SNDX-5613 + Gilteritinib for Acute Myeloid Leukemia

Recruiting at 2 trial locations

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Uma Borate

Must be taking: Strong CYP3A4 inhibitors

Disqualifiers: Acute promyelocytic leukemia, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of SNDX-5613 and gilteritinib for treating patients with acute myeloid leukemia that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and has a mutation in the FLT3 gene along with either a mutation in the NMP1 gene or a type of mutation called a rearrangement in the MLL gene. SNDX-5613 is in a class of medications called menin inhibitors. It works by blocking the action of mutated MLL and NMP1 proteins that signal cancer cells to multiply. Gilteritinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of mutated FLT3 proteins that signal cancer cells to multiply. Giving SNDX-5613 with gilteritinib may be safe, tolerable and/or effective in treating patients with relapsed/refractory FLT3 mutated acute myeloid leukemia.

Do I have to stop taking my current medications?

The trial requires participants to continue taking certain antifungal medications like itraconazole, ketoconazole, posaconazole, or voriconazole. However, you must not be on any other strong CYP3A4 inhibitors or inducers. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Gilteritinib (Xospata) for treating acute myeloid leukemia?

Gilteritinib has been shown to improve survival and response rates in patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations, compared to standard chemotherapy. Clinical trials have demonstrated its effectiveness in achieving complete remission and prolonging overall survival. ^{1 2 3 4 5}

Is the combination of SNDX-5613 and Gilteritinib safe for humans?

Gilteritinib, also known as Xospata, has been studied for safety in patients with acute myeloid leukemia (AML) and is generally considered manageable, with common side effects including fatigue, nausea, and diarrhea. Serious but manageable side effects include differentiation syndrome and QT interval prolongation (a heart rhythm issue), and it requires monitoring during treatment. ^{1 3 4 6 7}

What makes the drug SNDX-5613 + Gilteritinib unique for treating acute myeloid leukemia?

This treatment combines Gilteritinib, a targeted oral drug that inhibits a specific mutation in acute myeloid leukemia (AML) cells, with SNDX-5613, potentially enhancing its effectiveness. Gilteritinib is already known for improving survival in patients with relapsed or refractory AML with FLT3 mutations, making this combination a novel approach to potentially increase treatment efficacy. ^{1 2 3 4 7}

Research Team

Uma Borate, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with acute myeloid leukemia that has either returned after treatment or hasn't responded to treatment, and who have specific genetic changes (FLT3 mutation along with an NPM1 mutation or MLL rearrangement).

Inclusion Criteria

Signed informed consent must be obtained prior to participation in the study

Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73m^2

Ability to communicate with the investigator and comply with study procedures

Exclusion Criteria

I do not have any infections that are currently uncontrolled.

I have had cancer before, but it fits the exceptions.

I have HIV, HBV, or HCV but meet specific health criteria.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive SNDX-5613 orally twice per day and gilteritinib once per day on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Bone marrow biopsy, aspiration, and blood sample collection throughout the study

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 12 weeks for up to 2 years.

Up to 2 years

Treatment Details

Interventions

• Gilteritinib
• SNDX-5613

Trial Overview The trial is testing the safety and optimal doses of SNDX-5613 (a menin inhibitor) and gilteritinib (a tyrosine kinase inhibitor), which are drugs designed to block cancer cell growth by targeting certain mutated proteins.

Participant Groups

Group I: Treatment (SNDX-5613 and gilteritinib) Experimental Treatment 4 Interventions

Patients receive SNDX-5613 PO BID and gilteritinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration, and blood sample collection throughout the study.

Gilteritinib is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in European Union as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in Japan as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Who Is Running the Clinical Trial?

Uma Borate

Lead Sponsor

Trials

7

Recruited

310+

Findings from Research

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]

In a phase IB study involving 80 participants with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), gilteritinib combined with intensive chemotherapy achieved a high composite complete response rate of 89%, indicating strong efficacy in this patient population.

Gilteritinib was well-tolerated as both part of the chemotherapy regimen and as maintenance therapy, with a median overall survival time of 46.1 months, suggesting it is a safe and effective treatment option for patients with FLT3-mutant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML. Pratz, KW., Cherry, M., Altman, JK., et al.[2023]

In a phase 3 trial involving 371 patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), gilteritinib significantly improved overall survival compared to salvage chemotherapy, with a median survival of 9.3 months versus 5.6 months.

Gilteritinib also led to higher rates of complete remission (21.1% vs. 10.5%) and had fewer severe adverse events compared to chemotherapy, indicating it is a safer and more effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl, AE., Martinelli, G., Cortes, JE., et al.[2023]

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 is a newly approved second-generation FLT3 inhibitor specifically designed for treating relapsed or refractory acute myeloid leukemia (AML) in patients with FLT3 mutations, which are found in about one-third of AML cases.

This treatment targets the FLT3 mutation, which is associated with poor prognosis due to increased tumor growth and reduced cell differentiation, potentially improving outcomes for patients with this challenging form of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Novel FLT3 Inhibitor for Relapsed/Refractory Acute Myeloid Leukemia. Marjoncu, D., Andrick, B.[2021]

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]

Gilteritinib has been approved in the EU as a monotherapy for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, showing a significant improvement in overall survival (9.3 months) compared to salvage chemotherapy (5.6 months) in a phase III study with 371 participants.

The safety profile of gilteritinib is considered manageable, with common side effects including increases in liver enzymes and creatine phosphokinase, as well as gastrointestinal and general symptoms like fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. Tzogani, K., Røshol, H., Olsen, HH., et al.[2021]

References

1. 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]

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

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML. [2023]

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

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. [2023]

4. France pubmed.ncbi.nlm.nih.gov

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

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

Gilteritinib: A Novel FLT3 Inhibitor for Relapsed/Refractory Acute Myeloid Leukemia. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. [2021]