TerminatedNCT01000155Updated Jul 21, 2017Results posted

Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease

A Phase 2 interventional study of vorinostat in Sickle Cell Disease and Sickle Cell Anemia, sponsored by Dana-Farber Cancer Institute. Terminated at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-07-21.

Sponsored by Dana-Farber Cancer Institute · Phase 2, Interventional, and Treatment

Why this study was terminated

The study terminated early due to slow accrual.

Phase: Phase 2
Study type: Interventional
Enrollment: 5
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the detailed 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%.

Conditions studied

Sickle Cell Disease
Sickle Cell Anemia

Browse trials for

Anemia, Sickle Cell 1,103

Keywords

fetal hemoglobin
vorinostat
HDAC inhibitor
SAHA

In context

Anemia, Sickle Cell

1,103 studies on the registry are indexed under Anemia, Sickle Cell; 235 are open to participants now.

This study's enrollment of 5 is below the median of 40 across 750 interventional studies indexed under Anemia, Sickle Cell.

Browse Anemia, Sickle Cell studies →

Lead sponsor

Dana-Farber Cancer Institute is the lead sponsor of 813 studies on the registry; 124 are open to participants now.

Of its 113 completed or terminated interventional studies of FDA-regulated products, 77 (68%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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

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

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 5 participants (actual)

Study arms

Experimental
Vorinostat
Patients received vorinostat in a pulsed fashion, once a day for 3 consecutive days every week to a maximum dose of 400 mg per dose (1200 mg/wk), for 12 to 16 weeks at the maximum dose. The first 3 patients were enrolled in an intrapatient dose escalation schedule of 100 mg/d, then 200 mg/d, each for 3 consecutive days a week for 4 weeks, and then 400 mg/d, 3 consecutive days per week for 16 weeks. The last 2 patients were enrolled to receive 400 mg/d, 3 consecutive days per week for 12 weeks, without an initial dose escalation.
Drug: vorinostat

Interventions

Drugvorinostat
Also known as: SAHA

What researchers measure

Primary outcomes

Percent Fetal Hemoglobin (HbF%) Induction Success Rate
Success will be defined by comparing the maximum HbF% on study drug to the HbF% at baseline. An absolute increase in HbF% of 4% of more, or an increase to 100% or more of baseline in patients with HbF under 4% at baseline will be considered a success. HbF% induction success rate is calculated as the count of successes divided by the count of patients in the analysis population.
Time frame: HbF% was measured at baseline and weekly on treatment. Median duration of treatment was 3 months.

Secondary outcomes

F-Cell Percentage Level
F-cell percentage levels were estimated based on established methods.
Time frame: Measured at baseline and end of treatment, up to 16 weeks.
γ-globin to β-globin Ratio
Levels of peripheral blood γ-globin to β-globin messenger RNA were estimated based on established methods. The ratio of γ-globin to β-globin was then calculated.
Time frame: Measured at baseline and end of treatment, up to 16 weeks.

Results

Posted Oct 8, 2015

Limitations and caveats

The trial did not meet it's accrual goal due to slow accrual.

Participant flow

Participant flow — Overall Study
Milestone	Vorinostat
Started	5
Completed	3
Not completed	2
Withdrew: Withdrawal by subject	1
Withdrew: Adverse event	1

Outcome measures

PrimaryPercent Fetal Hemoglobin (HbF%) Induction Success Rate

Success will be defined by comparing the maximum HbF% on study drug to the HbF% at baseline. An absolute increase in HbF% of 4% of more, or an increase to 100% or more of baseline in patients with HbF under 4% at baseline will be considered a success. HbF% induction success rate is calculated as the count of successes divided by the count of patients in the analysis population.

Time frame:: HbF% was measured at baseline and weekly on treatment. Median duration of treatment was 3 months.
Reported as:: Number · proportion of patients

Percent Fetal Hemoglobin (HbF%) Induction Success Rate
proportion of patients	Vorinostat
Percent Fetal Hemoglobin (HbF%) Induction Success Rate	0.20 (.01 to .65)

SecondaryF-Cell Percentage Level

F-cell percentage levels were estimated based on established methods.

Time frame:: Measured at baseline and end of treatment, up to 16 weeks.
Reported as:: Median · F-cell percentage

F-Cell Percentage Level
F-cell percentage	Vorinostat
Baseline	9.8 (NA to NA)
End of Treatment	12.1 (NA to NA)

Secondaryγ-globin to β-globin Ratio

Levels of peripheral blood γ-globin to β-globin messenger RNA were estimated based on established methods. The ratio of γ-globin to β-globin was then calculated.

Time frame:: Measured at baseline and end of treatment, up to 16 weeks.
Reported as:: Median · Change in γ-globin to β-globin ratio

γ-globin to β-globin Ratio
Change in γ-globin to β-globin ratio	Vorinostat
γ-globin to β-globin Ratio	0.89 (0.34 to 1.4)

Adverse events

Collected over Assessed weekly throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 3 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Vorinostat	—	1/5 (20%)	4/5 (80%)

Most frequent serious events

Most frequent serious events
Event	Vorinostat
Constitutional, otherGeneral disorders	1/5

Most frequent other events

Most frequent other events
Event	Vorinostat
Necrosis, pancreasGastrointestinal disorders	1/5
IV116Renal and urinary disorders	1/5
Ascites (non-malignant)Gastrointestinal disorders	1/5
Stenosis (incl anastomotic) duodenumGastrointestinal disorders	1/5
BilirubinInvestigations	1/5
AlkalosisMetabolism and nutrition disorders	1/5
SweatingSkin and subcutaneous tissue disorders	1/5

Baseline characteristics

The analysis dataset is comprised of all treated patients.

Age, Continuous
Age, Continuous(years)	Vorinostat
Median	37 (21 to 44)

Sex: Female, Male
Sex: Female, Male(Participants)	Vorinostat
Female	3
Male	2

Region of Enrollment
Region of Enrollment(Participants)	Vorinostat
United States	5

Study locations

3 sites

Brigham and Women's Hospital
Boston, Massachusetts 02115, United States
Children's Hospital Boston
Boston, Massachusetts 02115, United States
Dana-Farber Cancer Institute
Boston, Massachusetts 02115, United States

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jul 21, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01000155
Lead sponsor: Dana-Farber Cancer Institute
Collaborators: Brigham and Women's Hospital, Boston Children's Hospital, Merck Sharp & Dohme LLC
Responsible party: Maureen Okam, MD, MPH (Associate Physician, Dana-Farber Cancer Institute) — Principal investigator
First posted: Oct 22, 2009
Start date: Oct 2009
Primary completion: Oct 2014
Completion: Oct 2014
Results posted: Oct 8, 2015
Last update: Jul 21, 2017

Study contacts

Maureen Okam, MD, MPH

principal investigator · Brigham and Women's Hospital

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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This study is terminated, as verified in Jun 2017. You cannot join it, but the record below documents what was studied.

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