A Phase I Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects With Stable Sickle Cell Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- The number of type, incidence, severity and relationship to study treatment of adverse events and serious adverse events
研究概览
简要总结
Background:
Sickle cell disease (SCD) is a genetic disease that causes the body to produce abnormal ( sickled ) red blood cells. SCD can cause anemia and life-threatening complications in the lungs, heart, kidney, and nerves. People with SCD are also at increased risk of forming blood clots in the veins and lungs, but the standard treatments for these clots can cause increased bleeding in people with SCD. Better treatments are needed.
Objective:
To test a drug (fostamatinib) in people with SCD.
Eligibility:
People aged 18 to 65 with SCD.
Design:
Participants will have 6 clinic visits over 12 weeks. Each visit will be 2 to 3 hours.
Participants will be screened. They will have a physical exam with blood tests. They will tell the researchers about the medications they take.
Fostamatinib is a tablet taken by mouth. Participants will take the drug at home, twice a day, for up to 6 weeks.
Participants will have a clinic visit every 2 weeks while they are taking the drug. At each visit they will have a physical exam with blood tests. They will talk about any side effects the drug may be causing. If they are tolerating the drug well after the first 2 weeks, they may begin taking a higher dose.
Participants will have a final visit 4 weeks after they stop taking the drug. They will have a physical exam and blood tests; they will be checked for any side effects of the drug.
详细描述
Study Description:
The overall objective of this study is to assess the clinical safety and tolerability of fostamatinib in subjects with stable sickle cell disease (SCD). Subjects enrolled in cohort 1 will receive fostamatinib 100 mg orally twice daily (BID) for 2 weeks then escalate to 150 mg orally BID for an additional four weeks. Subjects enrolled in cohort 2 will receive fostamatinib 100 mg orally once daily (QD) for 2 weeks then escalate to 150 mg orally QD for an additional four weeks. Cohort 2 will allow the subjects from cohort 1 the option to re-enroll to undergo the QD dosing regimen. Throughout the course of the study subjects will be monitored for signs and symptoms of adverse events. The effect of fostamatinib on laboratory biomarkers of inflammatory activity and red blood cell metabolism will be studied at specified timepoints.
Objectives:
Primary Objective:
To assess the clinical safety and tolerability of fostamatinib, a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (Syk), in subjects with stable SCD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of the following criteria during screening will not receive the study intervention but will be counted toward study accrual. Screen failures may be rescreened at a later time. In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
- •Age between 18-65 years
- •Unequivocal diagnosis of SCA (HbSS or HbSBeta^0) confirmed by hemoglobin electrophoresis performed on patients at least 60 days after a blood transfusion if previously transfused.
- •No transfusion in the 60 days prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
- •Have adequate organ function, as defined by:
- •Serum aspartate aminotransferase (AST) <=1.5 x Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis) and alanine aminotransferase (ALT) <=1.5 x ULN.
- •Absolute neutrophil count >=1.5 x 10^9/L.
- •Hemoglobin >= 7 g/dL
- •Platelet count >=100 x 10^9/L.
- •If on hydroxyurea, participant must have been on stable dose of hydroxyurea (defined as a stable dose for at least 3 months and inclusive of dose modifications for hematological toxicity per PI discretion) prior to signing consent.
- •For women of reproductive potential, have a negative serum pregnancy test during the screening period. Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 1 year prior to signing informed consent unrelated to hormonal contraception).
- •For women of reproductive potential as well as men and their partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days (both men and women) following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine or subdermal contraceptive implants, and barrier methods.
- •Be willing to comply with all study procedures for the duration of the study.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Pain crisis requiring parenteral treatment within 14 days of signing consent.
- •Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
- •History of neutropenia (benign ethnic neutropenia and/or acquired neutropenia related to drug suppression by hydroxyurea and/or cyclic hematopoiesis are permitted).
- •History of posterior reversible encephalopathy syndrome (PRES)
- •History of poorly controlled hypertension (defined as systolic blood pressure >=130 mmHg or average diastolic blood pressure >=90 mmHg based on an average of 3 blood pressure readings despite adequate antihypertensive therapy) unless controlled for >90 days prior to enrollment.
- •Active viral infection as evidenced by testing positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody (ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCV Ab, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.
- •History of drug-induced cholestatic hepatitis.
- •History of any primary malignancy.
- •Testing positive for human immunodeficiency virus 1 or 2 Ab with evidence for ongoing active infection (i.e., CD 4 count <400/microliter and viral load >100,000 copies/ml) on antiretroviral therapy.
- •Current or recent history of psychiatric disorder that, in the opinion of the Investigator or Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.
- •Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo.
- •Use of newly approved SCD therapy (L-glutamine or crizanlizumab) is NOT permitted on this study. Subjects who have received newly approved SCD therapy in the 7 days prior to signing consent will be excluded.
- •Having had a prior bone marrow or stem cell transplant.
- •Currently pregnant or lactating.
- •Currently receiving strong inhibitors of CYP3A4/5 that have not been stopped for >=5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for >=28 days or a time frame equivalent to 5 half-lives (whichever is longer), prior to signing consent. SCD patients that are receiving treatment with CYP3A4 substrate drugs, some BCRP substrate drugs (eg. rosuvastatin), and some P-glycoprotein substrate drugs (eg. Digoxin) are excluded from the study.
- •Currently receiving erythropoiesis stimulating agents.
- •Has not received fostamatinib in 3 months prior to signing consent
研究组 & 干预措施
Cohort 1: Fostamatinib 100 mg BID - 150 mg BID
Cohort 1: Four participants with sickle cell disease will receive fostamatinib 100 mg orally twice daily for 2 weeks, followed by 150 mg orally twice daily for 4 weeks.
干预措施: Fostamatinib (Drug)
Cohort 2: Fostamatinib 100 mg QD - 150 mg QD Cohort 2 re-enrollment subgroup
Up to 19 participants with sickle cell disease, including at least 15 treatment-naive participants and up to 4 participants from Cohort 1 who elect to continue under the revised dosing regimen, will receive fostamatinib 100 mg orally once daily for 2 weeks, followed by 150 mg orally once daily for 4 weeks.Up to 4 participants who previously completed Cohort 1 may re-enroll in Cohort 2 after a 3-month washout period. These participants receive the QD regimen and may be compared with their prior BID exposure in an exploratory, hypothesis-generating analysis.
干预措施: Fostamatinib (Drug)
结局指标
主要结局
The number of type, incidence, severity and relationship to study treatment of adverse events and serious adverse events
时间窗: Baseline (Day 0) to End of Study (Day 70)
The type, incidence, severity, and relationship to study treatment of AEs and serious adverse events (SAEs) from baseline to Day according to CTCAE.
Safety and tolerability of fostamatinib
时间窗: From baseline through Day 70 (end-of-study follow-up; approximately 28 days after the final dose)
Assess the frequency, type, severity, and relationship to fostamatinib of adverse events (AEs) and serious adverse events (SAEs); the number of participants who discontinue treatment because of AEs; and changes over time from baseline in clinical laboratory measures, including serum chemistry, liver function, hematology, and coagulation parameters. Specific laboratory measures include hemoglobin, reticulocyte count, bilirubin, lactate dehydrogenase, white blood cell count, absolute neutrophil count, and platelet count.
次要结局
- Number of participants that discontinued fostamatinib due to adverse events following CTCAE.(Baseline (Day 0) to End of Study (Day 70))
- RBC deformability(Baseline, Day 14, Day 43, and Day 70)
- Time to 50% sickling (t50)(Baseline, Day 14, Day 43, and Day 70)
- Percentage of sickled red blood cells(Baseline, Day 14, Day 43, and Day 70)
- Neutrophil activation and NETosis(Baseline, Day 14, Day 43, and end of study/Day 70)
- RBC Band 3 tyrosine(Baseline, Day 14, Day 43, and Day 70)
- Anti-sickling kinetics(Baseline, Day 14, Day 43, and Day 70)
- Oxygen affinity of hemoglobin (p50)(Baseline, Day 14, Day 43, and Day 70)
- Measure the oxygen tension at which hemoglobin is 50% saturated to evaluate treatment-related changes in RBC oxygen-binding properties.(Baseline, Day 14, Day 43, and Day 70)
- R406 exposure and pharmacodynamic effects(Cohort 1: baseline, 1, 2, 4, and 8 hours after dosing on Days 0 and 14)
- Dose-regimen comparison(Across the treatment period and scheduled assessment visits)