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.
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. Secondary Objectives: To assess the pharmacokinetics of fostamatinib in SCD and correlate drug exposure to effects on neutrophil, platelet function, and red cell metabolism to evaluate for anti-sickling and anti-inflammatory effects (Cohort 1). To evaluate anti-sickling and anti-inflammatory effects of fostamatinib in SCD via neutrophil function and red cell metabolism (Cohort 2). Exploratory Objectives: To gain insight into the exposure response and mechanistic effects of fostamatinib mediated Syk inhibition on intracellular signaling. Compare anti-sickling and anti-inflammatory effects of fostamatinib between 2 dose regimens. Endpoints: Primary Endpoint: * To evaluate the safety and tolerability of fostamatinib as assessed by: --frequency and severity of adverse events (AEs) from Baseline to Day 70 * Safety endpoints, including: * the type, incidence, severity, and relationship to study treatment of AEs and serious adverse events (SAEs) from Baseline to Day 70 * number of discontinuations due to AEs; from Baseline to Day 70 * results of clinical laboratory tests over time and change from baseline (e.g., serum chemistry, liver function test, hematology, coagulation) Secondary Endpoints: * Neutrophil activation and NETosis at regular time intervals (baseline, days 14, 43, and end of study) on fostamatinib and change from baseline. * Percentage of sickled cells and time to 50% sickling (t50) under normal and hypoxic ex vivo conditions at regular time intervals (baseline, days 14, 43, and end of study) on fostamatinib and change from baseline. * Evaluate anti-sickling effects of fostamatinib through measures of red blood cell (RBC) membrane band3 tyrosine phosphorylation, RBC deformability, anti-sickling kinetics and oxygen affinity (p50) at regular time intervals (baseline, days 14, 43, and end of study) on fostamatinib and change from baseline. * Change from baseline in intracellular reactive oxidative species (ROS) in RBCs at different doses of fostamatinib at regular time intervals (baseline, days 14, 43 and end of study). * Determine peak R406 levels and assess correlation of R406 exposure with inhibition of NETosis and its effect on red blood cell membrane band 3 tyrosine phosphorylation and sickling kinetics at baseline, 1 hr, 2 hrs, 4 hrs, and 8 hrs post dosing on 100 mg BID and 150 mg BID (Cohort 1) Exploratory Endpoints: * Proteomic, metabolomic and lipidomic studies to evaluate the effect of fostamatinib on RBCs and monocytes at regular time intervals (baseline, days 14, 43 and end of study). * Studies of extracellular vesicles (EVs) at regular time intervals (baseline, days 14, 43 and end of study). * Measures of neutrophil activation and neutrophil extracellular trap (NET) formation at baseline and following agonistactivation Z * Compare fostamatinib at different doses on secondary and exploratory endpoints by comparing data from subjects who have received both dose levels.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
35
Fostamatinib will be administered orally for 6 weeks. Dosing will begin at 100 mg and increase to 150 mg after 2 weeks. The dosing frequency will be once daily or twice daily, depending on cohort assignment.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
RECRUITINGSafety and tolerability of fostamatinib
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.
Time frame: From baseline through Day 70 (end-of-study follow-up; approximately 28 days after the final dose)
Time to 50% sickling (t50)
Measure the time required for 50% of red blood cells to sickle under ex vivo conditions as an indicator of anti-sickling activity.
Time frame: Baseline, Day 14, Day 43, and Day 70
Percentage of sickled red blood cells
Assess the percentage of sickled cells under normal and hypoxic ex vivo conditions and evaluate change from baseline.
Time frame: Baseline, Day 14, Day 43, and Day 70
Neutrophil activation and NETosis
Measure changes from baseline in neutrophil activation and neutrophil extracellular trap formation during fostamatinib treatment.
Time frame: Baseline, Day 14, Day 43, and end of study/Day 70
RBC Band 3 tyrosine
Evaluate the effect of fostamatinib on tyrosine phosphorylation of the RBC membrane Band 3 protein, a marker related to RBC membrane integrity and sickling biology.
Time frame: Baseline, Day 14, Day 43, and Day 70
RBC deformability
Baseline, Day 14, Day 43, and Day 70
Time frame: Baseline, Day 14, Day 43, and Day 70
Anti-sickling kinetics
Characterize the kinetics of RBC sickling under ex vivo conditions and determine whether fostamatinib alters sickling behavior.
Time frame: Baseline, Day 14, Day 43, and Day 70
Oxygen affinity of hemoglobin (p50)
Measure the oxygen tension at which hemoglobin is 50% saturated to evaluate treatment-related changes in RBC oxygen-binding properties.
Time frame: 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.
Assess change from baseline in intracellular oxidative stress in RBCs at the different fostamatinib dose levels.
Time frame: Baseline, Day 14, Day 43, and Day 70
R406 exposure and pharmacodynamic effects
Determine peak plasma levels of R406, the active fostamatinib metabolite, and correlate exposure with inhibition of NETosis, Band 3 tyrosine phosphorylation, RBC effects, and sickling kinetics.
Time frame: Cohort 1: baseline, 1, 2, 4, and 8 hours after dosing on Days 0 and 14
Dose-regimen comparison
Exploratorily compare secondary biomarker outcomes between the BID regimen in Cohort 1 and the QD regimen in Cohort 2, including within-participant comparisons for participants who complete both regimens.
Time frame: Across the treatment period and scheduled assessment visits
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