Trial record 1 of 1 for:    NCT00427661
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A Pilot Study of HSCT for Patients With High-Risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2008 by University of Pittsburgh.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Children's Hospital of Pittsburgh
Information provided by:
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT00427661
First received: January 18, 2007
Last updated: October 16, 2008
Last verified: October 2008
  Purpose

Hypothesis 1: A novel nonmyeloablative condition regimen will be safe and efficacious in producing stable donor chimerism and cure of severe hemoglobinopathy.

Hypothesis 2: Stable donor chimerism will result in amelioration of cerebral vasculopathy, improved cerebral perfusion and neurocognitive function.

Specific Aim 1: Study the safety and efficacy of a novel non-toxic conditioning regimen for HSCT for patients with severe hemoglobinopathies and the kinetics of lineage specific chimerism after HSCT

We will test our hypothesis that a novel nonmyeloablative condition regimen will be safe and efficacious in producing stable donor chimerism and cure of severe hemoglobinopathy:

Specific Aim 2: Optimize the immunosuppressive regimen for HSCT patients through a thorough understanding of the pharmacokinetics of Busulfan (BU) and mycophenolate mofetil (MMF) in the patient population. This will involve:

  1. Determine the pharmacokinetics of intravenously and orally administered MMF and intravenous BU in patients receiving HSCT.
  2. Determine the relationship of Area under the curve (AUC) of BU and mean trough concentrations of mycophenolic acid (MPA) to engraftment and graft versus host disease (GVHD).
  3. Determine the relationship of Area under the curve (AUC) and steady state concentration of BU to engraftment at day 30 and 1 year post HSCT.

Specific Aim 3: Study the effect of complete or partial donor chimerism on silent and overt cerebral vasculopathy, and neurocognitive functioning in patients with SCD undergoing HSCT. We will test our hypothesis that stable donor chimerism will result in improvement in cerebral vasculopathy and neurocognitive function. This will include.

  1. Determine effect of transplantation silent and overt cerebral vasculopathy by comparison MRA and TCD 1 year after HSCT to pre-HSCT studies.
  2. Determine effect on HSCT on neurocognitive function. Specific Aim 4: To determine the rate of T cell immune reconstitution in children with sickle cell disease following myeloablative compared to nonmyeloablative stem cell transplantation, using immunophenotyping assays, CDR3 spectratyping TREC analysis, and measurement of T cell specific donor engraftment.

Condition Intervention
Sickle Cell Disease
Thalassemia
Hemoglobinopathies
Drug: Busulfan; Fludarabine; cyclosporine A and MMF

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With High Risk Hemoglobinopathy Using a Non-Myeloablative Preparative Regimen to Achieve Stable Mixed Chimerism

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • GVHD at 100 days, 6 months and 1 year will be tabulated by grade. [ Time Frame: 100 days, 6 months and 1 year ] [ Designated as safety issue: Yes ]
  • The incidence of ≥5% chimerism at 100 days, 6 months and 1 year will be estimated, and reported with 95% confidence bounds. [ Time Frame: 100 days, 6 months and 1 year ] [ Designated as safety issue: No ]
  • The association between % donor chimerism of lymphocytes and erythroid precursors at day 30 to % donor chimerism in the bone marrow at 1 year will be assessed via the Spearman correlation coefficient. [ Time Frame: day 30 and 1 year ] [ Designated as safety issue: No ]
  • In addition, the Wilcoxon test will be used to assess association of the % chimerism on day 30 to successful transplantation, which is defined as ≥ 5% donor chimerism in the bone marrow at 1 year. [ Time Frame: Day 30, 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: June 2002
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Busulfan; Fludarabine; cyclosporine A and MMF
    Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen
Detailed Description:

Severe hemoglobinopathies such as sickle cell disease (SCD) and Thalassemia are associated with considerable morbidity, organ damage and premature mortality. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapy that can cure a hemoglobinopathy. The applicability of HSCT for hemoglobinopathies is limited by the paucity of suitable donors, and risk of early regimen-related toxicity and the late effects. Reduction of the dose of myelotoxic drugs in preparative regimens prior to HSCT has the potential to increase the applicability of this curative option for patients with hemoglobinopathies. We hypothesize that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic stem cells in patients with severe hemoglobinopathies. The long term objective of this research is to develop novel, less toxic approaches to HSCT for patients with severe hemoglobinopathies. Specific aims: 1. To evaluate the safety and efficacy of a novel nontoxic nonmyeloablative approach to hematopoietic stem cell transplantation for hemoglobinopathies. 2. To optimize the immunosuppressive regimen for HSCT patients through a thorough understanding of the pharmacokinetics of Busulfan (BU) and Mycophenolic acid (MPA) 3. To determine the effect of partial or complete donor chimerism on cerebral vasculopathy in patients with SCD. 4. To determine the rate of T cell immune reconstitution in children with sickle cell disease following myeloablative compared to nonmyeloablative stem cell transplantation, using immunophenotyping assays, CDR3 spectratyping TREC analysis, and measurement of T cell specific donor engraftment. Subjects meeting eligibility criteria in whom an human leukocyte antigen matched, partially mismatched related or unrelated donor of bone marrow or umbilical cord blood will receive a HSCT after a nonmyeloablative preparative regimen consisting of BU, Fludarabine (FLU), total lymphoid radiation and Anti-Thymocyte globulin followed by prophylaxis against graft versus host disease with cyclosporine A and MMF. Patients will be studied for survival, cure of hemoglobinopathy, absence of severe regimen related toxicity and graft versus host disease. The relationship of engraftment, survival and Graft versus host disease to kinetics of lineage specific donor chimerism and area under the curve for Mycophenolic acid and Busulfan will be studied.

  Eligibility

Ages Eligible for Study:   3 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with SCD 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched umbilical cord blood (UCB) donor with one or more of the following:

    • Stroke, CNS hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing,
    • Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions,
    • Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism,
    • Impaired neuropsychological function and abnormal cerebral MRI scan,
    • Stage I or II sickle lung disease,
    • Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate [GFR] 30-50% of the predicted normal value),
    • Bilateral proliferative retinopathy and major visual impairment in at least one eye,
    • Osteonecrosis of multiple joints with documented destructive changes,
    • Requirement for chronic transfusions but with RBC alloimmunization >2 antibodies during long term transfusion therapy.
    • Patients with transfusion dependent Thalassemia 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched UCB donor.
  • Second Transplants

    • Patients with sickle cell disease or Thalassemia who have failed to engraft or have autologous recovery are eligible for this protocol.
    • Patients must meet above criteria.
    • If first transplant was a non-myeloablative regimen, the second transplant can occur at any time.
    • If the first transplant was a myeloablative regimen, then the second transplant must be > 6 months from the first transplant.

Exclusion Criteria:

  • Patients with one or more of the following:

    • Karnofsky or Lansky performance score <70,
    • Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy,
    • Stage III-IV lung disease,
    • GFR<30% predicted normal values.
    • Pregnant or lactating females.
  • Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or ARC or HIV seropositivity. Any patient with invasive aspergillums infection within one year of study entry.
  • Psychologically incapable of undergoing BMT with associated strict isolation or documented history of medical non-compliance.
  • Patients not able to receive TLI due to prior radiation therapy.

Donor Inclusion Criteria

  • Donor must be in good health based on review of systems and results of physical examination.
  • Donor must have a normal hemoglobin, white count, platelet count and PTT.
  • Female donors of childbearing potential must have a negative pregnancy test.

Donor Exclusion Criteria

  • Donor has active infection (including HIV, hepatitis).
  • Donor is a lactating female.

Donor Selection

In the case where more than one donor meets the eligibility criteria, donor selection will be guided by the following considerations:

  • HLA A, B, DRB1 identical sibling donor is preferable to an unrelated donor
  • Homozygous normal donor is preferable to heterozygote (carrier)
  • ABO-compatible donor is preferable to ABO-incompatible donor
  • Younger donor is preferable to older
  • Cytomegalovirus seronegative donor is preferable to CMV seropositive donor, if the patient is CMV negative
  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: NCT00427661

Contacts
Contact: Lakshmanan Krishnamurti, MD 412-692-7192 lakshmanan.krishnamurti@chp.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
Children's Hospital of Pittsburgh
Investigators
Principal Investigator: Lakshmanan Krishnamurti, MD Children's Hospital Medical Center, Cincinnati
  More Information

No publications provided

Responsible Party: Lakshmanan Krishnamurti, M. D Associate Professor Pediatrics, Childrens Hospital of Pittsburgh
ClinicalTrials.gov Identifier: NCT00427661     History of Changes
Other Study ID Numbers: IRB #0504048
Study First Received: January 18, 2007
Last Updated: October 16, 2008
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
Sickle Cell Disease
Thalassemia
Hemoglobinopathies

Additional relevant MeSH terms:
Anemia, Sickle Cell
Hemoglobinopathies
Thalassemia
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases

ClinicalTrials.gov processed this record on October 22, 2014