Acute Graft Versus Host Disease
Conditions
Keywords
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
Brief summary
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
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 Follow-up data will be required unless consent for data collection is withdrawn: * Additional systemic GVHD therapy is added for disease progression or non-response * Steroid dose is escalated to ≥ 2.5 mg/kg/day of prednisone (or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
Interventions
DRUGTocilizumab
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.
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab | Day 56 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Partial, Mixed or no GVHD Responses | Day 56 | 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). |
| GVHD Flares | Day 90 | 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. |
| Discontinuation of Immunosuppression | Day 56, Day 180 and Day 365 | 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. |
| Overall Survival | 1 year | Number of subjects alive at one year. |
| Number of Subjects Experiencing at Least One Serious Adverse Event or Grade 3 Non-serious Adverse Event | Day 56 | 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. |
| Disease-free Survival | 6 and 12 months | 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. |
| Non-relapse Mortality | 6 months | Number of subjects expiring from causes other than relapse of GVHD disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab 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.
Tocilizumab: 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. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 10 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Study closed for safety | 3 |
Baseline characteristics
| Characteristic | Tocilizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 13 |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 13 / 13 |
Outcome results
Primary
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.
Time frame: Day 56
Population: 6 of the thirteen subjects were not evaluable due to expiring prior to Day 56.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Number of Subjects Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab | 7 Participants |
Secondary
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.
Time frame: Day 56, Day 180 and Day 365
Population: Six subjects expired prior to day 56.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tocilizumab | Discontinuation of Immunosuppression | Day 56 | 0 Participants |
| Tocilizumab | Discontinuation of Immunosuppression | Day 180 | 0 Participants |
| Tocilizumab | Discontinuation of Immunosuppression | Day 365 | 1 Participants |
Secondary
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.
Time frame: 6 and 12 months
Population: For this analysis, all thirteen participants originally meeting eligibility criteria were included for evaluation of survival status. Living patients were evaluated for symptoms.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tocilizumab | Disease-free Survival | 6 Month Timepoint | 4 Participants |
| Tocilizumab | Disease-free Survival | 12 Month Timepoint | 3 Participants |
Secondary
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.
Time frame: Day 90
Population: Six subjects expired prior to day 90.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | GVHD Flares | 1 Participants |
Secondary
Non-relapse Mortality
Number of subjects expiring from causes other than relapse of GVHD disease.
Time frame: 6 months
Population: All thirteen subjects meeting the initial eligibility criteria were included for evaluation of survival status and cause of death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Non-relapse Mortality | 8 Participants |
Secondary
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).
Time frame: Day 56
Population: Six subjects expired prior to day 56.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Number of Patients With Partial, Mixed or no GVHD Responses | 2 Participants |
Secondary
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.
Time frame: Day 56
Population: Six subjects expired prior to day 56.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Number of Subjects Experiencing at Least One Serious Adverse Event or Grade 3 Non-serious Adverse Event | 7 Participants |
Secondary
Overall Survival
Number of subjects alive at one year.
Time frame: 1 year
Population: For this analysis, all thirteen subjects meeting eligibility criteria were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tocilizumab | Overall Survival | 3 Participants |