Fludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By Donor Bone Marrow Transplant in Treating Patients With Sickle Cell Anemia and Other Blood Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00489281
First received: June 20, 2007
Last updated: March 23, 2014
Last verified: March 2014
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by a donor bone marrow transplant works in treating patients with sickle cell anemia and other blood disorders.


Condition Intervention Phase
Sickle Cell Disease
Biological: G-CSF
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: Sirolimus
Procedure: Allogeneic bone marrow transplantation
Radiation: total-body irradiation
Drug: Levetiracetam
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Anemia and Other Hemoglobinopathies

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Transplant-related mortality at day 100 and 1 year after bone marrow transplantation (BMT) [ Time Frame: 1 year after bone marrow transplant ] [ Designated as safety issue: No ]
  • Risk-stratified estimates of 2-year progression-free survival [ Time Frame: 2 years from bone marrow transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to recovery of circulating neutrophils and platelets after chemotherapy [ Time Frame: 60 days from bone marrow transplant ] [ Designated as safety issue: No ]
  • Donor chimerism at 30, 60, 180, and 365 days after bone marrow transplant [ Time Frame: 1 year from bone marrow transplant ] [ Designated as safety issue: No ]
  • Development of graft-vs-host disease [ Time Frame: 1 year from bone marrow transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: May 2007
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: G-CSF
    Donors will receive subcutaneous injections in the stomach (or other fatty area of the body) of G-CSF at 10 μg/kg/day for 5 consecutive days until the day of the harvest, the day we collect bone marrow for the transplant.
    Other Name: Filgrastim®
    Drug: cyclophosphamide
    Cyclophosphamide (CTX) 14.5 mg/kg intravenously for 2 days before and after transplant.
    Drug: fludarabine phosphate
    Fludarabine 30 mg/M2 intravenously for 5 days before bone marrow transplant
    Drug: mycophenolate mofetil
    Mycophenolate mofetil 15 mg/kg by mouth three times a day daily for 30 days beginning 5 days after bone marrow transplant.
    Drug: Sirolimus
    The first dose of Sirolimus is 6 mg and is taken by mouth 5 days after bone marrow transplant. On the 6th day after bone marrow transplant, the dose of Sirolimus is 2 mg by mouth daily for 1 year.
    Procedure: Allogeneic bone marrow transplantation
    An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
    Radiation: total-body irradiation
    Radiation of the total body will be administered the day before bone marrow transplant.
    Drug: Levetiracetam
    Levetiracetam 500 mg orally twice a day 6 days before transplant and for 1 year after transplant. Levetiracetam prevents seizures.
    Other Name: Keppra
Detailed Description:

OBJECTIVES:

  • Determine the transplant-related mortality and progression-free survival of patients with severe hemoglobinopathies receiving nonmyeloablative conditioning comprising fludarabine phosphate, cyclophosphamide, and total-body irradiation followed by partially HLA-mismatched bone marrow transplantation from first-degree relatives or HLA-matched donors.
  • Characterize donor hematopoietic chimerism at 30, 60, and 180 days after transplantation in these patients.
  • Determine the hematologic and non-hematologic toxicity of this regimen in these patients.

OUTLINE:

  • Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients also undergo total-body irradiation on day -1.
  • Bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Donors receive filgrastim (G-CSF) subcutaneously beginning on day -5 to day -1.
  • Graft-versus-host disease prophylaxis: Patients receive sirolimus orally daily on days 5-365 and oral mycophenolate mofetil 3 times a day on days 5-35.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   2 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following sickle cell anemias (Hb SS):

    • Hb S/β° thalassemia
    • Hb S/β+ thalassemia
    • Hb SC disease
    • Hb SE disease
    • Hb SD disease
    • Hemoglobin SO-Arab disease
    • Hb S/hereditary persistence of fetal hemoglobin
  • Meets 1 of the following criteria:

    • History of invasive pneumococcal disease
    • Stroke or CNS event lasting > 24 hours
    • MRI changes indicative of brain parenchymal damage
    • Evidence of cerebrovascular disease by magnetic resonance angiography
    • Acute chest syndrome requiring exchange transfusion or hospitalization
    • Recurrent vaso-occlusive pain crisis (> 2 per year for the last 2 years)
    • Stage I or II sickle lung disease
    • Sickle retinopathy
    • Osteonecrosis
    • Red cell alloimmunization (> 2 antibodies) during long-term transfusion
    • Constellation of dactylitis in the first year of life AND a baseline hemoglobin < 7 g/dL and leukocytosis (WBC > 13.4/mm^3) in the absence of infection during the second year of life
    • Pitted RBC count > 3.5% during the first year of life
  • Ineligible for or refused bone marrow transplantation from an HLA-matched sibling donor
  • Partially mismatched (at least haploidentical) first-degree relative donor available

    • No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100%
  • LVEF ≥ 35%
  • FEV_1 and forced vital capacity ≥ 40% predicted
  • Direct bilirubin < 3.1 mg/dL
  • No moderate to severe pulmonary hypertension by ECHO
  • No debilitating medical or psychiatric illness that would preclude study participation
  • No HIV positivity
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • No prior transfusions from donor
  • No immunosuppressive agents, including steroids as antiemetics, within 24 hours after the last dose of post-transplantation cyclophosphamide
  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: NCT00489281

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231-2410
Contact: Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce    410-955-8804    jhcccro@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Study Chair: Javier Bolanos-Meade, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00489281     History of Changes
Other Study ID Numbers: J0676 CDR0000540593, P30CA006973, P01CA015396, JHOC-J0676, JHOC-NA_00002479
Study First Received: June 20, 2007
Last Updated: March 23, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
sickle cell disease

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Cyclophosphamide
Mycophenolate mofetil
Fludarabine phosphate
Sirolimus
Everolimus
Fludarabine
Mycophenolic Acid
Etiracetam
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Enzyme Inhibitors
Antibiotics, Antineoplastic
Anticonvulsants

ClinicalTrials.gov processed this record on September 14, 2014