Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease

Study Overview
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Brief Summary
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This trial designed to evaluate the toxicity and efficacy of tocilizumab in the treatment of steroid refractory acute graft versus host disease (GVHD).

Detailed Description
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Patients who underwent an allogeneic hematopoietic stem cell transplantation, with biopsy proven GVHD, active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy (corticosteroids ± other agent). Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks. Patients with documented responses will continue to receive treatment at 8 mg/kg once every 3 weeks for at least two months (day 56). Patients that have some degree of response but without complete resolution of signs and symptoms of acute GVHD may continue to receive 8 mg/kg on a 3-week cycle until complete response is achieved or lack of further improvement. In patients who are beyond day 56 and whose GVHD has resolved, the dose of Tocilizumab will be reduced to 4 mg/kg every 3 weeks. Subsequent discontinuation of Tocilizumab will occur once patients are off other immune suppressive medications (including extracorporeal photopheresis, ECP) or are receiving sub therapeutic levels of immunosuppression (i.e., Tacrolimus (FK) levels <5 ng/mL) or prednisone dose <20 mg/day (or equivalent) and are free of acute GVHD signs or symptoms for at least one month. Patients who fulfill criteria of progression of GVHD not in the setting of immunosuppressive taper, no response of GVHD or require initiation of other immune suppressive treatment for GVHD will have Tocilizumab discontinued. Tocilizumab shall be discontinued and not re-instituted if any one of the following criteria is met. The patient will be taken off study drug therapy at that point, but still followed for primary and secondary study endpoints. A response assessment will be made at the time of therapy discontinuation and at subsequent defined study endpoints. The patient will not be replaced on study. Follow-up data will be required unless consent for data collection is withdrawn: Additional systemic GVHD therapy is added for disease progression or non-response Steroid dose is escalated to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone equivalent of 2 mg/kg/day) for GVHD progression or no response Development of toxicity that requires withholding of study medication for more then 14 days

Official Title
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Phase I-II Study Using Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease

Conditions
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Acute Graft Versus Host Disease

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients age 18 and older who underwent an allogeneic hematopoietic stem cell transplantation. Patients are required to have biopsy proven GVHD. Patients must have active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy. First line therapy needs to be a minimum of corticosteroids, methylprednisolone of 1.6mg/kg/day or prednisone of 2mg/kg/day, alone or combined to other agent. Failure of GVHD therapy is defined as flare of signs and symptoms of acute GVHD or progression of GVHD grade after at least 72 hours from starting therapy. No response to GVHD treatment (corticosteroids ± other agent) after a minimum of 7 days of treatment. Patient must be able to give informed consent. Exclusion Criteria: Intolerance or allergy to Tocilizumab Active uncontrolled infection requiring ongoing treatment with antifungals, antibiotics or anti-viral drugs. Relapsed/persistent malignancy requiring rapid immune suppression withdrawal. Liver enzymes: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3x upper limit of normal. Patients with severe sinusoidal obstruction syndrome who in the judgment of the treating physician are not expected to have normalized bilirubin by day 56 after enrollment. Serum bilirubin > 2x upper limit of normal.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Drug: Tocilizumab Other Names: Actemra Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks for three doses. After Day 56 doses may be decreased to 4mg/kg once every three weeks depending on GVHD response. | Drug: Tocilizumab<br>* Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks for three doses. After Day 56 doses may be decreased to 4mg/kg once every three weeks depending on GVHD response.<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 Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab | Number of subjects achieving Center for International Blood and Marrow Transplant Research (CIBMTR) score of 0 (complete response); or achieving improvement in one or more organs involved in GVHD without progression in other organs (partial response). CIBMTR score of 0 means no evidence of rash or diarrhea and bilirubin less than 2.0 mg/dl. CIBMTR score of 4 means rash with bullae desquamation, lower gastrointestinal diarrhea more than 1,500 ml, and bilirubin greater than 15.1 mg/dl. Higher score means worse disease. | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Partial, Mixed or no GVHD Responses | Number of subjects achieving improvement in one or more organs involved in GVHD with or without deterioration in another organ (mixed or partial response, respectively); or having received additional immune suppressive therapy (no response). | Day 56 | 
| GVHD Flares | Number of subjects exhibiting any progression requiring re-escalation of steroid dosing or initiation of additional topical or systemic therapy after achieving an initial complete or partial response prior to Day 90. | Day 90 | 
| Discontinuation of Immunosuppression | Number of subjects for whom immunosuppressive therapy (corticosteroid, cyclosporine, tacrolimus, sirolimus, etc.) was discontinued. This will be evaluated at Day 56, Day 180 and Day 365. | Day 56, Day 180 and Day 365 | 
| Overall Survival | Number of subjects alive at one year. | 1 year | 
| Number of Subjects Experiencing at Least One Serious Adverse Event or Grade 3 Non-serious Adverse Event | Number of subjects experiencing at least one serious adverse event or adverse event of CTCAE grade 3, 4, or 5 at Day 56 following the initiation of tocilizumab therapy. | Day 56 | 
| Disease-free Survival | Number of subjects alive and not experiencing GVHD signs or symptoms at 6 and 12 months. At the six month time point, seven subjects had expired. At the 12 month time point, 10 subjects had expired. | 6 and 12 months | 
| Non-relapse Mortality | Number of subjects expiring from causes other than relapse of GVHD disease. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute Graft versus Host Disease (aGVHD), steroid refractory acute Graft versus Host Disease (aGVHD), chronic Graft versus Host Disease (cGVHD), corticosteroids, allogeneic hematopoietic stem cell transplantation