Disease Sickle Cell Anemia, Hb-SS Disease, Hemoglobin S, Sickle Cell Disease, Sickle Cell Disorders
Conditions
Keywords
Sickle Cell, Tyrosine Kinase Inhibitor, Fostamatinib
Brief summary
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.
Detailed description
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.
Interventions
DRUGFostamatinib
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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: 1. Have provided signed written informed consent prior to performing any study procedure, including screening procedures. 2. Age between 18-65 years 3. 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. 4. No transfusion in the 60 days prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC) 5. Have adequate organ function, as defined by: 1. 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. 2. Absolute neutrophil count \>=1.5 x 10\^9/L. 3. Hemoglobin \>= 7 g/dL 4. Platelet count \>=100 x 10\^9/L. 6. 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. 7. 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). 8. 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. 9. Be willing to comply with all study procedures for the duration of the study.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: 1. Pain crisis requiring parenteral treatment within 14 days of signing consent. 2. 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: 1. History of neutropenia (benign ethnic neutropenia and/or acquired neutropenia related to drug suppression by hydroxyurea and/or cyclic hematopoiesis are permitted). 2. History of posterior reversible encephalopathy syndrome (PRES) 3. 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. 4. 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. 5. History of drug-induced cholestatic hepatitis. 6. History of any primary malignancy. 7. 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. 8. 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. 9. Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. 10. 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. 11. Having had a prior bone marrow or stem cell transplant. 12. Currently pregnant or lactating. 13. 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. 14. Currently receiving erythropoiesis stimulating agents. 3. Has not received fostamatinib in 3 months prior to signing consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of fostamatinib | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to 50% sickling (t50) | Baseline, Day 14, Day 43, and Day 70 | 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 | Baseline, Day 14, Day 43, and Day 70 | Assess the percentage of sickled cells under normal and hypoxic ex vivo conditions and evaluate change from baseline. |
| Neutrophil activation and NETosis | Baseline, Day 14, Day 43, and end of study/Day 70 | Measure changes from baseline in neutrophil activation and neutrophil extracellular trap formation during fostamatinib treatment. |
| RBC Band 3 tyrosine | Baseline, Day 14, Day 43, and Day 70 | 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. |
| RBC deformability | Baseline, Day 14, Day 43, and Day 70 | Baseline, Day 14, Day 43, and Day 70 |
| Anti-sickling kinetics | Baseline, Day 14, Day 43, and Day 70 | Characterize the kinetics of RBC sickling under ex vivo conditions and determine whether fostamatinib alters sickling behavior. |
| 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. |
| 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 | Assess change from baseline in intracellular oxidative stress in RBCs at the different fostamatinib dose levels. |
| R406 exposure and pharmacodynamic effects | Cohort 1: baseline, 1, 2, 4, and 8 hours after dosing on Days 0 and 14 | 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. |
| Dose-regimen comparison | Across the treatment period and scheduled assessment visits | 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. |
Countries
United States
Contacts
CONTACTJordan B Branch
CONTACTSwee Lay Thein, M.D.
PRINCIPAL_INVESTIGATORSwee Lay Thein, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Outcome results
None listed