Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease - Full Text View

Sponsor:	Dana-Farber Cancer Institute
Collaborators:	Brigham and Women's Hospital Children's Hospital Boston Merck
Information provided by:	Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01000155

Purpose

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	Intervention	Phase
Sickle Cell Disease Sickle Cell Anemia	Drug: vorinostat	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

Genetics Home Reference related topics: sickle cell disease

MedlinePlus related topics: Anemia Cancer Sickle Cell Anemia

Drug Information available for: Vorinostat

U.S. FDA Resources

Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:

To determine the efficacy of vorinostat when administered orally in inducing a 4% absolute increase or a 100% increase in fetal hemoglobin levels in subjects with severe sickle cell disease who have failed prior therapy. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To characterize the safety and tolerability of vorinostat in subjects with sickle cell disease. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To assess the effect of vorinostat on F-cell levels. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To determine the changes is y-globin, B-globin and E-globin RNA levels during treatment with vorinostat. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To describe the dose-response characteristics of vorinostat in inducing fetal hemoglobin in sickle cell disease [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	15
Study Start Date:	October 2009
Estimated Study Completion Date:	October 2012
Estimated Primary Completion Date:	October 2011 (Final data collection date for primary outcome measure)

Intervention Details:

Taken orally once-a-day on for 3 consecutive days, every week. (For example, Mon-Tues-Wed, Tues-Wed-Thurs or Wed-Thurs-Fri)

Other Name: SAHA

Detailed Description:

Since we are looking for the highest dose of vorinostat that can be administered safely without severe or unmanageable side effects in participants who have SCD, the participants dose may change while they are enrolled in the study.
Participants will receive an initial dose of vorinostat for the first cycle (or 4 weeks). If they tolerate this dose, they will receive a higher dose for the second cycle. The dose will be increased a 2nd time if they tolerate the dose of the second cycle. Participants will continue on that highest dose for as long as they can tolerate it, or, for a maximum of 4 cycles. The maximum dose participants could receive is 400mg a day, 3 times a week.
Participants will be given a study drug diary for each study cycle to record each time they take vorinostat and indicate if they have any changes in their health or in medications they are taking.
During the study participants will come to the clinic for visits with the study team and may have some of the following tests: physical examination, EKG, blood tests, urine tests and echocardiogram.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01000155

Contacts

Contact: Maureen Okam, MD, MPH	617-732-5048
Contact: Ainsley Ross	617-732-8537

Locations

United States, Massachusetts
Brigham and Women's Hospital	Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Maureen Okam, MD, MPH
Dana-Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Maureen Okam, MD, MPH
Children's Hospital Boston	Not yet recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Ellis Neufeld, MD, PhD

Sponsors and Collaborators

Dana-Farber Cancer Institute

Brigham and Women's Hospital

Children's Hospital Boston

Merck

Investigators

Principal Investigator:

Maureen Okam, MD, MPH

Brigham and Women's Hospital

More Information

No publications provided

Responsible Party:	Maureen Okam, MD, MPH, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT01000155 History of Changes
Other Study ID Numbers:	09-237
Study First Received:	October 20, 2009
Last Updated:	May 23, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:

fetal hemoglobin
vorinostat
HDAC inhibitor
SAHA

Additional relevant MeSH terms:

Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn

Vorinostat
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 23, 2012