Gilteritinib vs Midostaurin for Acute Myeloid Leukemia

Recruiting at 43 trial locations

Overseen By Soumya Chappidi, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: PrECOG, LLC.

Must not be taking: CYP3A inducers, P-gp inducers

Disqualifiers: M3 AML, CNS leukemia, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

181 Participants Needed

Trial Summary

What is the purpose of this trial?

Eligible untreated patients with FLT3 acute myeloid leukemia (AML) between the ages of 18 and 70 will be randomized to receive gilteritinib or midostaurin during induction and consolidation. Patients will also receive standard chemotherapy of daunorubicin and cytarabine during induction and high-dose cytarabine during consolidation. Gilteritinib, is an oral drug that works by stopping the leukemia cells from making the FLT3 protein. This may help stop the leukemia cells from growing faster and thus may help make chemotherapy more effective. Gilteritinib has been approved by the Food and Drug Administration (FDA) for patients who have relapsed or refractory AML with a FLT3 mutation but is not approved by the FDA for newly diagnosed FLT3 AML, and its use in this setting is considered investigational. Midostaurin is an oral drug that works by blocking several proteins on cancer cells, including FLT3 that can help leukemia cells grow. Blocking this pathway can cause death to the leukemic cells. Midostaurin is approved by the FDA for the treatment of FLT3 AML. The purpose of this study is to compare the effectiveness of gilteritinib to midostaurin in patients receiving combination chemotherapy for FLT3 AML.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take drugs that strongly affect certain liver enzymes (CYP3A and P-gp), so check with your doctor about your specific medications.

What data supports the effectiveness of the drugs Gilteritinib and Midostaurin for treating Acute Myeloid Leukemia?

Gilteritinib and Midostaurin are drugs that target a specific mutation in acute myeloid leukemia (AML) and have shown effectiveness in improving survival rates. Gilteritinib has been approved for relapsed or refractory AML with a specific mutation, showing better survival compared to standard chemotherapy, while Midostaurin, when combined with standard chemotherapy, has been effective in newly diagnosed cases with the same mutation. ^{1 2 3 4 5}

What is the safety profile of Gilteritinib and Midostaurin for treating acute myeloid leukemia?

Midostaurin is generally well-tolerated, with common side effects including febrile neutropenia (fever with low white blood cell count), nausea, and diarrhea. Gilteritinib has a manageable safety profile but requires monitoring for serious side effects like differentiation syndrome (a potentially life-threatening condition), QT prolongation (heart rhythm changes), and pancreatitis (inflammation of the pancreas). ^{1 3 5 6 7}

What makes the drug combination of Gilteritinib and Midostaurin unique for treating acute myeloid leukemia?

This drug combination is unique because it targets FLT3 mutations in acute myeloid leukemia (AML) with two different inhibitors, Gilteritinib and Midostaurin, which are used alongside standard chemotherapy drugs Cytarabine and Daunorubicin. Gilteritinib is particularly notable for its use in relapsed or refractory cases, offering a new option for patients who have not responded to other treatments. ^{1 2 3 4 8}

Research Team

Selena Luger, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

Adults aged 18-70 with previously untreated FLT3 mutated Acute Myeloid Leukemia (AML) who have good organ function and no severe heart conditions or other cancers. They must not be pregnant, agree to use contraception, and can't have had certain treatments for related diseases within the last 21 days.

Inclusion Criteria

I do not have another cancer that could affect this treatment's results.

I can care for myself but may not be able to do heavy physical work.

I haven't taken any hypomethylating agents in the last 21 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Participants receive standard chemotherapy of daunorubicin and cytarabine, and are randomized to receive either gilteritinib or midostaurin. Bone marrow aspirate and biopsy are done on Day 21 and after Induction to assess response.

3 months

Multiple visits (in-person)

Consolidation

Participants with a complete response proceed to consolidation chemotherapy with high-dose cytarabine and either gilteritinib or midostaurin. Bone marrow aspirate and biopsy are done after the first cycle of consolidation.

3 months

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of overall survival and event-free survival.

68 months

Treatment Details

Interventions

• Cytarabine
• Daunorubicin
• Gilteritinib
• Midostaurin

Trial Overview The trial is testing whether gilteritinib or midostaurin is more effective when combined with standard chemotherapy drugs daunorubicin and cytarabine in treating AML. Gilteritinib is investigational in this context while midostaurin is FDA-approved for FLT3 AML.

Participant Groups

Group I: Arm A Experimental Treatment 3 Interventions

Induction: Daunorubicin, cytarabine and gilteritinib. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and gilteritinib.

Group II: Arm B Active Control 3 Interventions

Induction: Daunorubicin, cytarabine and midostaurin. Depending on response, second cycle of Induction may be given. Consolidation: High-dose cytarabine and midostaurin.

Cytarabine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

PrECOG, LLC.

Lead Sponsor

Trials

19

Recruited

8,000+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Findings from Research

Midostaurin, when combined with standard chemotherapy (cytarabine and daunorubicin), significantly improves event-free survival, disease-free survival, and overall survival in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), based on a phase III trial.

The treatment with midostaurin is considered safe, showing no significant difference in overall toxicity compared to placebo, although it was associated with a higher incidence of grade 3 to 5 anemia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. Kim, M., Williams, S.[2019]

Gilteritinib, an FLT3 inhibitor approved by the FDA for relapsed or refractory acute myeloid leukemia, showed a 21% complete remission rate and a median overall survival of 9.3 months compared to 5.6 months with standard chemotherapy, indicating its efficacy in improving patient outcomes.

The treatment comes with safety warnings for serious conditions like differentiation syndrome and QT prolongation, necessitating careful monitoring of patients' heart rhythms and blood chemistry during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation. Pulte, ED., Norsworthy, KJ., Wang, Y., et al.[2023]

Midostaurin is an oral Type III receptor tyrosine kinase inhibitor that effectively targets FLT3 mutations in acute myeloid leukemia (AML), showing robust anti-blast responses in relapsed/refractory patients and potentially bridging them to transplant.

While generally well tolerated as a single agent, midostaurin's hematologic toxicity increases when combined with standard chemotherapy, but it may prolong survival in patients with FLT3-ITD mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin: an emerging treatment for acute myeloid leukemia patients. Gallogly, MM., Lazarus, HM.[2020]

Midostaurin, a multikinase inhibitor, was found to have a manageable safety profile in a study of 103 patients with FLT3 mutation-positive acute myeloid leukemia, with no new safety events reported during treatment.

The treatment showed promising outcomes, including high rates of transplant success and low relapse rates during maintenance therapy, indicating its efficacy when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Roboz, GJ., Strickland, SA., Litzow, MR., et al.[2021]

Gilteritinib significantly improves overall survival and response rates in adults with relapsed or refractory acute myeloid leukaemia (AML) with FLT3 mutations, as demonstrated in the phase III ADMIRAL trial.

While gilteritinib is effective, it can cause serious side effects like anaemia and febrile neutropenia, but these are generally manageable with dose adjustments, highlighting the importance of monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. Kang, C., Blair, HA.[2021]

Gilteritinib fumarate is a highly selective oral FLT3 inhibitor that has shown significant efficacy in treating relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), with clinical trials indicating higher response rates and longer overall survival compared to traditional salvage chemotherapy.

The drug was well tolerated in clinical trials, with dose-proportional plasma concentrations observed at doses ranging from 20 to 450 mg/day, supporting its safety profile for patients in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of gilteritinib (Xospata® tablets 40 mg), a therapeutic agent for relapsed or refractory FLT3-mutated acute myeloid leukemia]. Mori, M., Hidaka, K.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

The growing landscape of FLT3 inhibition in AML. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Midostaurin: an emerging treatment for acute myeloid leukemia patients. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. [2021]

7. France pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of gilteritinib (Xospata® tablets 40 mg), a therapeutic agent for relapsed or refractory FLT3-mutated acute myeloid leukemia]. [2021]