- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00336362
Evaluating the Safety of G-CSF Mobilization in Individuals With Beta Thalassemia Major
A Pilot Study to Assess the Safety and Efficacy of G-CSF Mobilization With and Without Hydroxyurea Pretreatment in Adults With Beta Thalassemia Major
Beta thalassemia major is a serious genetic disease of the blood. Treatments are limited, and although a bone marrow transplant from a compatible donor can be curative, only a limited percentage of individuals with this disease have a matched donor available. A long-term goal of study researchers is to develop a gene transfer process as a method of curing beta thalassemia major. Gene transfer involves obtaining blood stem cells from an individual, adding a normal globin gene to the stem cells, and putting the cells back into the individual.
Before gene transfer methods can be attempted in individuals with beta thalassemia major, a safe method of obtaining blood stem cells needs to be developed. The purpose of this study is to investigate the safety and feasibility of collecting peripheral blood stem cells (PBSC) from individuals with beta thalassemia major. Research participants will be given G-CSF (filgrastim) for several days to increase the number of stem cells in the blood, a process called "mobilization." After mobilization, participants will undergo a procedure called apheresis to remove the white blood cells. Researchers in the laboratory will purify the stem cells from the mixture and test methods of putting a normal globin gene into the stem cells. Half of the participants will receive hydroxyurea (HU) prior to G-CSF mobilization. HU is used in splenectomized patients to attempt to reduce the risk of clotting during mobilization. In non-splenectomized patients, HU is given in an attempt to decrease the size of the spleen.
Study Overview
Detailed Description
Primary Objective: To determine the safety of PBSC mobilization with G-CSF, with or without HU pretreatment in adults with beta thalassemia major.
Secondary Objective: To determine the number of CD34+ stem/progenitor cells that are mobilized under these conditions, as well as the ability of these cells to be transduced with a recombinant lentivirus vector for beta-globin and engraft immunodeficient mice.
Study Design: The ability of G-CSF to safely and effectively mobilize PBSC in adults with beta thalassemia major will be assessed in 12 splenectomized and 12 non-splenectomized patients. Of the 12 splenectomized patients, 6 will be treated with HU and G-CSF, and 6 will be treated only with G-CSF. Likewise, of the 12 non-splenectomized patients, 6 will be treated with HU and G-CSF, and 6 will be treated only with G-CSF. G-CSF mobilized participants will undergo leukapheresis on 2 consecutive days, with a target yield of 2 million CD34+ cells per kg of body weight. Safety will be assessed by monitoring for study-related toxicity. Efficacy will be assessed by measuring the total number of CD34+ cells, the ability of these cells to be transduced with a recombinant lentivirus vector for beta-globin, and the ability of these cells to engraft immunodeficient mice.
Population: Adults with beta thalassemia major.
Sample size: A total of 24 subjects will be enrolled: 12 splenectomized participants and 12 non-splenectomized participants.
End Points: This is a pilot study and no specific hypotheses are being tested. However, the study will allow for qualitative comparisons if outcomes between the various arms are markedly different. For example, the study will provide qualitative data on the safety and feasibility of utilizing HU and G-CSF to mobilize stem cells in individuals with beta thalassemia major. The study will be completed upon full enrollment, or when stopping criteria are met within specific study arms.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
-
Thessaloniki, Greece
- George Papanicolaou Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- β-thalassemia major
- Karnofsky performance status greater than or equal to 80%
- Splenectomized patients or patients with spleen volume less than 800 cm^3 (V=0.523 x length x thickness x width)
- Compliant with regular transfusions and regular chelation
- Liver iron by magnetic resonance imaging (MRI) less than 280 μmol/gr or greater than or equal to 1.7 msec by T2*MRI
- Heart iron by MRI greater than 2.8 (SI/SD)or greater than or equal to 9 msec by T2*MRI
- Hepatitis B or C virus load negative by polymerase chain reaction (PCR)
- Left ventricular ejection fraction (LVEF) greater than 45% by echocardiogram or multiple gated acquisition scan (MUGA)
- Adequate respiratory function with diffusing capacity of the lung for carbon monoxide (DLCO) greater than 50%
- Negative pregnancy test, if female
- Ability to give informed consent and willingness to meet all the expected requirements of the protocol for the duration of the study
Exclusion Criteria:
- History of thrombosis or known thrombophilia
- Symptomatic viral, bacterial, or fungal infection within 6 weeks of eligibility evaluation
- Pregnant or breastfeeding
- HIV positivity
- History of cancer, other than local skin cancer
- Other systematic disease
- Splenectomized patients with platelet count greater than 900,000
- Additional risk factors for thrombosis, including Factor V Leiden; antiphospholipid antibodies; and less than 50% of the lowest normal value for the following procoagulants: antithrombin 3, protein C, or protein S
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 1
Participants will receive hydroxyurea pretreatment.
|
Hydroxyurea: Subjects will be treated for one month with hydroxyurea at a starting dose of 10 mg/kg orally (closest approximation to 500 mg capsule, alternate day dosing, e.g. 500 alternating with 1000 to achieve 750 mg average daily dose), once daily, with a gradual dose escalation up to 20 mg/kg (in non-splenectomized patients) and up to 25 mg/kg (in splenectomized patients). G-CSF: G-CSF will be administered subcutaneously. In general, G-CSF will be administered at 10μg/kg/day (5μg/kg on a twice a day schedule) for at least 4-5 days before leukapheresis and for 1-2 additional days during collections. For the splenectomized patients who are not receiving HU pretreatment, and for the splenectomized patients who receive HU pretreatment who have greater than or equal to 12,000 WBCs before G-CSF, G-CSF will start at a lower dose (for example, 1.5 or 2.5 µg/kg); the next doses will be adjusted by the Principal Investigator based on the observed degree of leukocytosis.
Other Names:
|
No Intervention: 2
Participants will not receive hydroxyurea pretreatment.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Safety of PBSC mobilization with G-CSF with or without hydroxyurea pretreatment in adults with beta thalassemia major
Time Frame: Measured at Month 2
|
Measured at Month 2
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of CD34+ stem/progenitor cells that are mobilized
Time Frame: Measured at Month 2
|
Measured at Month 2
|
Ability of the obtained stem cells to be transduced with a recombinant lentivirus vector for beta-globin and engraft immunodeficient mice
Time Frame: Measured at Year 1
|
Measured at Year 1
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: George Stamatoyannopoulos, MD, DrSci, University of Washington
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Hematologic Diseases
- Genetic Diseases, Inborn
- Anemia
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Hemoglobinopathies
- Thalassemia
- beta-Thalassemia
- Molecular Mechanisms of Pharmacological Action
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antineoplastic Agents
- Antisickling Agents
- Hydroxyurea
Other Study ID Numbers
- 464
- 2U01HL066947 (U.S. NIH Grant/Contract)
- IRB no. 27527
- EudraCT no. 2005-000315-10
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Beta-Thalassemia
-
M.D. Anderson Cancer CenterWithdrawnSickle Cell Disease | Sickle Beta Thalassemia | Beta Thalassemia Major | Sickle Cell-SS Disease | Sickle Beta 0 Thalassemia | Sickle Beta Plus ThalassemiaUnited States
-
CelgeneTerminatedBeta Thalassemia Intermedia | Beta Thalassemia MajorFrance, United Kingdom, Italy, Greece
-
University of British ColumbiaCompletedSickle Cell Disease | Beta-Thalassemia | Sickle Cell Trait | Sickle Cell-Beta Thalassemia | Sickle Cell-SS DiseaseCanada, Nepal
-
Editas Medicine, Inc.RecruitingHemoglobinopathies | Thalassemia Major | Thalassemia Intermedia | Transfusion Dependent Beta ThalassemiaUnited States, Canada
-
Ionis Pharmaceuticals, Inc.TerminatedBeta Thalassemia IntermediaAustralia, Thailand, Greece, Lebanon, Turkey
-
Agios Pharmaceuticals, Inc.Active, not recruitingTransfusion-dependent Alpha-Thalassemia | Transfusion-dependent Beta-ThalassemiaSpain, Taiwan, Thailand, United States, France, Canada, Malaysia, Germany, Netherlands, Bulgaria, United Kingdom, Turkey, Italy, Greece, United Arab Emirates, Brazil, Denmark, Lebanon, Saudi Arabia
-
Agios Pharmaceuticals, Inc.Active, not recruitingNon-Transfusion-dependent Alpha-Thalassemia | Non-Transfusion-dependent Beta-ThalassemiaSpain, Taiwan, Thailand, United Kingdom, Malaysia, United States, Netherlands, Bulgaria, Turkey, Italy, Canada, Brazil, France, United Arab Emirates, Denmark, Greece, Lebanon, Saudi Arabia
-
Children's Hospital of PhiladelphiaNot yet recruiting
-
CorrectSequence Therapeutics Co., LtdFirst Affiliated Hospital of Guangxi Medical UniversityNot yet recruiting
-
Bristol-Myers SquibbRecruiting
Clinical Trials on Hydroxyurea
-
Shiraz University of Medical SciencesCompletedCombination Therapy of Hydroxyurea With L-Carnitine and Magnesium Chloride in Thalassemia Intermediaβ-Thalassemia IntermediaIran, Islamic Republic of
-
Vanderbilt University Medical CenterAminu Kano Teaching Hospital; Murtala Muhammed Specialist HospitalCompletedStroke | Sickle Cell Disease | Sickle Cell AnemiaNigeria
-
Ain Shams UniversityUnknownThalassemia IntermediaEgypt
-
Vanderbilt University Medical CenterNational Institute of Neurological Disorders and Stroke (NINDS); Aminu Kano... and other collaboratorsCompletedStroke | Sickle Cell DiseaseNigeria
-
ItalfarmacoCompletedPolycythemia VeraItaly
-
St. Jude Children's Research HospitalTerminatedSickle Cell Disease | ThalassemiaUnited States
-
UNICANCERCompletedBrain and Central Nervous System TumorsFrance
-
St. Jude Children's Research HospitalCompleted
-
St. Jude Children's Research HospitalCompletedAnemia, Sickle CellUnited States
-
Duke UniversityCompleted