Fostamatinib for Sickle Cell Disease

Overseen By Jordan B Branch

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must be taking: Hydroxyurea

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pain crisis, Hypertension, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 6 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of fostamatinib, a new oral medication, in people with sickle cell disease (SCD). Sickle cell disease is a genetic condition that causes red blood cells to have an unusual shape, leading to complications like anemia and blood clots. The trial seeks individuals diagnosed with SCD who are not currently experiencing a pain crisis. Participants will take fostamatinib at home and visit the clinic every two weeks for check-ups. The goal is to determine if fostamatinib can safely reduce complications without causing significant side effects. As a Phase 1 trial, this research focuses on understanding how fostamatinib works in people, offering participants the unique opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, such as newly approved SCD therapies and specific drugs that affect liver enzymes (CYP3A4/5 inhibitors or inducers) before joining. If you are on hydroxyurea, you must be on a stable dose for at least 3 months. Please discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that fostamatinib is likely to be safe for humans?

Research shows that fostamatinib is being tested for safety and effectiveness in treating sickle cell disease (SCD). The FDA has already approved fostamatinib for treating immune thrombocytopenia, and it is sold under the brand name Tavalisse. Earlier studies identified common side effects, including diarrhea, high blood pressure, nausea, and breathing problems, most of which were mild to moderate.

The trial is in its early phase, focusing primarily on the drug's safety and tolerability. Researchers are closely monitoring participants for any side effects. Fostamatinib has shown promise in stabilizing red blood cells, which might reduce sickling in SCD. While some information exists from its use in other conditions, this trial will help determine how well people with SCD can tolerate the drug. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Fostamatinib is unique because it targets spleen tyrosine kinase (SYK), a mechanism not typically addressed by existing sickle cell disease treatments. Most current options, like hydroxyurea or blood transfusions, focus on managing symptoms or preventing complications rather than targeting the biochemical pathways involved in the disease. Researchers are excited about Fostamatinib because it offers a new approach by potentially reducing inflammation and improving blood flow, which could directly address some underlying issues of sickle cell disease. Additionally, its oral administration makes it a convenient option compared to more invasive treatments.

What evidence suggests that fostamatinib might be an effective treatment for sickle cell disease?

Research has shown that fostamatinib might help people with sickle cell disease (SCD) by stabilizing red blood cells. This stabilization could reduce the problem of red blood cells changing shape, a major issue in SCD. Other studies have found fostamatinib effective in increasing platelet counts, suggesting it might address blood-related issues. Although primarily approved for other uses, these effects indicate potential benefits for SCD. Early results appear promising, but further research is needed to confirm its effectiveness for SCD specifically. Participants in this trial will receive fostamatinib to further investigate its potential benefits for SCD. ^{1 2 3 4 6}

Who Is on the Research Team?

Swee Lay Thein, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

Adults aged 18-65 with stable Sickle Cell Anemia (SCA) who haven't had a blood transfusion in the last 12 weeks. Participants must not be pregnant, agree to use two forms of contraception, and have normal organ function. They can't join if they have certain medical conditions like uncontrolled hypertension, active infections, or history of malignancy.

Inclusion Criteria

No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)

My sickle cell anemia (SCA) diagnosis is confirmed and not affected by recent transfusions.

Have provided signed written informed consent prior to performing any study procedure, including screening procedures.

Exclusion Criteria

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.

History of neutropenia, History of posterior reversible encephalopathy syndrome (PRES), History of poorly controlled hypertension, 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, 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, Current or recent history of psychiatric disorder that could compromise the ability to cooperate with study visits and procedures, 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, voxelotor or crizanlizumab) is NOT permitted on this study, 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, Currently receiving erythropoiesis stimulating agents.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive fostamatinib, starting at 100 mg twice daily for 2 weeks, then escalating to 150 mg twice daily for 4 weeks if tolerated

6 weeks

3 visits (in-person, every 2 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Fostamatinib

Trial Overview The trial is testing Fostamatinib's safety and how well people with SCA tolerate different doses. Over 12 weeks, participants will take the drug orally twice daily for up to six weeks and attend clinic visits every two weeks to monitor effects and possibly increase dosage based on tolerance.

How Is the Trial Designed?

Group I: Fostamatinib in participants with Sickle Cell Disease Experimental Treatment 1 Intervention

Participants with Sickle Cell Disease will receive Fostamatinib which will be administered orally, at a dose of 100 mg twice a day for 14 days and if tolerated, will be escalated to a dose of 150 mg, taken orally, twice a day for 28 days (total 42 days).

Fostamatinib is already approved in United States for the following indications:

Approved in United States as Tavalisse for:

• Chronic immune thrombocytopenia (ITP)

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Fostamatinib (TAVALISSE™) is a spleen tyrosine kinase (SYK) inhibitor developed by Rigel Pharmaceuticals, recently approved in the US for treating thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who did not respond adequately to prior treatments.

The approval was based on positive outcomes from the phase III FIT clinical trial program, highlighting its efficacy in increasing platelet counts in patients with ITP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostamatinib: First Global Approval. Markham, A.[2022]

Midostaurin, when combined with standard chemotherapy, significantly improves overall survival in adult patients with newly diagnosed acute myeloid leukaemia (AML) who have a specific mutation, with a median survival of 74.7 months compared to 25.6 months for those receiving placebo.

In patients with aggressive systemic mastocytosis (ASM) and related conditions, midostaurin showed an overall response rate of 28.3%, with higher rates in specific subgroups, indicating its efficacy as a monotherapy for these rare diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency review of midostaurin (Rydapt) for the treatment of adult patients with acute myeloid leukaemia and systemic mastocytosis. Tzogani, K., Yu, Y., Meulendijks, D., et al.[2021]

Pemigatinib, a tyrosine kinase inhibitor targeting FGFR1-3, shows high complete hematologic and cytogenetic response rates in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangements (MLNFGFR1), indicating its efficacy as a treatment option.

While pemigatinib appears to offer better outcomes than traditional treatments, the long-term effects and safety are still unknown, and allogeneic hematopoietic stem cell transplant remains the best option for long-term disease-free survival in patients who respond to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement. Freyer, CW., Hughes, ME., Carulli, A., et al.[2023]

Fostamatinib (Tavalisse) is effective for treating thrombocytopenia in adults with chronic immune thrombocytopenia, helping to increase platelet counts.

Coagulation factor Xa (recombinant), inactivated-zhzo (Andexxa) is used for reversing anticoagulation effects, providing a critical intervention for patients experiencing bleeding complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

Fostamatinib is an effective treatment for chronic immune thrombocytopenia (ITP) in patients who have not responded adequately to at least one prior therapy, as demonstrated in two phase 3 randomized controlled trials (FIT1 and FIT2) across North America, Australia, and Europe.

The drug works by inhibiting spleen tyrosine kinase, which plays a crucial role in the immune response, thereby helping to increase platelet counts in ITP patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostamatinib for the treatment of chronic immune thrombocytopenia. Connell, NT., Berliner, N.[2021]

Midostaurin is FDA-approved for treating aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), showing meaningful clinical activity despite limited complete remission rates.

In a trial with 142 patients, over half experienced dose modifications due to toxicity, with common side effects including nausea, vomiting, and diarrhea, highlighting the need for careful monitoring and potential dose adjustments during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis. Kasamon, YL., Ko, CW., Subramaniam, S., et al.[2020]

In a study of 116 patients with advanced systemic mastocytosis, midostaurin demonstrated a 60% overall response rate, with 45% achieving a major response, indicating significant efficacy in treating this challenging condition.

Despite its effectiveness, midostaurin was associated with notable side effects, leading to dose reductions in 56% of patients, highlighting the need for careful monitoring and management of adverse events during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. Gotlib, J., Kluin-Nelemans, HC., George, TI., et al.[2022]

Avapritinib is a highly selective inhibitor of the KIT D816V mutation and has been approved for treating advanced systemic mastocytosis (AdvSM), showing the ability to achieve complete and durable clinical responses in patients.

The phase 1 EXPLORER and phase 2 PATHFINDER trials confirmed that avapritinib can lead to molecular remission of the KIT D816V mutation, although managing AdvSM can be complicated due to its diverse mutational landscape.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avapritinib for advanced systemic mastocytosis. Gotlib, J., Reiter, A., DeAngelo, DJ.[2023]

Fostamatinib is an oral spleen tyrosine kinase inhibitor that effectively increases platelet counts in adults with immune thrombocytopenia who did not respond adequately to previous treatments, as shown in two Phase III trials.

The treatment is generally well tolerated, with lower rates of severe bleeding-related side effects, although common adverse events include diarrhea, nausea, and liver function test elevations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostamatinib for the treatment of immune thrombocytopenia in adults. Moore, DC., Gebru, T., Muslimani, A.[2021]

Fostamatinib is an effective oral treatment for adults with chronic immune thrombocytopenia (ITP) who have not responded to previous therapies, showing durable responses and maintaining platelet counts above 50 × 10^9/L for at least 12 months.

The drug works by inhibiting the spleen tyrosine kinase (SYK) pathway, which is involved in platelet destruction, but it can cause side effects such as diarrhea, hypertension, nausea, and increased liver enzymes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostamatinib in chronic immune thrombocytopenia: a profile of its use in the USA. McKeage, K., Lyseng-Williamson, KA.[2022]

Citations

1. rigel.com rigel.com/news-media/press-releases/detail/408/rigels-fostamatinib-being-studied-by-national-institute-of

Rigel's Fostamatinib Being Studied by National Institute of ... "Our Phase 1 study evaluating fostamatinib in patients with sickle cell disease is an opportunity to explore a potential new treatment ...

2. prnewswire.com prnewswire.com/news-releases/rigels-fostamatinib-being-studied-by-national-institute-of-health-in-patients-with-sickle-cell-disease-302356919.html

Rigel's Fostamatinib Being Studied by National Institute of ... By impacting phosphorylation of RBC Band 3 protein, fostamatinib offers the potential for enhanced RBC membrane stability and reduced sickling ...

3. tavalissehcp.com tavalissehcp.com/efficacy

TAVALISSE® (fostamatinib disodium hexahydrate) tablets ROBUST IMPROVEMENTS IN PLATELET COUNTS WERE OBSERVED AFTER PRIOR STEROID AND/OR TPO-RA USE · 56% of 2nd-line patients responded within 4 weeks · 76% of 2nd-line ...

4. hcplive.com hcplive.com/view/phase-3-data-fostamatinib-published

Phase 3 Data of Fostamatinib Published in American ... Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P=0.0003). Overall responses occurred in 43% of patients on ...

5. rarediseaseadvisor.com rarediseaseadvisor.com/therapies/tavalisse-fostamatinib-itp/

Tavalisse The approval of Tavalisse was based on results from two multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trials ...

6. tavalissehcp.com tavalissehcp.com/safety

TAVALISSE® (fostamatinib disodium hexahydrate) tablets THE 5-YEAR SAFETY ANALYSIS CONTINUES TO SUPPORT LONG-TERM USE OF TAVALISSE. The majority of adverse reactions observed in clinical trials were mild or moderate1.