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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01917708
Recruitment Status : Recruiting
First Posted : August 7, 2013
Last Update Posted : May 17, 2018
Information provided by (Responsible Party):
Elizabeth Stenger, Emory University

Brief Summary:
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 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

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 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 2018
Estimated Study Completion Date : January 2020

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Proportion of Participants experiencing Immunological effects [ Time Frame: 1 year post-transplant ]
    • 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.

  2. Proportion of Participants experiencing Regimen-related toxicity [ 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

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 identifier (NCT number): NCT01917708

Contact: Ashley Griffin 404-785-0653
Contact: Chanta Whitlow 4047850696

United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Ashley Griffin    404-785-0653   
Principal Investigator: Elizabeth Stenger, MD         
Sponsors and Collaborators
Emory University
Principal Investigator: Elizabeth Stenger, MD Children's Healthcare of Atlanta/Emory University

Responsible Party: Elizabeth Stenger, Assistant Professor, Emory University Identifier: NCT01917708     History of Changes
Other Study ID Numbers: IRB00069836
First Posted: August 7, 2013    Key Record Dates
Last Update Posted: May 17, 2018
Last Verified: May 2018

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

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