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BMT Abatacept for Non-Malignant Diseases

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Emory University
Information provided by (Responsible Party):
Elizabeth Stenger, Emory University Identifier:
First received: July 24, 2013
Last updated: August 16, 2016
Last verified: August 2016
This is a single arm phase I study to assess the tolerability of abatacept when combined with cyclosporine and mycophenolate mofetil as graft versus host disease prophylaxis in children undergoing unrelated hematopoietic stem cell transplant for serious non-malignant diseases as well as to assess the immunological effects of abatacept.

Condition Intervention 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
Chediak-Higashi Syndrome
Severe Aplastic Anemia
Thalassemia Major
Hemophagocytic Lymphohistiocytosis
Sickle Cell Disease
Drug: Abatacept
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by Emory University:

Primary Outcome Measures:
  • 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.

Secondary Outcome Measures:
  • 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.

Estimated Enrollment: 20
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)
Arms Assigned Interventions
Experimental: Abatacept
4 doses of abatacept 10 mg/kg/dose will be given on days -1, +5, +14, and +28.
Drug: Abatacept
All patients will receive 4 doses of abatacept in addition to standard GVHD prophylaxis with cyclosporine and mycophenolate mofetil.
Other Name: Orencia

Detailed Description:

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.

Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Must be between the ages of 0-21 years at the time of admission for transplant.
  • Must have one of the following diseases:

    1. Glanzmann thrombasthenia
    2. Wiskott-Aldrich syndrome or other combined immune deficiency
    3. Chronic-granulomatous disease
    4. Severe congenital neutropenia (with resistance to GCSF or chronic requirement of GCSF doses ≥10 mcg/kg)
    5. Leukocyte adhesion deficiency
    6. Shwachman-Diamond syndrome
    7. Diamond-Blackfan anemia ((transfusion dependent, including steroid failure or inability to wean steroids)
    8. Thalassemia major
    9. Fanconi anemia
    10. Hemophagocytic lymphohistiocytosis (inherited or acquired refractory to therapy or with recurrent episodes of hyperinflammation)
    11. Dyskeratosis-congenita
    12. Hurler Syndrome
    13. Chediak-Higashi syndrome
    14. Acquired (immune; non-inherited, non-congenital) severe aplastic anemia
    15. Other inherited or congenital marrow failure syndromes complicated by severe aplastic anemia
    16. Other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy.
    17. Congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years).
    18. Other inherited or congenital granulocyte disorders resulting in at least three inpatient hospitalizations in the past three years for infection.
    19. SCD (Hgb SS or S-Beta 0 thalassemia) will be eligible between ages 3 and 9.99 and with severe disease. Patients who meet one of the following criteria will qualify as having severe SCD:

    (i) Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.

(ii) Asymptomatic cerebrovascular disease, as evidenced by one the following:

  1. Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
  2. Cerebral arteriopathy, as evidenced by abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV > 200 cm/sec for non-imaging TCD) or by significant vasculopathy on MRA (greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).

(iii) Frequent (greater than or equal to 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting greater than or equal to 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.

(iv) Recurrent (greater than or equal to 3 in lifetime) acute chest syndrome events which have necessitated erythtocyte transfusion therapy.

(v) Any combination of greater than or equal to 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.

  • Must have an unrelated adult donor (marrow or PBSC) who is matched at least seven of eight HLA alleles (A, B, C, DRB1; the mismatch can be at an allele or antigen level)* or an unrelated cord blood unit that is matched at least seven of eight loci (A, B and C antigen level-DRB1 allele level) and provides a minimum pre-cryopreservation TNC dose of 7.5 x 107 TNC/kg recipient weight. Mismatches at the DRB1 locus may be at an antigen or allele level.

Exclusion Criteria:

  • Human leukocyte antigen (HLA) matched related donor.
  • Severe combined immune deficiency.
  • Bridging (portal to portal) fibrosis or cirrhosis of the liver.
  • Pulmonary: DLCO (corrected for hemoglobin), FEV1 or FVC < 40% of predicted. In child unable to perform pulmonary function testing, a chronic need for supplemental oxygen will serve as the exclusionary criterion.
  • Severe renal dysfunction defined as estimated GFR of <60 ml/min/1.73m2.
  • Severe cardiac dysfunction defined as shortening fraction < 25%.
  • Neurologic impairment other than hemiplegia, defined as full-scale IQ less than or equal to 70, quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in decline of Lansky performance score to < 70%.
  • Clinical stroke within 6 months of anticipated transplant.
  • Karnofsky or Lansky functional performance score < 50%
  • HIV infection.
  • Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
  • Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
  • Patient or patient's guardian(s) unable to understand the nature and risks inherent in the blood and marrow transplant process.
  • History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.
  • Patient is pregnant or lactating
  • Patients HLA antibody testing demonstrates an antibody directed against a disparate HLA molecule.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01917708

Contact: Jaclyn Smith, MBA 404-785-0692

United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jaclyn Smith, MBA    404-785-0692   
Principal Investigator: Elizabeth Stenger, MD         
Sponsors and Collaborators
Emory University
Principal Investigator: Elizabeth Stenger, MD Children's Healthcare of Atlanta/Emory University
  More Information

Responsible Party: Elizabeth Stenger, Assistant Professor, Emory University Identifier: NCT01917708     History of Changes
Other Study ID Numbers: IRB00069836 
Study First Received: July 24, 2013
Last Updated: August 16, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Emory University:
non malignant conditions
blood and marrow transplant

Additional relevant MeSH terms:
Wiskott-Aldrich Syndrome
Anemia, Sickle Cell
Anemia, Aplastic
Fanconi Anemia
Fanconi Syndrome
Granulomatous Disease, Chronic
Anemia, Diamond-Blackfan
Lymphohistiocytosis, Hemophagocytic
Mucopolysaccharidosis I
Dyskeratosis Congenita
Chediak-Higashi Syndrome
Bone Marrow Diseases
Exocrine Pancreatic Insufficiency
Pathologic Processes
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Genetic Diseases, Inborn
Leukocyte Disorders processed this record on October 21, 2016