Graft Versus Host Disease
Conditions
Brief summary
In this study the investigators are proposing to treat patients with steroid-refractory Graft-versus-host Disease (GVHD) stabilization using IL-2 and azacitidine
Detailed description
High-dose cyclophosphamide and sirolimus have been successfully used for the prevention of Graft-versus-host Disease (GVHD) and have shown to enhance the Tregs subpopulation. The addition of low dose IL-2 and a demethylating agent such as azacitidine will also be studied in an attempt to promote and stabilize the FoxP3 expression of Tregs.
Interventions
On the first day of treatment, cyclophosphamide will be administered at a dose of 4g/m2 IV x 1 dose. Patients who are \>40% above ideal weight will be dosed based on adjusted weight and adjusted BSA. One day after the administration of cyclophosphamide, patients will receive sirolimus 6 mg PO x 1 and on the following day will start sirolimus at a dose of 2 mg PO daily.
DRUGLow dose IL-2 with Cytoxan + Sirolimus
Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. IL-2 will be administered at a dose of 0.5E6 IU/m2 SQ daily x 8 weeks followed by 4 weeks off, starting 14 days after the cyclophosphamide.
DRUGLow dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus
Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza). The Vidaza will be initiated between day 27 and 32 following the cyclophosphamide. The dose administered will be 10 mg SQ daily for 5 days followed by 3 weeks off.
DRUGLow dose IL-2, Vidaza, Cytoxan & Sirolimus
Vidaza will be initiated between day 27 and 32 following the cyclophosphamide.
Sponsors
Hackensack Meridian Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as graft versus host disease (GVHD) occurring within the first 100 days of transplantation * Patients must be steroid-refractory defines as progression after 3 days of corticosteroid therapy or no response after 5 days of corticosteroid therapy. * Progression is defined as up-grading * No response is defined as no down-grading * Progression after 3 days requires patients to have received at least 2 mg/mg/day for a total of 6 mg/kg of methylprednisolone or its equivalent. * No response after 5 days requires patient to have received at least 2 mg/kg/d for a total of 10 mg/kg of methylprednisolone or its equivalent. * Patients with exacerbation of GVHD during steroid taper will require re-treatment with 2mg/kg/d of corticosteroids and will need to meet the criteria * Age 18-70 * Patients must have received an allogeneic hematopoietic stem cell transplant within 100 days of study enrollment. * Serum creatinine \< 2 mg/dL
Exclusion criteria
* Patients cannot have active central nervous system (CNS) disease. * Patients must not have received cyclophosphamide for GVHD prophylaxis * Patients must not have pneumonia requiring oxygen supplementation * Unable or unwilling to sign informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza. | 28 days to 100 days post transplant | The primary objective of this study is to determine the response rate of patients treated steroid-refractory graft-versus-host disease (GVHD) using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza with an outcome goal of promoting CD4+CD25+FoxP3+ Tregs. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichele Donato, MD
Hackensack Meridian Health
Participant flow
Recruitment details
4/11/2011 - 5/1/2013 - recruitment at Hackensack University Medical Center
Pre-assignment details
Pts.must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as GVHD (graft versus host disease) within 100 days p transplantation. Patients must be steroid-refractory defined as progression after 3 days of corticosteroid therapy or no response after 5 days of same. see study details.
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide and Sirolimus Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Cyclophosphamide and Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| other Total, other adverse events | 0 / 3 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 3 / 3 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza.
The primary objective of this study is to determine the response rate of patients treated steroid-refractory graft-versus-host disease (GVHD) using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza with an outcome goal of promoting CD4+CD25+FoxP3+ Tregs.
Time frame: 28 days to 100 days post transplant
Population: No patients were enrolled in the Low dose IL-2 with Cytoxan + Sirolimus or Low dose IL-2, Vidaza, Cytoxan \& Sirolimus arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclophosphamide and Sirolimus | Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza. | 0 Participants |