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.
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)
Pain crisis requiring parenteral treatment within 14 days of signing consent.
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.
Single group
Fostamatinib
DrugFostamatinib 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.
Safety 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 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.
Percentage of sickled red blood cells
Assess the percentage of sickled cells under normal and hypoxic ex vivo conditions and evaluate change from baseline.
Neutrophil activation and NETosis
Measure changes from baseline in neutrophil activation and neutrophil extracellular trap formation during fostamatinib treatment.
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.
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