CLINICAL TRIALS PROFILE FOR GILTERITINIB FUMARATE

All Clinical Trials for GILTERITINIB FUMARATE

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT04140487 ↗	Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm	Recruiting	National Cancer Institute (NCI)	Phase 1/Phase 2	2019-12-17	This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.
NCT04140487 ↗	Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm	Recruiting	M.D. Anderson Cancer Center	Phase 1/Phase 2	2019-12-17	This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.
NCT04293562 ↗	A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations	Recruiting	National Cancer Institute (NCI)	Phase 3	2020-07-20	This phase III trial compares standard chemotherapy to therapy with CPX-351 and/or gilteritinib for patients with newly diagnosed acute myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as daunorubicin, cytarabine, and gemtuzumab ozogamicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. CPX-351 is made up of daunorubicin and cytarabine and is made in a way that makes the drugs stay in the bone marrow longer and could be less likely to cause heart problems than traditional anthracycline drugs, a common class of chemotherapy drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene called FLT3. Genes are pieces of DNA (molecules that carry instructions for development, functioning, growth and reproduction) inside each cell that tell the cell what to do and when to grow and divide. FLT3 plays an important role in the normal making of blood cells. This gene can have permanent changes that cause it to function abnormally by making cancer cells grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with standard chemotherapy may work better in treating patients with acute myeloid leukemia compared to standard chemotherapy alone.

Clinical Trial Conditions for GILTERITINIB FUMARATE

Condition Name

Condition Name for GILTERITINIB FUMARATE
Intervention	Trials
Recurrent Acute Myeloid Leukemia	2
Recurrent Myelodysplastic/Myeloproliferative Neoplasm	1
Refractory Acute Myeloid Leukemia	1

Condition MeSH

Condition MeSH for GILTERITINIB FUMARATE
Intervention	Trials
Leukemia, Myeloid, Acute	2
Leukemia, Myeloid	2
Leukemia	2

Clinical Trial Locations for GILTERITINIB FUMARATE

Trials by Country

Trials by Country for GILTERITINIB FUMARATE
Location	Trials
United States	48
Canada	6
Puerto Rico	1

Trials by US State

Trials by US State for GILTERITINIB FUMARATE
Location	Trials
California	2
Texas	2
Hawaii	1
Washington	1
Georgia	1

Clinical Trial Progress for GILTERITINIB FUMARATE

Clinical Trial Phase

Clinical Trial Phase for GILTERITINIB FUMARATE
Clinical Trial Phase	Trials
Phase 3	1
Phase 1/Phase 2	1
Phase 1	1

Clinical Trial Status

Clinical Trial Status for GILTERITINIB FUMARATE
Clinical Trial Phase	Trials
Recruiting	2
Not yet recruiting	1

Clinical Trial Sponsors for GILTERITINIB FUMARATE

Sponsor Name

Sponsor Name for GILTERITINIB FUMARATE
Sponsor	Trials
National Cancer Institute (NCI)	3
M.D. Anderson Cancer Center	1
Children's Oncology Group	1

Sponsor Type

Sponsor Type for GILTERITINIB FUMARATE
Sponsor	Trials
NIH	3
Other	3

Gilteritinib Fumarate: Clinical Trials, Market Analysis, and Projections

Introduction to Gilteritinib Fumarate

Gilteritinib fumarate, marketed as Xospata, is a tyrosine kinase inhibitor specifically designed to target the FMS-like tyrosine kinase 3 (FLT3) mutation, which is commonly found in patients with acute myeloid leukemia (AML). Here, we will delve into the clinical trials, market analysis, and projections for this drug.

Clinical Trials Overview

Phase 3 ADMIRAL Trial

The approval of gilteritinib was primarily based on the results of the Phase 3 ADMIRAL trial (NCT02421939). This multicenter, open-label study involved 138 adult patients with relapsed or refractory AML who had a FLT3 mutation detected by the LeukoStrat CDx FLT3 Mutation Assay. Patients were administered gilteritinib orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit occurred.

Key findings from the trial include:

• Complete Remission Rates: After a median follow-up of 4.6 months, 29 patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 21% (95% CI: 14.5%, 28.8%)[1][2].
• Transfusion Independence: Among the 106 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 33 (31.1%) became independent of these transfusions during any 56-day post-baseline period. For the 32 patients who were independent of both RBC and platelet transfusions at baseline, 17 (53.1%) remained transfusion-independent during any 56-day post-baseline period[1].

Safety and Adverse Effects

The trial also highlighted potential safety concerns, including the risk of differentiation syndrome, a condition that can occur with FLT3 inhibitors. Additional postmarketing studies are needed to fully assess the long-term safety and to characterize the risk of gilteritinib-induced differentiation syndrome[2].

Mechanism of Action

Gilteritinib inhibits multiple receptor tyrosine kinases, including FLT3, which is crucial for the proliferation and survival of AML cells with FLT3 mutations. In vitro studies have shown that gilteritinib effectively inhibits FLT3 receptor signaling and proliferation in cells expressing FLT3 mutants[3].

Market Analysis

Budget Impact Analysis

A budget impact analysis was conducted to estimate the economic impact of introducing gilteritinib for the treatment of relapsed/refractory FLT3 mutation-positive AML from a US payer's perspective. Here are the key findings:

• Market Share and Cost Impact: In a hypothetical health plan with 1 million members, the market share of gilteritinib increased from 30% in Year 1 to 45% in Years 2-3. This increase led to a total plan budget impact of $663,795 in Year 1, and $1,078,371 and $1,087,230 in Years 2 and 3, respectively. The per-member-per-month (PMPM) cost increased by $0.055 in Year 1 and by $0.090 and $0.091 in Years 2 and 3, respectively[5].

• Total Costs: The analysis included costs for drugs, administration, hospitalization, monitoring, adverse events, transfusions, subsequent hematopoietic stem cell transplantation, post-progression care, and FLT3 testing. The model remained robust in deterministic sensitivity analyses and scenario analyses[5].

Market Projections

Given the efficacy and safety profile of gilteritinib, it is projected to become a significant player in the treatment of relapsed/refractory FLT3 mutation-positive AML.

• Patient Population: The target population for gilteritinib includes adults with relapsed or refractory AML who have a confirmed FLT3 mutation. This population is estimated to be around 20.9 adults per 1 million health plan members[5].

• Market Uptake: The market share of gilteritinib is expected to increase over the years as more patients are treated with this drug. The analysis suggests that the market share will rise to 45% by the third year after its introduction, significantly impacting the total plan budget[5].

Economic Considerations

Cost-Benefit Analysis

The introduction of gilteritinib is expected to increase healthcare costs due to the drug's high price. However, the benefits of gilteritinib, including improved complete remission rates and reduced need for transfusions, may offset these costs in the long term.

• Reduced Transfusion Costs: By reducing the dependency on RBC and platelet transfusions, gilteritinib can lower the overall healthcare costs associated with managing AML patients[1].

• Hospitalization and Monitoring: The drug may also reduce the need for hospitalizations and monitoring, further mitigating costs[5].

Patient Experience and Quality of Life

Clinical Outcome Assessments

Patient experience data, including clinical outcome assessments (COAs), are crucial in understanding the impact of gilteritinib on patients' quality of life. While the current data primarily focus on clinical outcomes, future studies should include more detailed patient-reported outcomes (PROs) to provide a comprehensive view of the drug's benefits[2].

Regulatory Approval and Companion Diagnostic

FDA Approval

Gilteritinib was approved by the FDA on November 28, 2018, for the treatment of adult patients with relapsed or refractory AML who have a FLT3 mutation detected by an FDA-approved test. The approval also included an expanded indication for the LeukoStrat CDx FLT3 Mutation Assay, a companion diagnostic used to detect the FLT3 mutation in AML patients[1].

Non-Clinical Toxicity Studies

Preclinical Findings

Preclinical studies in rats and dogs have shown that gilteritinib can cause toxicity in various organ systems, including the lymphohematopoietic system, gastrointestinal tract, lungs, liver, kidneys, eyes, urinary bladder, and epithelial tissues. However, most of these effects were reversible after a recovery period[3].

Future Directions and Postmarketing Studies

Long-Term Safety and Differentiation Syndrome

Postmarketing studies are necessary to fully assess the long-term safety of gilteritinib, particularly to characterize the risk of differentiation syndrome and other potential adverse effects. These studies will help in refining the safety mitigation plan and ensuring that the benefits of gilteritinib outweigh the risks[2].

Key Takeaways

• Clinical Efficacy: Gilteritinib has shown significant efficacy in treating relapsed or refractory AML with FLT3 mutations, with a CR/CRh rate of 21% and improved transfusion independence.
• Market Impact: The introduction of gilteritinib is expected to increase healthcare costs but may offer long-term benefits by reducing transfusion and hospitalization costs.
• Safety Considerations: The drug carries risks, including differentiation syndrome, which requires careful monitoring and postmarketing studies to fully characterize.
• Regulatory Approval: Gilteritinib was approved by the FDA in 2018, along with a companion diagnostic assay to detect FLT3 mutations.

FAQs

What is gilteritinib used for?

Gilteritinib is used for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a FLT3 mutation.

How is gilteritinib administered?

Gilteritinib is administered orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit occurs.

What are the key findings from the ADMIRAL trial?

The ADMIRAL trial showed a complete remission (CR) or CR with partial hematologic recovery (CRh) rate of 21%, and significant improvements in transfusion independence among patients.

What are the potential side effects of gilteritinib?

Potential side effects include differentiation syndrome, and toxicity in various organ systems as observed in preclinical studies.

How does gilteritinib affect healthcare costs?

Gilteritinib is expected to increase healthcare costs in the short term but may reduce costs associated with transfusions and hospitalizations in the long term.

Sources

1. FDA Approves Gilteritinib for Relapsed or Refractory AML with a FLT3 Mutation. FDA.
2. 211349Orig1s000 - accessdata.fda.gov.
3. Summary Basis of Decision for Xospata. Health Products and Food Branch.
4. Gilteritinib Fumarate - Drug Targets, Indications, Patents - Synapse.
5. A budget impact analysis of gilteritinib for the treatment of relapsed/refractory FLT3 mutation-positive acute myeloid leukemia. PubMed.