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Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders

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ClinicalTrials.gov Identifier: NCT00489281
Recruitment Status : Terminated (Initiation of CMS BMT study for sickle-cell disease operating under NCT01166009 made further accrual to this study impossible.)
First Posted : June 21, 2007
Results First Posted : April 17, 2019
Last Update Posted : April 17, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:

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 or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Cyclophosphamide Drug: Fludarabine Drug: Mycophenolate mofetil Drug: Sirolimus Procedure: Allogeneic bone marrow transplant Radiation: Total body irradiation - 200 Drug: Levetiracetam Biological: Anti-thymocyte globulin Radiation: Total body irradiation - 400 Phase 2

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.
  • 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : June 23, 2008
Actual Primary Completion Date : December 29, 2018
Actual Study Completion Date : December 29, 2018


Arm Intervention/treatment
Experimental: Transplant - 200 cGy
Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 200. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.
Drug: Cyclophosphamide
Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.
Other Names:
  • Cytoxan
  • Cy
  • CTX

Drug: Fludarabine
Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.
Other Name: Fludara

Drug: Mycophenolate mofetil
Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.
Other Names:
  • MMF
  • CellCept

Drug: Sirolimus
The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.
Other Name: Rapamune

Procedure: Allogeneic bone marrow transplant
An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
Other Name: Allo BMT

Radiation: Total body irradiation - 200
200 centigray (cGy) in one fraction on Day -1.
Other Name: TBI

Drug: Levetiracetam
Given at 500 mg PO twice daily from Day -6 to Day +365.
Other Name: Keppra

Biological: Anti-thymocyte globulin
Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.
Other Names:
  • ATG
  • Thymoglobulin

Experimental: Transplant - 400 cGy
Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 400. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.
Drug: Cyclophosphamide
Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.
Other Names:
  • Cytoxan
  • Cy
  • CTX

Drug: Fludarabine
Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.
Other Name: Fludara

Drug: Mycophenolate mofetil
Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.
Other Names:
  • MMF
  • CellCept

Drug: Sirolimus
The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.
Other Name: Rapamune

Procedure: Allogeneic bone marrow transplant
An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
Other Name: Allo BMT

Drug: Levetiracetam
Given at 500 mg PO twice daily from Day -6 to Day +365.
Other Name: Keppra

Biological: Anti-thymocyte globulin
Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.
Other Names:
  • ATG
  • Thymoglobulin

Radiation: Total body irradiation - 400
400 centigray (cGy) in one fraction on Day -1.
Other Name: TBI




Primary Outcome Measures :
  1. Transplant-related Mortality [ Time Frame: Up to one year ]
    Number of participants who died for reasons related to bone marrow transplant.

  2. Progression-free Survival [ Time Frame: 2 years ]
    Percentage of participants who are alive without relapse.


Secondary Outcome Measures :
  1. Donor Chimerism at 30 Days [ Time Frame: 30 days ]
    Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.

  2. Donor Chimerism at 1 Year [ Time Frame: 1 year ]
    Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00489281


Locations
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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Investigators
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Study Chair: Javier Bolanos-Meade, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  Study Documents (Full-Text)

Documents provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00489281     History of Changes
Other Study ID Numbers: J0676
P30CA006973 ( U.S. NIH Grant/Contract )
P01CA015396 ( U.S. NIH Grant/Contract )
NA_00002479 ( Other Identifier: JHMIRB )
First Posted: June 21, 2007    Key Record Dates
Results First Posted: April 17, 2019
Last Update Posted: April 17, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Cyclophosphamide
Fludarabine phosphate
Sirolimus
Everolimus
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Mycophenolic Acid
Vidarabine
Levetiracetam
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents