Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease

NCT01000155 | Terminated Phase 2 Results DMC

• 1 other identifier: 09-237
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 3

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.

Conditions

Sickle Cell Disease; Sickle Cell Anemia

Keywords

fetal hemoglobin; vorinostat; HDAC inhibitor; SAHA

Outcome Measures

Primary Outcomes (1)

• 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.

  HbF% was measured at baseline and weekly on treatment. Median duration of treatment was 3 months.

Secondary Outcomes (2)

• F-Cell Percentage Level

  Measured at baseline and end of treatment, up to 16 weeks.

• γ-globin to β-globin Ratio

  Measured at baseline and end of treatment, up to 16 weeks.

Study Arms (1)

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.

Drug: vorinostat

Interventions

vorinostat DRUG

Also known as: SAHA

Vorinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Brigham and Women's Hospital: collaborator
• Boston Children's Hospital: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; beta-Thalassemia

Interventions

Vorinostat

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Thalassemia

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Limitations and Caveats

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

Results Point of Contact

• Title: Maureen Okam, MD, MPH
• Organization: Brigham&Women's Hospital

mokam@partners.org

617-732-5048

Study Officials

• Maureen Okam, MD, MPH

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Physician

Study Record Dates

• First Submitted: October 20, 2009
• First Posted: October 22, 2009
• Study Start: October 1, 2009
• Primary Completion: October 1, 2014
• Study Completion: October 1, 2014
• Last Updated: July 21, 2017
• Results First Posted: October 8, 2015

Record last verified: 2017-06

Locations

US (3)