Phase 1 Study of Oral Decitabine and Tetrahydrouridine (THU) in Patients With High Risk Sickle Cell Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Non-hematologic toxicity
研究概览
简要总结
The purposes of this study are to observe if oral tetrahydrouridine and decitabine can increase fetal hemoglobin levels and improve the symptoms of sickle cell disease, and to monitor how patient's bodies react to oral tetrahydrouridine and decitabine.
详细描述
The purposes of this study are to observe if oral tetrahydrouridine and decitabine can increase fetal hemoglobin levels and improve the symptoms of sickle cell disease, and to monitor how patient's bodies react to oral tetrahydrouridine and decitabine. The overall purpose is to develop disease modifying treatment for sickle cell disease that is less cytotoxic than the current standard of care, and which can directly and more efficiently reactivate fetal hemoglobin levels. The hypothesis is that patients treated with oral tetrahydrouridine and decitabine will have the same chance of severe non-hematologic toxicities as the placebo group. The primary end-point is ≥ grade 3 non-hematologic toxicity. The investigators' hypothesis is that patients in the treatment groups receiving oral THU-decitabine 2X/week over 8 weeks (n=15) will be equivalent to placebo group (n=10) with regards to the chance of ≥ grade 3 non-hematologic toxicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
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
- •Age 18 years or older.
- •Written, informed consent provided by the subject before study entry.
- •Confirmed Sickle Cell Disease (SCD) (SS, S-b0-thalassemia, S-b+-thalassemia or SC on hemoglobin electrophoresis).
- •Symptomatic SCD while on 6 months of HU OR symptomatic SCD and intolerant of HU (unable or unwilling to take HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following:
- •Fetal Hemoglobin (HbF) <5%, OR
- •3 or more pain episodes per year requiring parenteral narcotics, OR
- •1 or more acute chest syndrome episodes, OR
- •Hemoglobin <9 g/dL and absolute reticulocyte count <250,000/mm
- •Subject is in his/her steady state and not amidst any acute complication due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days).
- •Regular compliance with comprehensive care and previous therapy.
排除标准
- •Inability to give informed consent.
- •Experienced severe sepsis or septic shock within the previous 12 weeks.
- •Last HU dose was ingested within the previous 4 weeks.
- •Currently pregnant or breast-feeding.
- •Alanine aminotransferase (ALT) greater than or equal to two times (2X) the upper limit of normal or albumin <2.0 mg/dL or direct (conjugated) bilirubin greater than or equal to 1.5 mg/dl.
- •Serum creatinine >2.9 mg/dL and calculated creatinine clearance <30 mL/min.
- •Platelet count >800 x 109/L.
- •Absolute neutrophil count <1.5 x 109/L.
- •Female of active childbearing potential who is unwilling to use at least one of the two following forms of birth control:
- •(i) not having heterosexual sexual contact beginning at the screening visit and continuing until 4 weeks after the last dose of THU-decitabine OR (ii) intrauterine device (IUD).
- •Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of THU-decitabine. This requirement applies also to males who have had a successful vasectomy.
- •Altered mental status or recurrent seizures requiring anti-seizure medications.
- •Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely.
- •Concurrent diagnosis of malignancy including myelodysplastic syndromes (MDS), leukemia, or an abnormal karyotype.
- •Vitamin-B12, folate, or iron deficient (until corrected).
- •New York Heart Association (NYHA) class III/IV status.
- •Eastern Co-operative Oncology Group (ECOG) performance status greater than or equal to
- •Participant is on chronic transfusion therapy (e.g., for history of Transient Ischemic Attack (TIA) or stroke) and medically contraindicated to discontinue transfusions (unless multiple allo-antibodies prevent the patient from getting transfusions as scheduled).
- •Known history of illicit drug or alcohol abuse within the past 12 months.
- •Other experimental or investigational drug therapy in the past 28 days.
研究组 & 干预措施
Oral Decitabine and Tetrahydrouridine
Oral Decitabine and Tetrahydrouridine
干预措施: Oral Decitabine and Tetrahydrouridine (Drug)
Placebo
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Non-hematologic toxicity
时间窗: 12 weeks
Toxicities will be evaluated on a weekly basis and will be classified according to their grade and relationship to study treatment. Chi-square testing will be employed to examine the difference in number of patients with grade 3 or greater non-hematologic toxicity between treatment and placebo groups.
次要结局
未报告次要终点
研究者
Yogen Saunthararajah
Staff in the Department of Hematology and Oncology
The Cleveland Clinic