Abatacept as GVHD Prophylaxis Phase 2

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Emory University
Sponsor:
Information provided by (Responsible Party):
Leslie Kean, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT01743131
First received: December 4, 2012
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

This is a phase II multi-center, randomized, double blind, placebo-controlled trial.

The investigators are doing this study to see if a new drug, abatacept, can be used together with a calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate to provide better protection against Acute Graft versus Host Disease (aGvHD) without causing more infections.

Funding Source - FDA OOPD


Condition Intervention Phase
Graft vs Host Disease
Malignancy
Drug: Abatacept
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: Abatacept Combined With a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease Prophylaxis: A Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Cumulative incidence of severe aGVHD at day +100 post-transplant in the standard and investigational study arms [ Time Frame: First 100 days after transplant ] [ Designated as safety issue: Yes ]
    The primary analysis will consist of estimating the cumulative incidence of severe aGVHD at day +100 post-transplant in the standard and investigational study arms. All registered patients will be considered for this analysis. The primary null hypothesis of the study is that there will be no difference in severe aGVHD between the investigational and standard GVHD prophylaxis arms. The primary outcome will be assessed in a final analysis to be performed after the last enrolled patient has been followed for 100 days post-transplant. The cumulative incidence and confidence interval will be calculated. The cumulative incidence will be compared between treatment arms using logistic regression models. Relapse will be considered a competing risk for aGVHD to negate the effect of measures, such as withdrawal of immune suppression and donor-lymphocyte infusion, often used in response to relapse.


Secondary Outcome Measures:
  • A cumulative incidence of serious infection, engraftment, relapse, and overall survival will be computed. [ Time Frame: 5 years post transplant ] [ Designated as safety issue: Yes ]
    A cumulative incidence of infection, serious infection, CMV viremia, CMV invasive disease, EBV viremia, PTLD, BK viremia and disease, adenovirus viremia and disease, engraftment of: neutrophils, platelets, lymphocyte count, total T cell counts, CD4+ T cell counts, and CD8+ T cell counts, secondary graft failure, graft rejection, all grades of early and late aGvHD, overlap syndrome, chronic GvHD, RRT, TRM, DFS, immunosuppression-free survival, immunosuppressive-free/relapse-free survival, relapse, and OS.


Estimated Enrollment: 104
Study Start Date: February 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm A- Placebo
Arm A-standard GVHD prophylaxis with a calcineurin inhibitor, methotrexate and placebo
Drug: placebo
Active Comparator: Arm B- Abatacept
Arm B-investigational prophylaxis with abatacept, a calcineurin inhibitor and methotrexate
Drug: Abatacept
Arm B-investigational prophylaxis with abatacept, a calcineurin inhibitor and methotrexate
Other Name: Orencia

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   6 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Must be at least 6 years old and weigh 20 kg.
  2. Must have a willing unrelated adult donor (bone marrow or peripheral blood). Donors may have a single mismatch (i.e. be a 7/8) and this mismatch may be at the allele or antigen level; however, donors with allele level disparity should be given preference over those with antigen level disparity. The use of mismatched donors in which disparity is only in the host versus graft direction (because of recipient homozygosity) is discouraged because of the potentially heightened risk for graft rejection. Centers may perform extended typing (e.g. DQB1 and DPB1) according to institutional practices and use these results in selecting donors; however, it is recommended that this extending typing be used only to select between donors who are equally well matched with the recipient at the A, B, C and DRB1.
  3. 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.
  4. Must have a high risk hematologic malignancy as defined below:

    1. Acute myeloid leukemia (AML).
    2. Myelodysplastic syndrome

    (i) Adult patients (≥21 years) must meet criteria for intermediate, high or very high-risk disease based on the World Health Organization classification based prognostic scoring system.

Intermediate risk (2 points), high risk (3-4 points), very high risk (4-5 points)

  • RA = refractory anemia, RARS = refractory anemia with ringed sideroblasts, RCMD = refractory cytopenia with multilineage dysplasia, RCMD-RS = refractory cytopenia with multilineage dysplasia and ringed sideroblasts, RAEB-1 = refractory anemia with excess of blasts-1 (5-9% blasts), RAEB-2 = refractory anemia with excess of blasts-2 (10-19% blasts).
  • *Karyotype: Good = normal, -Y, del(5q), del(20q), Poor = complex (≥ 3 abnormalities), chromosome 7 anomalies, Intermediate = other abnormalities.

    • *RBC transfusion requirement = having ≥ 1 RBC transfusion every 8 weeks over a 4-month period.

(ii) Pediatric patients with MDS, regardless of subtype, will be eligible.

(c) Acute lymphoblastic leukemia (ALL). (i) Given the poor prognosis of adults (≥21 years) with ALL, adults in 1st or greater complete remission will be eligible.. CR is defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Complete remissions without platelet recovery (CRp) will be considered remissions (ii) Given the generally good prognosis of children (<21 years) with ALL, they will have to meet one of the criteria listed below. Additionally, children who are enrolled on a COG ALL trial for newly diagnosed or relapsed disease will have to meet the criteria for BMT outlined in that trial. CR is defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Complete remissions without platelet recovery (CRp) will be considered remissions.

  1. In 1st complete remission with a very high risk for relapse.

    1. Haplodiploidy (<44 chromosomes)
    2. >1% residual marrow blasts by flow cytometry at the end of induction.
    3. >0.01% residual marrow blasts by flow cytometry at the end of consolidation.
    4. Early T-Cell Precursor (ETP) phenotype
  2. In 2nd complete remission with B-lineage disease after a marrow relapse occurring less than 36 months from diagnosis.
  3. In 2nd complete remission with T-lineage disease or Ph+ disease after a marrow relapse occurring at any time.
  4. In a 2nd complete remission with T-lineage disease after an extra-medullary relapse occurring less than 18 months from diagnosis.
  5. In 3rd or greater complete remission after a marrow or extramedullary relapse

    (d) Patients with acute undifferentiated, biphenotypic, or bilineal leukemia, which is in 1st or greater complete remission (CR) or partial remission (PR). Cr will be defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. CR without platelet recovery (CRp) will be considered complete remissions.) PR will be defined as an M2 marrow (5-19% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L.).

    (e) Chronic myelogenous leukemia (CML). (i) Chronic phase with resistance to tyrosine kinase inhibitors. (ii) accelerated phase (development of cytogenetic abnormality in addition to t(9:22), blood blast percentage ≥10, blood basophil percentage ≥20, platelet count <100,000 X 109/L) (iii) blast crisis. (iv) 2nd or greater chronic phase.

    (f) Acute Lymphoblastic Lymphoma in 2nd or greater complete remission. Complete remission includes confirmed complete response (CR) defined as the disappearance of all evidence of disease from all sites for at least 4 weeks. Bone marrow and CSF must be normal and any macroscopic nodules in any organs detectable on imaging techniques should no longer be present. Imaging should include PET scanning. CR will also include unconfirmed complete responses defined as a residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 75% in sum of the products of the greatest perpendicular diameters (SPD), or any residual lesions in organs that have decreased by > 75%, with a negative PET scan, negative bone marrow and CSF.

    (g) Peripheral T cell lymphoma (PTCL).

    (h) Chronic lymphocytic leukemia (CLL) (i) Newly diagnosed disease with 17p- (ii) Disease beyond first CR that has been treated with a fludarabine containing regimen.

    (i) Chronic myelomonocytic leukemia.

    (j) Atypical (BCR-ABL negative) chronic myelogenous leukemia

    (k) Hodgkin lymphoma that has recurred or progressed after an autologous BMT. Disease must be chemosensitive; salvage chemotherapy must produce at least a partial response.

    (l) Non-Hodgkin lymphomas that has recurred or progressed after an autologous BMT.

Exclusion Criteria:

  1. Prior allogeneic HSCT.
  2. The patient is enrolled on a COG trial that uses criteria for unrelated donor HSCT, which conflict with our eligibility criteria.
  3. The patient is enrolled on a COG trial that utilizes unrelated donor HSCT and requires that patients be transplanted using an approach specified by the protocol that is in conflict with the approach specified in this protocol.
  4. Availability of a willing and suitable HLA identical related donor.
  5. Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
  6. HIV infection.
  7. Serious psychiatric disease including schizophrenia, bipolar disorder and severe depression.
  8. Inherited marrow failure syndrome, including, but not limited to Fanconi Anemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome.
  9. Known inherited or constitutional predisposition to cancer including, but not limited to Li-Fraumeni syndrome, Down syndrome and BRCA1 and BRCA2 mutations.
  10. Incompletely treated active tuberculosis Infection.
  11. Pregnancy (positive serum b-HCG) or breastfeeding.
  12. Estimated GFR of < 50 mL/min/1.73m2.
  13. Cardiac ejection fraction < 50.
  14. bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved veno-occlusive disease.
  15. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected for hemoglobin) or requiring supplemental oxygen. Children who are developmentally unable to perform pulmonary function testing will be assessed solely on their need for supplemental oxygen.
  16. Karnofsky performance score or Lansky Play-Performance Scale score <80
  17. Presence of antibodies to a mismatched donor HLA antigen
  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: NCT01743131

Contacts
Contact: Sindy Midoro 404-785-1441 sindy.midoro@choa.org
Contact: Jackie Smith 404-785-0692 jaclyn.smith@choa.org

Locations
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Lamis Eldjerou, MD    352-273-5941    leldjerou@peds.ufl.edu   
Principal Investigator: Lamis Eldjerou, MD         
United States, Georgia
Emory University/Winship Cancer Center Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jaclyn Smith    404-785-0692    jaclyn.smith@choa.org   
Contact: Audrey Grizzle    404-785-2125    audrey.grizzle@choa.org   
Principal Investigator: Leslie Kean, MD, PhD         
Children's Healthcare of Atlanta at Egleston Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jaclyn Smith    404-785-0692    jaclyn.smith@choa.org   
Contact: Audrey Grizzle    404-785-2125    audrey.grizzle@choa.org   
Principal Investigator: Leslie Kean, MD, PhD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sung Won Choi, MD    734-232-8838    sungchoi@med.umich.edu   
Principal Investigator: Sung Won Choi, MD         
United States, Missouri
Washington University Recruiting
St. Louis, Missouri, United States, 63141
Contact: Shalini Shenoy, MD    314-454-6018    Shenoy@kids.wustl.edu   
Principal Investigator: Shalini Shenoy, MD         
United States, Ohio
Michael Grimley Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Michael Grimley, MD    513-636-5917    michael.grimley@cchmc.org   
Principal Investigator: Michael Grimley, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84113
Contact: Michael Pulsipher, MD    801-662-4700    Michael.pulsipher@hsc.utah.edu   
Principal Investigator: Michael Pulsipher, MD         
United States, Washington
Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98101
Contact: Leslie S Kean, MD/PhD    206-884-4079    leslie.kean@seattlechildrens.org   
Principal Investigator: Leslie S Kean, MD,PhD         
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Leslie Kean, MD, PhD Seattle Children's Hospital
  More Information

No publications provided

Responsible Party: Leslie Kean, Associate Professor, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT01743131     History of Changes
Other Study ID Numbers: IRB00058187, Abatacept Phase 2, Aba2, FDA R01 #4099-01
Study First Received: December 4, 2012
Last Updated: April 25, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Graft vs Host Disease
Immune System Diseases
Methotrexate
Abatacept
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 26, 2014