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Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01000155
Recruitment Status : Terminated (The study terminated early due to slow accrual.)
First Posted : October 22, 2009
Results First Posted : October 8, 2015
Last Update Posted : July 21, 2017
Brigham and Women's Hospital
Boston Children's Hospital
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Maureen Okam, MD, MPH, Dana-Farber Cancer Institute

Brief 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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Sickle Cell Anemia Drug: vorinostat Phase 2

Detailed Description:



  • 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.


  • 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.


  • 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.


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%.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : October 2009
Actual Primary Completion Date : October 2014
Actual Study Completion Date : October 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Vorinostat

Arm Intervention/treatment
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
Other Name: SAHA

Primary Outcome Measures :
  1. Percent Fetal Hemoglobin (HbF%) Induction Success Rate [ Time Frame: HbF% was measured at baseline and weekly on treatment. Median duration of treatment was 3 months. ]
    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.

Secondary Outcome Measures :
  1. F-Cell Percentage Level [ Time Frame: Measured at baseline and end of treatment, up to 16 weeks. ]
    F-cell percentage levels were estimated based on established methods.

  2. γ-globin to β-globin Ratio [ Time Frame: Measured at baseline and end of treatment, up to 16 weeks. ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   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:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01000155

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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Boston Children's Hospital
Merck Sharp & Dohme Corp.
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Principal Investigator: Maureen Okam, MD, MPH Brigham and Women's Hospital
Additional Information:
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Responsible Party: Maureen Okam, MD, MPH, Associate Physician, Dana-Farber Cancer Institute Identifier: NCT01000155    
Other Study ID Numbers: 09-237
First Posted: October 22, 2009    Key Record Dates
Results First Posted: October 8, 2015
Last Update Posted: July 21, 2017
Last Verified: June 2017
Keywords provided by Maureen Okam, MD, MPH, Dana-Farber Cancer Institute:
fetal hemoglobin
HDAC inhibitor
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action