Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease

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

Status Completed

Clinical Trial Summary

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.

Clinical Trial Description

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%. ;

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Anemia
• Sickle Cell Disease

• NCT number: NCT01000155
• Study type: Interventional
• Source: Dana-Farber Cancer Institute
• Status: Completed
• Phase: Phase 2
• Start date: October 2009
• Completion date: October 2014