5-Azacytidine and Phenylbutyrate to Treat Severe Thalassemia
Status:
Completed
Trial end date:
2003-06-01
Target enrollment:
Participant gender:
Summary
This study will evaluate the safety and effectiveness of 5-azacytidine and phenylbutyrate for
treating thalassemia major. Patients with this disease have abnormal production of hemoglobin
(the oxygen-carrying protein in red blood cells), which leads to red blood cell destruction.
As a result, patients require frequent red cell transfusions over many years. Because of
these transfusions, however, excess iron is deposited in various body organs-such as the
heart, liver, thyroid gland and, in men, the testes-impairing their function.
Fetal hemoglobin-a type of hemoglobin that is produced during fetal and infant life-can
substitute for adult hemoglobin and increase the levels of red cells in the body. After
infancy, however, this type of hemoglobin is no longer produced in large quantities.
5-azacytidine can increase fetal hemoglobin levels, but this drug can damage DNA, which in
turn can increase the risk of cancer. This study will try to lessen the harmful effects of
5-azacytidine by using only one or two doses of it, followed by long-term therapy with
phenylbutyrate, a drug that may be as effective as 5-azacytidine with less harmful side
effects.
Patients 18 years of age and older with severe thalassemia major may be eligible for this
study. Before beginning treatment, candidates will have a medical history and physical
examination, blood tests, chest X-ray, electrocardiogram (EKG), bone marrow biopsy (removal
of a small sample of bone marrow from the hip for microscopic examination) and whole-body
magnetic resonance imaging (MRI). For the biopsy, the area of the hip is anesthetized and a
special needle is inserted to draw bone marrow from the hipbone. For the MRI scan, a strong
magnetic field is used to produce images that will identify sites where the body is making
red blood cells. During this procedure, the patient lies on a table in a narrow cylinder
containing a magnetic field. Earplugs are placed in the ears to muffle the loud thumping
sounds the machine makes when the magnetic fields are being switched.
An intravenous (IV) catheter (flexible tube inserted into a vein) is placed in a large vein
of the patient's neck, chest or arm for infusion of 5-azacytidine at a constant rate over 4
days. Patients who do not respond to this first dose of 5-azacytidine will be given the drug
again after about 50 days. If they do not respond to the second dose, alternate treatments
will have to be considered. Patients who respond to 5-azacytidine will begin taking
phenylbutyrate on the 14th day after 5-azacytidine was started. They will take about 10 large
pills 3 times a day, continuing for as long as the treatment is beneficial. All patients will
be hospitalized for at least 6 days starting with the beginning of 5-azacytidine therapy.
Those who are well enough may then be discharged and continue treatment as an outpatient.
Patients will be monitored with blood tests daily for 2 weeks and then will be seen weekly
for about another 5 weeks. Bone marrow biopsies will be repeated 6 days after treatment
begins and again at 2 weeks and 7 weeks. MRI will be repeated 7 weeks after treatment begins.
After 7 weeks, patients will be seen at 3-month intervals. Bone marrow biopsies will be done
every 6 months for the first 3 years after treatment. Patients will have red cell
transfusions as needed and chelation therapy to remove excess iron.
Phase:
Phase 2
Details
Lead Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)