Graft vs Host Disease
Conditions
Keywords
GVHD
Brief summary
To study the effectiveness of an immunosuppressive drug sirolimus, in the treatment of chronic graft versus host disease in combination with prednisone.
Detailed description
The purpose of this trial is to study the effectiveness of an immunosuppressive drug, sirolimus, in the treatment of chronic graft versus host disease in combination with prednisone. Graft versus host disease (GVHD) is a common complication in patients who have received blood or marrow transplantation from a related or unrelated donor. Chronic GVHD occurs approximately 100 days after transplantation and is the result of the donor immune system recognizing the patient's tissues as foreign and creating harmful effects on the patient's organs. We hope the use of sirolimus will decrease the significant disabling effects and deaths caused by chronic GVHD.
Interventions
DRUGSirolimus
Patients will receive sirolimus at 2 mg/day orally with monitoring of trough drug levels weekly for 2 weeks to achieve trough drug levels 7-12 ng/ml. Along with prednisone therapy.
DRUGPrednisone
Prednisone therapy will remain at the dose the patient received at the time sirolimus was begun. Withdrawal of prednisone will began after first evidence of improvement of chronic GVHD.
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 13 years * Weight ≥ 40 kg. * Biopsy or clinical presentation diagnostic of chronic GVHD \>100 days following allogeneic bone marrow/peripheral blood/umbilical cord blood transplantation that has failed prior corticosteroid therapy or corticosteroid taper. In the event that histological confirmation poses undue risk, clinical evaluation is sufficient. * Women of child-bearing potential must have a negative pregnancy test before sirolimus administration and agree to use a medically acceptable contraceptive throughout the treatment period until 3 months after discontinuation of sirolimus. * Any woman becoming pregnant during the treatment period must discontinue the use of sirolimus. * Absolute neutrophil count (ANC) \> 1000/mm³, unless receiving G-CSF to maintain neutrophil count \> 500/mm³. * At the time of initiating sirolimus the cyclosporine trough level is recommended to be \< 100 mg/dl and FK506 level is recommended to be \< 5 mg/dl. FK506 or cyclosporine is to be discontinued soon after initiation of sirolimus. * Karnofsky performance score ≥ 50 during pre-study screening. * Written, signed, and dated informed consent
Exclusion criteria
* Uncontrolled systemic infection * Unstable disease states (i.e., hepatic failure, ventilatory-dependent respiratory failure, etc.) * Serum creatinine ≥ 3.0 mg/dL * Platelet count ≤ 50,000/mm³ * History of Post-transplant microangiopathic hemolytic anemia * Uncontrolled hyperlipidemia * Use of any investigational drug within 4 weeks of entry into the study * Use of methotrexate or antibody therapies within 24 hours of sirolimus administration * Inability to tolerate oral therapy for any reason * Evidence of infiltrate, cavitation, or consolidation on chest x-ray during pre-study screening * Known hypersensitivity to macrolide antibiotics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Activity | 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus | Determined by discontinuation of immunosuppression with resolution of all reversible CGVHD manifestations. Evaluated at 2 years after enrollment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus | Administration of Sirolimus and Prednisone |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Administration of Sirolimus and Prednisone | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Enrolled | Adverse Event | 9 |
| Enrolled | Death | 1 |
| Enrolled | Ineligible | 1 |
| Enrolled | Loss insurance | 1 |
| Enrolled | Withdrawal by Subject | 1 |
| Remained on Study Median of 514 Days | Death | 2 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 5 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 14 / 35 |
Outcome results
Primary
Clinical Activity
Determined by discontinuation of immunosuppression with resolution of all reversible CGVHD manifestations. Evaluated at 2 years after enrollment
Time frame: 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus
Population: 23 patients that remained on the study for a median of 514 days (96-814 days). Numbers based on resolution/ improvement in clinical manifestations of cGVHD with a median of 90% reduction in prednisone dose and no additional immunosuppressive therapy over a two year treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus Therapy | Clinical Activity | Complete Remission | 4 participants |
| Sirolimus Therapy | Clinical Activity | Partial Remission | 4 participants |
Secondary
Overall Survival
Administration of Sirolimus and Prednisone
Time frame: 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus
Population: 23 patients that remained on the study for a median of 514 days (96-814 days), 2 died (1- second cancer and 1- progressive cardiac failure)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus Therapy | Overall Survival | 21 participants |