Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease

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%.

Inclusion Criteria:

- Diagnosis of sickle cell disease

- Clinically significant disease defined as at least 1 painful episode per year
averaged over the previous 3 years or a history of priapism, stroke, acute chest
syndrome, avascular necrosis, multi-organ failure or the need for chronic narcotic
medications for pain from sickle cell disease

- Must have failed a previous attempt at treatment with hydroxyurea defined as the
inability to achieve a significant absolute increase in % fetal hemoglobin or the
inability to tolerate hydroxyurea treatment due to severe side effects such as but
not limited to myelosuppression, gastrointestinal symptoms, edema or hepatic enzyme
elevations or have contraindications to hydroxyurea

- 18 years of age or older

- Hematologic laboratory values as outlined in the protocol

- Non-hematologic laboratory values as outlined in the protocol

- Must agree not to donate blood or other bodily fluid while taking the study drug and
for 28 days thereafter

- Women of child-bearing potential (WCBP) must have a negative serum pregnancy test 72
hours or less prior to starting treatment

- Women of child-bearing potential and men must agree to use 2 forms of adequate
contraception prior to study entry and for the duration of study participation

Exclusion Criteria:

- Subjects with hemoglobin SC or SB+ thalassemia

- Subjects on chronic transfusion program

- Subjects who have received RBC transfusions cannot have >15% adult hemoglobin

- Known positive status for HIV, active hepatitis B or hepatitis C

- Pregnant or breast feeding women

- Individuals with a history of malignancy are ineligible except for the following
circumstances. Individuals with a history of malignancy are eligible if they have
been disease-free for at least 5 years and are deemed by the investigator to be at
low risk for recurrence of that malignancy. Individuals with the following cancer are
eligible if diagnosed and adequately treated within the past 5 years: cervical or
breast cancer in situ, and basal cell or squamous cell carcinoma of the skin

- Subjects with a history of thrombosis or other reason (other than sickle cell
disease) for enhanced thrombotic risk

- Subjects with unresolved infections

- Severe or uncontrolled medical conditions that could compromise study participation

- Subjects on fetal hemoglobin inducing agents

- Subjects on any other experimental treatment within 90 days of the first dose of
study drug or who have not recovered from the side effects of such therapy

- Known allergic reaction to a histone deacetylase inhibitor

- Subjects who have received valproic acid for treatment of epilepsy within 30 days of
enrollment

- Subjects who have received any HDAC inhibitors other than valproic acid