Gilteritinib + Ivosidenib/Enasidenib for Acute Myeloid Leukemia

Recruiting at 6 trial locations

Overseen By Eytan Stein, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Investigational agents

Disqualifiers: Acute promyelocytic leukemia, Active infections, Significant cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination to determine its safety and effectiveness in treating acute myeloid leukemia (AML) that has returned or is unresponsive to treatment. Researchers aim to find the optimal dose of gilteritinib (Xospata) combined with either ivosidenib (Tibsovo) or enasidenib (Idhifa) that minimizes side effects. This trial targets individuals with AML who have specific gene mutations in FLT3 and IDH1 or IDH2, confirmed by testing. Those with AML unresponsive to previous treatments and possessing these gene mutations may find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that gilteritinib, when used alone, is generally easy for patients to handle. In a study with 319 patients who had relapsed or hard-to-treat acute myeloid leukemia (AML), gilteritinib demonstrated a manageable safety profile. Patients experienced some side effects, but these were often mild and manageable. Similarly, enasidenib, a drug targeting specific gene mutations, has succeeded in patients with those mutations, showing good results.

For ivosidenib, another drug targeting similar gene mutations, studies have shown it works well when combined with gilteritinib. The safety information for ivosidenib also suggests it is generally easy for patients to handle, with side effects similar to those seen with enasidenib.

This trial is in its early stages, so researchers are still determining the best dose to keep side effects mild. The fact that gilteritinib is already approved by the FDA for other uses adds some confidence about its safety. However, since combining these drugs is new, researchers are closely monitoring to ensure safety for all participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination treatments of gilteritinib with ivosidenib or enasidenib for Acute Myeloid Leukemia (AML) because they target cancer in a novel way. Most standard AML treatments, like chemotherapy, focus on eliminating rapidly dividing cells, which can affect healthy cells too. However, gilteritinib targets specific mutations in the FLT3 gene, while ivosidenib and enasidenib target IDH1 and IDH2 mutations, respectively. This precision approach could potentially reduce side effects and improve outcomes by directly interrupting cancer cell growth pathways, offering a more tailored and effective treatment option for patients with these mutations.

What evidence suggests that this trial's treatments could be effective for relapsed/refractory AML?

Research shows that gilteritinib alone can achieve a 37% remission rate in patients with relapsed and refractory acute myeloid leukemia (AML) who have FLT3 mutations. In this trial, one group of participants will receive a combination of gilteritinib and enasidenib, which targets a different mutation called IDH2. This combination might enhance treatment effectiveness because these drugs address different genetic changes causing AML. Studies have found that using FLT3 and IDH inhibitors like gilteritinib and enasidenib together has a modest success rate of 17% after other treatments have been tried. Another group in this trial will receive a combination of gilteritinib with ivosidenib, which targets IDH1 mutations. Combining gilteritinib with ivosidenib shows promise; when ivosidenib is used with another drug, it has resulted in complete remission for 51% of patients with IDH1 mutations. These drug combinations aim to address multiple mutation types in AML, potentially leading to better outcomes. ^{1 4 6 7 8}

Who Is on the Research Team?

Eytan Stein, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with relapsed or refractory Acute Myeloid Leukemia (AML) and specific gene mutations (FLT3/IDH1 or FLT3/IDH2). They must be able to follow the study plan, have adequate organ function, and not be pregnant. Men and women must agree to use birth control. Exclusions include uncontrolled infections, severe leukemia complications, heart issues, absorption problems, certain neurological diseases, and those on other cancer trials.

Inclusion Criteria

My tests show FLT3 and IDH mutations in my recent relapse.

My kidney function is good, with a creatinine clearance rate of at least 30 mL/min or my serum creatinine is less than 2.0.

I have had a stem cell transplant for my AML.

Exclusion Criteria

I have a history of a brain infection called PML.

I have an ongoing serious infection that isn't under control.

Patient on any other investigational anti-cancer agents

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the combination of gilteritinib with ivosidenib or enasidenib in continuous 28-day cycles

1 year

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Enasidenib
• Gilteritinib
• Ivosidenib

Trial Overview

The trial is testing if combining gilteritinib with ivosidenib or enasidenib is safe and effective for AML patients with certain genetic mutations. It aims to find the highest dose that causes few side effects before using this dose in new participant groups.

How Is the Trial Designed?

Group I: gilteritinib + ivosidenib (Cohort 1) Experimental Treatment 2 Interventions

Each patient will take the combination of gilteritinib/ ivosidenib (Cohort 1) , daily, in continuous 28-day cycles at the dose level that they are assigned.

Group II: gilteritinib + enasidenib (Cohort 2) Experimental Treatment 2 Interventions

Each patient will take the combination of gilteritinib/enasidenib (Cohort 2) daily, in continuous 28-day cycles at the dose level that they are assigned.

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

Approved in United States as Idhifa for:

• Relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation

Approved in European Union as Idhifa for:

• Acute myeloid leukaemia (AML) with an isocitrate dehydrogenase 2 (IDH2) mutation

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Astellas Pharma US, Inc.

Industry Sponsor

Trials

90

Recruited

12,900+

Naoki Okamura

Astellas Pharma US, Inc.

Chief Executive Officer since 2023

Not available

Tadaaki Taniguchi

Astellas Pharma US, Inc.

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

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, 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 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 an effective and well-tolerated treatment for patients with relapsing or refractory FLT3-positive acute myeloid leukemia, showing promise in managing the disease with lower toxicity compared to earlier treatments.

The drug's oral formulation makes it suitable for a wide range of patients, including elderly and frail individuals, allowing for outpatient treatment that reduces hospitalization risks and costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy. Bocchia, M., Carella, AM., Mulè, A., et al.[2022]

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