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Abatacept for GVHD Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease

This study is currently recruiting participants.
See Contacts and Locations
Verified August 2016 by Monica Bhatia, Columbia University
Sponsor:
Information provided by (Responsible Party):
Monica Bhatia, Columbia University
ClinicalTrials.gov Identifier:
NCT02867800
First received: August 11, 2016
Last updated: August 16, 2016
Last verified: August 2016
  Purpose
To assess the tolerability of the costimulation blocking agent abatacept (CTLA4-Ig) when added to the standard graft versus host disease (GVHD) prophylaxis regimen of a calcineurin inhibitor and methotrexate in patients receiving early alemtuzumab followed by fludarabine, thiotepa, melphalan, and alemtuzumab for conditioning.

Condition Intervention Phase
Sickle Cell Disease Graft Versus Host Disease Drug: Diphenhydramine Drug: Acetaminophen Drug: Methylprednisolone Drug: Meperidine Drug: Alemtuzumab Drug: Thymoglobulin Drug: Fludarabine Drug: Melphalan Drug: Thiotepa Drug: Cyclosporine Drug: Tacrolimus Drug: Methotrexate Drug: Abatacept Procedure: Marrow infusion Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Abatacept for Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease: a Sickle Transplant Alliance for Research Trial

Resource links provided by NLM:


Further study details as provided by Monica Bhatia, Columbia University:

Primary Outcome Measures:
  • Number of patients who tolerated abatacept [ Time Frame: Within 100 days of receiving the last prescribed dose of abatacept ]

    Patients will be deemed to be evaluable for tolerability if they received all prescribed doses of abatacept.

    Abatacept will deemed to be tolerated, if no more than one dose is withheld per protocol stipulations, no death from an infection that occurs within 30 days of or develops post-transplant lymphoproliferative disease (PTLD) within 100 days of receiving the last prescribed dose of abatacept.



Secondary Outcome Measures:
  • Bearman Scale Score of Regimen-Related Toxicity (RRT) [ Time Frame: Day 42 post-transplant ]
    RRT will be assessed according to Bearman Scale.

  • Number of infections [ Time Frame: Up to 180 days post transplant ]
    Infections will include viremia, posttransplant lymphoproliferative disease and immune reconstitution.


Estimated Enrollment: 10
Study Start Date: July 2016
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Standard GVHD Prophylaxis + Abatacept

Subjects will receive

  • premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed)
  • immunosuppression (Alemtuzumab, or Thymoglobulin)
  • conditioning regimen (Fludarabine, Thiotepa, and Melphalan)
  • GVHD prophylaxis: calcineurin inhibitor (Cyclosporine, or Tacrolimus) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0.
Drug: Diphenhydramine

(Standard of Care) Premedication

Diphenhydramine: 1 mg/kg IV or PO q 8 hours (maximum=50 mg)

Other Name: Benadryl
Drug: Acetaminophen

(Standard of Care) Premedication

Acetaminophen: 10-15 mg/kg PO q 6 hours (maximum=1000 mg)

Other Name: Tylenol
Drug: Methylprednisolone

(Standard of Care) Premedication

Methylprednisolone: 0.25-0.5 mg/kg IV q 6 hours

Other Name: Medrol
Drug: Meperidine

(Standard of Care) Premedication

Use as needed (PRN) Meperidine: 0.5 mg/kg IV q 4-6 hours (for rigors)

Other Name: Demerol
Drug: Alemtuzumab

(Standard of Care) Immunosuppression

Alemtuzumab:

A test dose of alemtuzumab, 3 mg, should be administered IV over 2 hours the first day. If the test dose is tolerated, administration of three treatment doses should begin within 24 hours. The three treatment doses should be administered on consecutive days. 10 mg/m2 should be given the first day, 15 mg/m2 the second and 20 mg/m2 the third.

Other Name: Lemtrada
Drug: Thymoglobulin

(Standard of Care) Immunosuppression

Thymoglobulin: A 4 mg/kg dose of anti-thymocyte globulin should be administered in place of each alemtuzumab dose not completed.

Other Name: Genzyme
Drug: Fludarabine

(Standard Conditioning Regimen)

Fludarabine should be administered 30 mg/m2 IV daily for five days. It should be infused over 30 to 60 minutes.

Other Name: Fludara
Drug: Melphalan

(Standard Conditioning Regimen)

Melphalan should be administered 140 mg/m2 IV 3 days before marrow infusion. It should be infused within 60 minutes of preparation and over a maximum of 30 minutes. It should be infused immediately after the fludarabine infusion is complete.

Other Name: Alkeran
Drug: Thiotepa

(Standard Conditioning Regimen)

Thiotepa should be administered 8 mg/kg IV 3 days before marrow infusion. It should be infused immediately after the fludarabine infusion is complete. The thiotepa should be infused over one hour.

Other Name: Thioplex
Drug: Cyclosporine

(Standard GVHD Prophylaxis) Calcineurin inhibitor

Cyclosporine: Administration will commence no later than at least 36 hours before marrow infusion; Cyclosporine doses will be adjusted to maintain a level of 150-300 ng/ml.

Other Name: Neoral
Drug: Tacrolimus

(Standard GVHD Prophylaxis) Calcineurin inhibitor

Tacrolimus: Administration will commence no later than at least 36 hours before marrow infusion; Tacrolimus doses will be adjusted to maintain a level of 8-15 ng/ml.

Other Name: Protopic
Drug: Methotrexate

(Standard GVHD Prophylaxis)

Methotrexate will be given at a dose of 15 mg/m2 IV on day 1 and a dose of 10 mg/m2 IV on days 3, 6 and 11. Dosing shall be based on actual weight.

Other Name: Trexall
Drug: Abatacept

(Investigational)

Abatacept will be administered intravenously at a dose of 10 mg/kg based on actual weight with a maximum of 750 mg. In cases where the calculated dose is less than or equal to 110% of a simple multiple of a 250 mg vial: 250 mg (275mg), 500 mg (550 mg) or 750 mg (825 mg), the dose may be rounded down to the nearest multiple. No rounding up of the abatacept dose is permitted.

Other Names:
  • CTLA4-Ig
  • Orencia
Procedure: Marrow infusion

(Standard)

A procedure that infuses healthy cells, called stem cells, into your body to replace damaged or diseased bone marrow. A bone marrow transplant may also be used to treat certain types of cancer

Other Name: stem cell transplant

Detailed Description:
Outcomes of hematopoietic stem cell transplantation (HSCT) for children and adolescents with sickle cell disease (SCD) have improved. Graft versus host disease (GVHD), however, remains a barrier to success. GVHD accounts for most of the transplant related mortality and much of the morbidity in this setting-in part through the injury it directly causes and in part through the deleterious effects of steroids and the other immunosuppressive agents used to prevent and treat it. The results of pre-clinical studies and a phase I clinical study in patients with hematologic malignancies suggest that the costimulation blocking agent CTLA4-Ig may hold promise an agent for GVHD prophylaxis. In the present trial, we are assessing the tolerability of adding abatacept to standard GVHD prophylaxis-a calcineurin inhibitor and methotrexate-in pediatric SCD patients receiving early alemtuzumab (completed by day -18) followed by fludarabine, thiotepa, and melphalan for conditioning. This trial will provide the foundation for subsequent trials designed to test the long-term hypothesis that abatacept is a safe, steroid-sparing effective adjunct to standard GVHD prophylaxis in this setting.
  Eligibility

Ages Eligible for Study:   3 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with Hgb SS or SB0 thalassemia between the ages of 3 and 20.99 years who are at least 10 kg getting an HLA matched bone marrow transplant, will be eligible if they are at increased risk for GVHD and have severe SCD.

    (a) Patients falling into one of the following three groups will be considered to be at increased risk for GVHD:

    (i) Are between 10 and 20.99 years and receiving their transplant from an HLA matched related donor.

    (ii) Are between 3 and 9.99 years and receiving their transplant from an HLA matched related donor who is at least 10 years.

    (iii) Are between 3 and 20.99 years and receiving their transplant from an HLA matched unrelated donor. Donors must be matched at the A, B, C and DRB1 loci at the allele level.

    (b) 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:

    • 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.
    • 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 ( ≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting ≥ 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 ( ≥ 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.

    (v) Any combination of ≥ 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.

  2. All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
  3. Must have been evaluated and adequately counseled regarding treatment options for severe SCD by a pediatric hematologist.
  4. Because of the elective and non-urgent nature of HSCT for SCD, it is important that all patients and families be counseled regarding fertility preservation measures available to them. All patients and/or their parents or legal guardians must indicate on the consent and assent forms that they have received this counseling.

Exclusion Criteria:

  1. Bridging (portal to portal) fibrosis or cirrhosis of the liver.
  2. Parenchymal lung disease stemming from SCD or other process defined as a DLCO (corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
  3. Renal dysfunction with an estimated GFR < 50% of predicted normal for age.
  4. Cardiac dysfunction with shortening fraction < 25%.
  5. Neurologic impairment other than hemiplegia, defined as full-scale IQ ≤70, quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in decline of Lansky performance score to < 70%.
  6. Clinical stroke within 6 months of anticipated transplant.
  7. Karnofsky or Lansky functional performance score < 70%.
  8. Patient is HIV infected.
  9. Donor is HIV infected.
  10. Donor has Hgb SS, SC or SB0 thalassemia.
  11. Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
  12. Patient or patient's guardian(s) unable to understand the nature and risks inherent in the BMT process.
  13. History of lack of compliance with medical care that would jeopardize transplant course.
  14. Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
  15. Active viral, bacterial, fungal or protozoal infection.
  16. Donor is pregnant.
  17. Patient is pregnant.
  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 ClinicalTrials.gov identifier: NCT02867800

Contacts
Contact: Elana Smilow, NP 212-305-8443 eha9001@nyp.org
Contact: Jean Sosna, RN 212-305-2050 js4403@columbia.edu

Locations
United States, District of Columbia
Children's National Medical Center Not yet recruiting
Washington DC, District of Columbia, United States, 20010
Contact: Divyesh Kukadiya    202-476-6850    dkukadiy@childrensnational.org   
Principal Investigator: Allistair Abraham, MD         
United States, Georgia
Children's Healthcare of Atlanta Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Megan Hanby    404-785-7749    Megan.Hanby@choa.org   
Principal Investigator: Ann Haight, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Joseph Laskowski    312-227-4871    jlaskowski@luriechildrens.org   
Principal Investigator: Sonali Chaudhury, MD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Elana Smilow, NP    212-305-8443    eha9007@nyp.org   
Principal Investigator: Monica Bhatia, MD         
United States, North Carolina
North Carolina Cancer Hospital Not yet recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Juanita Cuffee    919-962-8733    cuffee@med.unc.edu   
Principal Investigator: Kimberly Kasow, MD         
United States, Ohio
Nationwide Children's Hospital Not yet recruiting
Columbus, Ohio, United States, 43205
Contact: Kelly Reynolds    614-722-3558    kelly.reynolds@nationwidechildrens.org   
Principal Investigator: Hemalatha Rangarajan, MD         
Canada, Alberta
Alberta Children's Hospital Not yet recruiting
Calgary, Alberta, Canada, T3B 6AB
Contact: Pina Giuliano    403-955-7269    Pina.Giuliano@albertahealthservices.ca   
Principal Investigator: Greg Guilcher, MD         
Sponsors and Collaborators
Monica Bhatia
Investigators
Study Chair: Monica Bhatia, MD Columbia University
  More Information

Responsible Party: Monica Bhatia, Associate Professor of Pediatrics at the Columbia University Medical Center, Columbia University
ClinicalTrials.gov Identifier: NCT02867800     History of Changes
Other Study ID Numbers: AAAQ2350
Study First Received: August 11, 2016
Last Updated: August 16, 2016
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Monica Bhatia, Columbia University:
Sickle Cell Disease
Graft Versus Host Disease
Abatacept
Hematopoietic Stem Cell Transplantation

Additional relevant MeSH terms:
Graft vs Host Disease
Anemia, Sickle Cell
Immune System Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Methotrexate
Fludarabine phosphate
Cyclosporine
Promethazine
Tacrolimus
Cyclosporins
Melphalan
Abatacept
Thiotepa
Vidarabine
Fludarabine
Alemtuzumab
Methylprednisolone Hemisuccinate
Prednisolone
Calcineurin Inhibitors
Acetaminophen
Meperidine
Diphenhydramine
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone

ClinicalTrials.gov processed this record on June 26, 2017