BMT Abatacept for Non-Malignant Diseases
Chronic Granulomatous Disease
Severe Congenital Neutropenia
Leukocyte Adhesion Deficiency
Severe Aplastic Anemia
Sickle Cell Disease
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
|Official Title:||Abatacept for Post-Transplant Immune Suppression in Children and Adolescents Receiving Allogeneic Hematopoietic Stem Cell Transplants for Non-Malignant Diseases|
- Tolerability of abatacept [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
The primary endpoint for this trial will be tolerability, defined in terms of the success in administering all prescribed doses of abatacept.
Abatacept will be deemed to be poorly tolerated if any of the following conditions are met:
- More than one dose is withheld.
- Death from an infection that occurs within 30 days of receiving the last prescribed dose of abatacept, but that is not preceded by systemic immunosuppressive therapy for GVHD
- Post-transplant lymphoproliferative disorder (PTLD) that occurs within 100 days of receiving the last prescribed dose, but that is not preceded by systemic immunosuppressive therapy for GVHD.
If less than 4 patients (of at least 18 evaluable patients) tolerate abatacept poorly, abatacept will be deemed tolerable. If there are fewer than 18 evaluable patients, if 3 of the first 10 patients treated tolerate abatacept poorly, abatacept will be deemed tolerable.
- Proportion of Participants experiencing Immunological effects [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
- CMV viremia defined as positive blood antigen or PCR test.
- CMV invasive disease defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.
- Post-transplant lymphoproliferative disorder (PTLD) defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures and the World Health Organization's Classification of Tumours of Haematopoietic and Lymphoid Tissues.
- Other infections defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.
- Immune reconstitution assessed by the day 100 CD4+ T cell count and by the reaccumulation of NK cells, B cells, total T cells, and CD8+ T cells as assessed by multicolor flow cytometry.
- Proportion of Participants experiencing Regimen-related toxicity [ Time Frame: Day 42 post-transplant ] [ Designated as safety issue: Yes ]RRT will be scored according to the Bearman scale. Major RRT, defined as grade 4 (causing death) in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal, neurologic or hepatic, will be recorded.
- Proportion of Participants experiencing Engraftment failure [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
- Incidence of primary and secondary graft failure.
- Time (days) to neutrophil and platelet recovery.
- Proportion of Participants experiencing Graft versus Host Disease [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
- Incidence and severity of acute and chronic GVHD, scored according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures using the NIH consensus criteria.
- Immune Suppression-Free Survival and Immune Suppression-Free/Disease-Free Survival.
- Survival Rate [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
- Disease-free survival defined as survival without recurrence of underlying disease.
- Overall survival defined as survival with or without relapse of underlying disease.
- Pharmacokinetics of abatacept [ Time Frame: Day 100 post-transplant ] [ Designated as safety issue: No ]Abatacept serum peak and trough measurements will be performed through ELISA analysis (biochemistry assay) to determine the pharmacokinetic profile.
|Study Start Date:||January 2014|
|Estimated Study Completion Date:||January 2020|
|Estimated Primary Completion Date:||January 2018 (Final data collection date for primary outcome measure)|
4 doses of abatacept 10 mg/kg/dose will be given on days -1, +5, +14, and +28.
All patients will receive 4 doses of abatacept in addition to standard GVHD prophylaxis with cyclosporine and mycophenolate mofetil.
Other Name: Orencia
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only viable cure for children who suffer from a wide variety of rare, serious non-malignant diseases, such as Fanconi Anemia, Hurler syndrome, and hemophagocytic lymphohistiocytosis. A major obstacle to the success of HSCT is morbidity and mortality from graft versus host disease (GVHD), driven by donor T cells recognizing and reacting against disparate host antigens. This trial is being conducted as a step toward testing the long-term hypothesis that the costimulation blockade agent abatacept can be added to a standard post-transplant GVHD prophylaxis regimen, cyclosporine and mycophenolate mofetil, to improve disease-free survival after unrelated hematopoietic stem cell transplantation (HSCT) using reduced intensity conditioning for children with non-malignant diseases (NMD). This study will have the following Specific Aims:
Specific Aim #1: To conduct a multicenter pilot assessing the tolerability of abatacept (n=20). Patients will receive four doses (10 mg/kg IV on days -1, +5, +14 and +28), a schedule well tolerated by adolescents and adults with hematologic malignancies in a previous pilot. Abatacept will be combined with cyclosporine and mycophenolate mofetil.
Specific Aim #2: To examine the immunological effects of abatacept in this setting.
Three reduced intensity conditioning regimens that have been shown to be effective in achieving sustained engraftment in patients with non-malignant diseases are available for use, depending on the patient's disease:
- Patients with Fanconi anemia will receive fludarabine, low dose cyclophosphamide, and anti-thymocyte globlulin.
- Patients with severe aplastic anemia will receive low dose total body irradiation, fludarabine, cyclophosphamide, and anti-thymocyte globlulin.
- Patients with other NMD will receive either the low dose total body irradiation regimen or an alemtuzmab, fludarabine, thiotepa, and melphalan regimen.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01917708
|Contact: Jaclyn Smith, MBAfirstname.lastname@example.org|
|United States, Georgia|
|Children's Healthcare of Atlanta||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Jaclyn Smith, MBA 404-785-0692 email@example.com|
|Principal Investigator: Elizabeth Stenger, MD|
|Principal Investigator:||Elizabeth Stenger, MD||Children's Healthcare of Atlanta/Emory University|