Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute Graft Versus Host Disease (aGVHD) During Transplant

The recruitment status of this study is unknown because the information has not been verified recently.
Verified November 2009 by Emory University.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
Emory University
ClinicalTrials.gov Identifier:
NCT01012492
First received: November 11, 2009
Last updated: November 12, 2009
Last verified: November 2009
  Purpose

The primary objective of the study is to determine the safety and tolerability when adding abatacept to acute Graft versus Host Disease in transplants for malignant diseases using unrelated donor bone marrow or peripheral blood stem cell grafts.


Condition Intervention Phase
AML
ALL
Undifferentiated Leukemia
Biphenotypic Leukemia
Refractory Anemia
Refractory Anemia With Ringed Sideroblasts
Refractory Cytopenia With Multilineage Dysplasia
Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts
Refractory Anemia With Excess Blasts-1 (5-10% Blasts)
Refractory Anemia With Excess Blasts-2 (10-20% Blasts)
Myelodysplastic Syndrome, Unclassified
MDS Associated With Isolated Del (5q)
Drug: Abatacept
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor Hematopoietic Stem Cell Transplant

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Safety and tolerability of the addition of abatacept to aGvHD prophylaxis in transplants for malignant hematologic disease using unrelated donor bone marrow or peripheral blood stem cell grafts. [ Time Frame: 3 years after transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence and severity of aGvHD in patients receiving the abatacept-based protocol. [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
  • Immune phenotype of donor cells in patients receiving abatacept. [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
  • The ability of donor T-cells in patients receiving abatacept to respond to both polyclonal and recipient-specific immune stimulation. [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 10
Study Start Date: November 2009
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abatacept
Participants will receive one of two standard myeloablative conditioning regimens for their stem cell transplant, and will receive an aGvHD prophylaxis regimen including cyclosporine, methotrexate, and abatacept.
Drug: Abatacept
Participants will receive one of two standard myeloablative conditioning regimens for their stem cell transplant, and will receive an aGvHD prophylaxis regimen including cyclosporine, methotrexate, and abatacept.

Detailed Description:

Acute Graft versus Host Disease (aGvHD) is the most deadly complication facing children who have allogeneic hematopoietic stem cell transplant (HSCT). aGvHD occurs, in large part, because the T cells in the bone marrow graft do not "accept" the presence of the transplant recipient's cells, and mount a severe, debilitating, and often deadly attack against the recipient, striking the skin, the liver, and the gastrointestinal track, most prominently. For patients receiving bone marrow from an unrelated donor, the rate of aGvHD can reach as high as 80%, with up to half of patients dying from this complication. These serious outcomes occur despite our best efforts at aGvHD prevention. Given the lack of success in preventing aGvHD with current therapies, novel therapies to prevent this disease are desperately needed.

In this study, we plan to test a novel drug to prevent aGvHD. This drug, known as abatacept, specifically blocks the activation pathway critical to T cell function known as "T cell costimulation." In particular, it blocks the CD28-mediated costimulation pathway that is critical for optimal T cell activation and proliferation. My research group has done extensive pre-clinical work with this compound. Our work has demonstrated its efficacy in inducing immune tolerance after transplantation in both mouse models and primate models. In addition, patient trials have demonstrated that blocking CD28-directed T cell costimulation can prevent T cell-mediated diseases, including rheumatoid arthritis and psoriasis, and can improve solid organ transplant acceptance. Abatacept is currently FDA approved for use in rheumatoid arthritis. Given this drug's safety and efficacy profile, we have been granted an IND-exemption from the FDA for the inclusion of abatacept in a GvHD-prevention strategy.

This is a safety and tolerability study of the addition of abatacept to a GvHD-prophylaxis regimen. Thus, the primary objective of the study is to determine the safety and tolerability of the addition of abatacept to aGvHD prophylaxis in transplants for malignant hematologic disease using unrelated donor bone marrow or peripheral blood stem cell grafts.

Three secondary objectives will also be addressed:

  1. We will estimate the incidence and severity of aGvHD in patients receiving the abatacept-based protocol.
  2. We will determine the immune phenotype of donor cells in patients receiving abatacept.
  3. We will determine the ability of donor T-cells in patients receiving abatacept to respond to both polyclonal and recipient-specific immune stimulation.

These secondary objectives will allow us to determine the impact of abatacept-containing GvHD prevention on both T cell alloreactivity and on T cell-mediated protective immunity.

This study is for patients older than 12 who have been diagnosed with high-risk leukemia and for whom an unrelated bone marrow transplant is planned. We plan to enroll 10 patients on the study, over a 1-year period from the opening of the trial. Of these ten patients, at least five will be pediatric patients; the other five may be from adult patients taken care of by Winship Cancer Center physicians. All clinical study coordination and biologic studies will be performed by CHOA personnel.

Participants will receive one of two standard myeloablative conditioning regimens for their stem cell transplant, and will receive an aGvHD prophylaxis regimen including cyclosporine, methotrexate, and abatacept. They will have immunologic analysis for 1 year after transplant and clinical analysis for 3 years after transplant.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with AML, with or without a history of myelodysplastic syndrome in one of the following categories.

    (a) Patients in first complete remission with high-risk features

  2. Patients with ALL, in either of the following categories:

    1. In 2nd or greater complete remission (complete remission is defined as > 5% blasts in marrow)
    2. Delayed 1st CR-Failure to achieve complete remission after a single round of induction therapy
  3. Patients with undifferentiated or biphenotypic leukemia in 1st or greater complete remission.
  4. Patients with Myelodysplastic Syndrome(s) with an IPSS score of >1.5 and <10% blasts in the bone marrow at the time of transplant. These conditions will include:

    1. Refractory anemia
    2. Refractory anemia with ringed sideroblasts
    3. Refractory cytopenia with multilineage dysplasia
    4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
    5. Refractory anemia with excess blasts-1 (5-10% blasts)
    6. Refractory anemia with excess blasts-2 (10-20% blasts)
    7. Myelodysplastic syndrome, unclassified
    8. MDS associated with isolated del (5q)
    9. Patients diagnosed with AML in CR1 after an initial diagnosis of MDS.
  5. Age 12 years or older.
  6. No prior allogeneic transplant
  7. Karnofsky performance score or Lansky Play-Performance of at least 80.
  8. Signed informed consent for adults and for minors the provision of pediatric assent and parental permission.

Exclusion Criteria:

  1. Age <12 years old.
  2. Patients requiring >2 courses of induction chemotherapy to achieve remission status.
  3. HIV infection
  4. Tuberculosis Infection
  5. Chronic Obstructive Pulmonary Disease
  6. Pregnancy (positive serum b-HCG) or breastfeeding
  7. Creatinine clearance or nuclear medicine GFR of < 50 mL/min
  8. Cardiac ejection fraction < 50%
  9. bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved veno-occlusive disease.
  10. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected for hemoglobin) or O2 saturation <92% on room air.
  11. Karnofsky performance score or Lansky Play-Performance Scale <80
  12. Uncontrolled viral, bacterial, or fungal infection at the time of study enrollment
  13. Availability of a willing and fully MHC-matched related donor.
  14. Positive cytotoxic recipient-donor cross-match or positive HLA antibody screen against donor-disparate antigens.
  15. Any active infection.
  16. Unable to obtain informed consent.
  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: NCT01012492

Contacts
Contact: Sindy Midoro 404-785-1441 sindy.midoro@choa.org
Contact: Cindy Couture 404-785-2125 cynthia.couture@choa.org

Locations
United States, Georgia
Emory University -Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Sindy Midoro    404-785-1441    sindy.midoro@choa.org   
Contact: Cindy Couture    404-785-2125    cynthia.couture@choa.org   
Principal Investigator: Leslie Kean, MD, PhD         
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Sindy Midoro    404-785-1441    sindy.midoro@choa.org   
Contact: Cindy Couture    404-785-2125    cynthia.couture@choa.org   
Principal Investigator: Leslie Kean, MD, PhD         
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Leslie Kean, MD, PhD Emory University
  More Information

No publications provided

Responsible Party: Leslie Kean/Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT01012492     History of Changes
Other Study ID Numbers: Abatacept
Study First Received: November 11, 2009
Last Updated: November 12, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by Emory University:
cancer
leukemia
transplant
bone marrow

Additional relevant MeSH terms:
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Graft vs Host Disease
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid, Acute
Hematologic Diseases
Bone Marrow Diseases
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Precancerous Conditions
Leukemia, Myeloid
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 01, 2014