Sickle Cell DiseasePhase 2NCT01000155
Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease
A Phase 2 study testing vorinostat in people with Sickle Cell Disease and Sickle Cell Anemia, run by Dana-Farber Cancer Institute at 3 sites in United States.
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sickle Cell Disease, Sickle Cell Anemia
- What is being tested?
- vorinostat
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 3 sitesUnited States
- Study dates
- Oct 2009to Oct 2014
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Children's Hospital Boston
Boston, Massachusetts, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, 02115
About this study
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.
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
- Sickle Cell Disease, Sickle Cell Anemia
- Being tested
- vorinostat
- Keywords
- fetal hemoglobin, vorinostat, HDAC inhibitor, SAHA
- Medical subject headings
- Anemia, Sickle Cell, beta-Thalassemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
vorinostatDrug
Also called SAHA
| Study group | Role | What they receive |
|---|---|---|
| Vorinostat | Experimental | 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. Receives: Drug: vorinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: HbF% was measured at baseline and weekly on treatment. Median duration of treatment was 3 months.
Secondary outcomes (2)
F-Cell Percentage Level
F-cell percentage levels were estimated based on established methods.
Measured: 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.
Measured: Measured at baseline and end of treatment, up to 16 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Oct 2009 (estimated)
- Study startOct 2009
- Primary completionOct 2014
- Study completionOct 2014
Why it stopped: The study terminated early due to slow accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maureen Okam, MD, MPH, Dana-Farber Cancer Institute
- Investigators
- Maureen Okam, MD, MPH, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01000155
- Sponsor's protocol ID
- 09-237
- Status last verified
- Jun 2017
- First submitted
- 20 Oct 2009
- Last updated
- 21 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01000155
- Acronym / sponsor ID
- 09-237
- Conditions
- Sickle Cell Disease, Sickle Cell Anemia
- Keywords
- fetal hemoglobin, vorinostat, HDAC inhibitor, SAHA
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study terminated early due to slow accrual.
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Collaborators
- Brigham and Women's Hospital, Boston Children's Hospital, Merck Sharp & Dohme LLC
- Study start
- Oct 2009
- Primary completion
- Oct 2014 (actual)
- Study completion
- Oct 2014 (actual)
- First posted
- 22 Oct 2009 (estimated)
- Results
- Posted 8 Oct 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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%.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Vorinostat | Experimental | Drug: vorinostatPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| vorinostatAlso: SAHA | Drug | Vorinostat |
Primary outcome
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.
2 secondary outcomes
F-Cell Percentage Level
Time frame: Measured at baseline and end of treatment, up to 16 weeks.
γ-globin to β-globin Ratio
Time frame: Measured at baseline and end of treatment, up to 16 weeks.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jul 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Blood Letter to the EditorLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maureen Okam, MD, MPH principal investigator
Brigham and Women's Hospital
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing vorinostat in people with Sickle Cell Disease and Sickle Cell Anemia, run by Dana-Farber Cancer Institute at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 21 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Oct 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jul 2017.