BMT Abatacept for Non-Malignant Diseases
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01917708|
Recruitment Status : Active, not recruiting
First Posted : August 7, 2013
Last Update Posted : November 6, 2018
|Condition or disease||Intervention/treatment||Phase|
|Hurler Syndrome Fanconi Anemia Glanzmann Thrombasthenia Wiskott-Aldrich Syndrome Chronic Granulomatous Disease Severe Congenital Neutropenia Leukocyte Adhesion Deficiency Shwachman-Diamond Syndrome Diamond-Blackfan Anemia Dyskeratosis-congenita Chediak-Higashi Syndrome Severe Aplastic Anemia Thalassemia Major Hemophagocytic Lymphohistiocytosis Sickle Cell Disease||Drug: Abatacept||Phase 1|
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 globulin.
- Patients with severe aplastic anemia will receive low dose total body irradiation, fludarabine, cyclophosphamide, and anti-thymocyte globulin.
- Patients with other NMD will receive either the low dose total body irradiation regimen or an alemtuzumab, fludarabine, thiotepa, and melphalan regimen.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (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|
|Study Start Date :||January 2014|
|Estimated Primary Completion Date :||September 29, 2019|
|Estimated Study Completion Date :||September 29, 2019|
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
- Tolerability of abatacept [ Time Frame: 1 year post-transplant ]
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 ]
- Cytomegalovirus (CMV) viremia defined as positive blood antigen or polymerase chain reaction (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 natural killer (NK) cells, B cells, total T cells, and CD8+ T cells as assessed by multicolor flow cytometry.
- Proportion of Participants experiencing regimen-related toxicity (RRT) [ Time Frame: Day 42 post-transplant ]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 ]
- 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 ]
- 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 ]
- 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 ]Abatacept serum peak and trough measurements will be performed through ELISA analysis (biochemistry assay) to determine the pharmacokinetic profile.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01917708
|United States, Georgia|
|Children's Healthcare of Atlanta|
|Atlanta, Georgia, United States, 30322|
|Principal Investigator:||John T Horan, MD||Children's Healthcare of Atlanta/Emory University|