose from enrollment to 6 months (mo). TERTIARY OBJECTIVES: I. Biologic studies will be done to determine possible mechanisms of response. OUTLINE: Patients receive tocilizumab intravenously (IV) over 1 hour every 2 weeks for 12 weeks (weeks 1, 3, 5, 7, 9, and 11) and then every 4 weeks for 12 weeks (weeks 13, 17, and 21). After completion of study treatment, patients are followed up at 3 and 6 months.

Official Title
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Tocilizumab in Chronic GVHD Refractory to at Least Two Prior Therapies

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Biological: tocilizumab
* Other: laboratory biomarker analysis
* Other: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has moderate or severe overlap chronic (c)GVHD according to National Institutes of Health (NIH) criteria Active cGVHD despite treatment with at least two immunosuppressive treatments (not including GVHD prophylaxis) in the past year Subject underwent allogeneic stem cell transplantation at least 6 months prior to enrollment Subject has not started any new systemic immunosuppressive therapies within 2 weeks prior to enrollment Female subjects of child bearing potential must have a negative pregnancy test prior to first dose of tocilizumab and must agree to practice effective contraception during the study Subject meets the following medication restriction requirements and agrees to follow medication restrictions during the study; the following concomitant medications are not allowed: cyclophosphamide, abatacept, etanercept, adalimumab infliximab, golimumab, tofacitinib, and alemtuzumab; these medications also cannot have been used for 5 half-lives prior to enrollment Subject agrees to comply with the study requirements and agrees to come to the clinic for required study visits Exclusion Criteria: Donor lymphocyte infusion in the preceding 100 days Subject has bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia or cryptogenic organizing pneumonia as the sole manifestation of cGVHD Uncontrolled bacterial, viral infection or invasive fungal infection Evidence of malignancy within 6 months of study enrollment; this is defined as clear morphologic, radiologic or molecular evidence of disease; mixed chimerism is allowed at the discretion of the clinician Treatment with any non-Food and Drug Administration (FDA) approved agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of study enrollment Immunization with a live, attenuated vaccine within 4 weeks prior to study enrollment History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies Tuberculosis requiring treatment within the past 3 years; all patients must have a negative quantiferon test within 4 weeks prior to starting study drug Pregnant or breast-feeding women Patients (both men and women) with reproductive potential not willing to use an effective method of contraception Serum creatinine > 1.6 mg/dL (141 umol/L) in females and > 1.9 mg/dL (168 umol/L) in males; patients with serum creatinine values exceeding these limits are eligible for the study if their estimated glomerular filtration rates (GFR) are > 30 ml/min/1.73 m^2 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN) Total bilirubin > upper limit of normal (ULN) Absolute neutrophil count < 1.5 x 10^9/L (1500/mm^3) Known active hepatitis B or C; patients must have a negative test for hepatitis B surface antigen, hepatitis B core antibody and hepatitis C antibody within 4 weeks prior to starting study drug Known uncontrolled cytomegalovirus (CMV) polymerase chain reaction (PCR) reactivation per institutional standards; once CMV has been treated and stable per institutional standards, patient may be enrolled; CMV PCR will be tested within two weeks prior to starting study drug History of diverticulitis, Crohn's disease or ulcerative colitis History of demyelinating disorder

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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (tocilizumab)<br>Patients receive tocilizumab IV over 1 hour every 2 weeks for 12 weeks (weeks 1, 3, 5, 7, 9, and 11) and then every 4 weeks for 12 weeks (weeks 13, 17, and 21). | Biological: tocilizumab<br>* Given IV<br>* Other names: RoActemra;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FFS |  | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients achieving CR or PR based on objective measures, as recommended by the NIH Consensus Conference for chronic GVHD |  | At 6 months | 
| Patients achieving a CR or PR based on clinician judged response |  | At 6 months | 
| Relative change in daily prednisone dose | Prednisone is not a pre-specified intervention; however, some patients may take prednisone while on this study. | Baseline to 6 months |