Iadademstat + Gilteritinib for Acute Myeloid Leukemia

(FRIDA Trial)

Recruiting at 15 trial locations

Overseen By Mónica Reale-Vidal, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Oryzon Genomics S.A.

Must not be taking: KDM1A/LSD1 inhibitors

Disqualifiers: Acute promyelocytic leukemia, BCR-ABL-positive leukemia, uncontrolled infections, others

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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two drugs, iadademstat and gilteritinib, can effectively treat people with acute myeloid leukemia (AML) that has either returned or not responded to treatment, specifically in those with the FLT3 gene mutation. Gilteritinib (Xospata) is already approved for this condition, and researchers seek to discover if adding iadademstat (ORY-1001) can improve outcomes. This trial targets individuals with AML and the FLT3 mutation who have experienced a relapse or have refractory disease after previous treatments. Participants must be able to swallow pills and have a life expectancy of at least three months. 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.

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 have had treatment with iadademstat before, and any treatment with KDM1A/LSD1 inhibitors must have ended at least 3 weeks before starting the trial. Also, you cannot have taken any investigational products within 3 weeks prior to the trial.

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

Research has shown that combining iadademstat and gilteritinib is generally safe for people with FLT3-mutated acute myeloid leukemia. In earlier studies, patients tolerated the combination well. Some side effects occurred, but they were not serious. The two drugs together proved very effective against leukemia. Gilteritinib is already approved for treating this type of leukemia, indicating its safety as a standalone treatment. Early evidence suggests promising results for using these two drugs together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Iadademstat and Gilteritinib for Acute Myeloid Leukemia (AML) because it offers a fresh approach to tackling this aggressive cancer. Iadademstat is a novel drug that targets LSD1, an enzyme involved in cancer cell growth, which is not addressed by current chemotherapy or targeted therapies. Gilteritinib, on the other hand, is already known for inhibiting the FLT3 mutation, a common driver in AML, but when combined with Iadademstat, it could enhance the treatment's effectiveness. This combination aims to not only inhibit cancer growth more effectively but also potentially reduce resistance, offering hope for better outcomes in patients with AML.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that gilteritinib, when used alone, has helped about 20% of patients with relapsed or refractory acute myeloid leukemia (R/R AML) with the FLT3 mutation achieve complete remission, meaning their cancer temporarily went away. On average, these patients experienced 2.8 months without significant cancer-related events. In this trial, participants will receive a combination of iadademstat and gilteritinib. Although researchers are still studying iadademstat, it has been used in patients with similar conditions and alongside other drugs. Researchers aim to determine whether combining iadademstat with gilteritinib can lead to better results than using gilteritinib alone. Early findings suggest that the combination might offer more benefits because the drugs work together in different ways. ^{1 2 3 6 7}

Who Is on the Research Team?

Mónica Reale-Vidal, MD

Principal Investigator

Oryzon Genomics

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) that has returned or hasn't responded to treatment, and they must have specific FLT3 mutations. They should be able to perform daily activities with ease to moderate difficulty, have a life expectancy of at least 3 months, and normal liver and kidney function. Women must not be pregnant and use contraception; men agree to use barrier contraception.

Inclusion Criteria

I can take care of myself and perform daily activities.

Life expectancy of at least 3 months in the opinion of the investigator

My liver and kidney functions are normal.

Exclusion Criteria

I cannot take gilteritinib according to its usage instructions.

Pregnant or lactating women

I haven't had major surgery or radiation therapy in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

Evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and emerging activity of iadademstat and gilteritinib combination, and determine the pharmacologically-active dose

Up to 26 days

Expansion

Evaluate the activity of iadademstat in combination with gilteritinib at the selected dose in patients with FLT3-mutated R/R AML

Up to 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Gilteritinib
• Iadademstat

Trial Overview The study tests Iadademstat in combination with Gilteritinib, an approved drug for AML with FLT3 mutation. It's aimed at patients whose AML has relapsed or is refractory. The goal is to see if adding Iadademstat can improve outcomes compared to using Gilteritinib alone.

How Is the Trial Designed?

Group I: Active arm Experimental Treatment 2 Interventions

iadademstat and gilteritinib

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?

Oryzon Genomics S.A.

Lead Sponsor

Trials

5

Recruited

350+

Published Research Related to This Trial

Gilteritinib is an effective oral treatment for acute myeloid leukaemia (AML) with FLT3 mutations, approved in both Japan and the USA for patients with relapsed or refractory cases.

It works by inhibiting FLT3 signaling, leading to apoptosis in cancer cells, and also targets ALK mutations, reducing tumor cell proliferation, showcasing its dual mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: First Global Approval. Dhillon, S.[2020]

In a real-life study of 17 patients with FLT3-positive relapsed/refractory acute myeloid leukemia (AML) treated with gilteritinib, the overall response rate was an impressive 100%, indicating its strong efficacy.

However, the study also highlighted safety concerns, as common adverse events included anemia and hypokalemia, with patients experiencing peripheral edema having a significantly higher risk of death compared to those without it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib (XOSPATA®) in Turkey: Early Access Program Results. Dogu, MH., Tekgunduz, AIE., Deveci, B., et al.[2023]

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]

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 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]

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 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]

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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5974/505887/Iadademstat-and-Gilteritinib-for-the-Treatment-of

Iadademstat and Gilteritinib for the Treatment of FLT3-Mutated ... The Phase 3 randomized ADMIRAL trial of gilteritinib demonstrated a 20% CR rate and 2.8 months event-free-survival (EFS) (Perl, et al., NEJM ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS7075

Iadademstat in combination with gilteritinib for patients ... Use of the FLT3 inhibitor (FLT3i) gilteritinib as monotherapy for R/R pts resulted in improved outcomes but the duration of remission achieved ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05546580

NCT05546580 | Study of Iadademstat and Gilteritinib in ... Iadademstat is being studied as a treatment for subjects with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) with FMS-like tyrosine kinase mutation ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123125730

Iadademstat and Gilteritinib for the Treatment of FLT3 ... The Phase 3 randomized ADMIRAL trial of gilteritinib demonstrated a 20% CR rate and 2.8 months event-free-survival (EFS) (Perl, et al., NEJM ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9430636/

A DOSE FINDING AND EXPANSION ... More than 100 subjects have been treated with iada, including R/R AML pts with monotherapy and naïve AML pts in combination with azacitidine, ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123125730

Iadademstat and Gilteritinib for the Treatment of FLT3- ... The FRIDA study (NCT05546580) aims to establish the safety, tolerability, and the recommended phase 2 dose (RP2D) of the combination of iada plus gilteritinib ...

7. oryzon.com oryzon.com/en/news-events/news/oryzon-presents-preliminary-data-ongoing-phase-ib-frida-trial-iadademstat-plus

ORYZON presents preliminary data from ongoing Phase Ib ... Data from the first two cohorts demonstrated that combination of iadademstat plus gilteritinib was safe and showed strong antileukemic ...