Sickle Cell Disease Clinical Trial
Official title:
A Phase II Pharmacodynamic Investigation of the Efficacy of Vorinostat to Induce Fetal Hemoglobin in Adults With Severe Sickle Cell Disease Who Have Not Benefitted From Prior Therapy
Sickle Cell Disease (SCD) is a hereditary anemia that causes the red blood cells to change their shape from a round and doughnut-like shape to a half-moon/crescent, or sickled shape. People who have SCD have a different type of hemoglobin (protein that carries oxygen). This different type of hemoglobin makes the red blood cells change into a crescent shape under certain conditions. Sickle-shaped cells are a problem because they often get stuck in the blood vessels blocking the flow of blood and can cause inflammation and injury to important areas of the body. All babies are born with hemoglobin called fetal hemoglobin (HbF). Soon after birth, HbF production slows down and another hemoglobin called adult hemoglobin (HbA) is made. Clinical studies have shown that increasing the amount of HbF in the blood may prevent sickling of the red blood cells. Vorinostat has been used in the treatment of cancers and in other research studies and information from those suggests that it may help treat SCD by increasing the amount of HbF in the blood. The purpose of this research study is to determine the effectiveness and safety of vorinostat when used to treat SCD.
OBJECTIVES:
Primary
- To determine the efficacy of vorinostat (suberoylanilide hydroxamic acid, SAHA), when
administered orally, in a pulsed fashion, once-a-day for 3 consecutive days every week,
in inducing a 4% absolute increase or a 100% increase in fetal hemoglobin percent
levels (HbF%) in subjects with severe sickle cell disease who have failed prior
therapy.
- To characterize the safety and tolerability.
Secondary
- To assess the effect of vorinostat on F-cell levels.
- To determine the changes in y-globin, B-globin and E-globin RNA levels during treatment
with vorinostat.
- To describe the dose-response characteristics of vorinostat in inducing fetal
hemoglobin in sickle cell disease.
Exploratory
- To determine the extent and duration of global histone acetylation with intermittent
vorinostat dosing.
- To correlate the status of polymorphisms near the BCL11A, c-myb, and HBB gene loci, all
of which are associated with levels of fetal hemoglobin, to assess for an association
of polymorphism status with therapeutic response to vorinostat.
- To evaluate red blood cell rheology before and after treatment with vorinostat.
STATISTICAL DESIGN:
This was a single stage design to evaluate induction of HbF on treatment with target
enrollment of 15 patients. A 25% success rate was considered evidence of activity in this
patient population while 5% success rate deemed ineffective. If at least 3 patients achieved
success, the treatment would be considered promising. With 15 eligible patients, the
probability of observing this was 0.76 assuming a true rate of 25% and 0.04 assuming a true
rate of 5%.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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