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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 3
- 主要终点
- Percent Fetal Hemoglobin (HbF%) Induction Success Rate
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: vorinostat (Drug)
结局指标
主要结局
Percent Fetal Hemoglobin (HbF%) Induction Success Rate
时间窗: 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.
次要结局
- 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.)
研究者
Maureen Okam, MD, MPH
Associate Physician
Dana-Farber Cancer Institute