Iadademstat + Gilteritinib for Acute Myeloid Leukemia
(FRIDA Trial)
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Trial Summary
What is the purpose of this trial?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 (FLT3 mut+). During the trial, iadademstat will be given in combination with gilteritinib, a drug that is already approved to treat patients with FLT3-mutated R/R 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 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.
What data supports the effectiveness of the drug Gilteritinib for treating Acute Myeloid Leukemia?
Gilteritinib has been shown to improve survival in patients with relapsed or refractory acute myeloid leukemia (AML) with a specific mutation (FLT3). In studies, it led to higher rates of complete remission and longer survival compared to standard chemotherapy.
12345Is the combination of Iadademstat and Gilteritinib safe for treating acute myeloid leukemia?
Gilteritinib, also known as Xospata, has been approved for treating acute myeloid leukemia with a specific mutation and has a known safety profile. Common side effects include anemia, fever, and low platelet counts, while serious risks include differentiation syndrome, brain-related issues, heart rhythm changes, and pancreatitis. Safety measures include regular monitoring of heart and blood health, and it is important to use contraception during treatment due to potential risks to unborn babies.
23678What makes the drug combination of Iadademstat and Gilteritinib unique for treating acute myeloid leukemia?
The combination of Iadademstat and Gilteritinib is unique because it targets acute myeloid leukemia with a specific FLT3 mutation, using Gilteritinib's ability to inhibit the FLT3 enzyme, which is involved in cancer cell growth, and Iadademstat's potential to enhance this effect, offering a novel approach compared to standard chemotherapy.
237910Eligibility Criteria
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.
+6 more
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.
+10 more
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Active armExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sarah Cannon Research Institute, LLCNashville, TN
Duke University Medical CenterDurham, NC
Massachusetts General Hospital (MGH)Boston, MA
UPMC Hillman Cancer CenterPittsburgh, PA
More Trial Locations
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Who Is Running the Clinical Trial?
Oryzon Genomics S.A.Lead Sponsor
References
Gilteritinib: A Novel FLT3 Inhibitor for Relapsed/Refractory Acute Myeloid Leukemia. [2021]Acute myeloid leukemia (AML) is the most common adult leukemia, with an overall poor prognosis. New agents targeting various receptors may improve treatment outcomes and overall survival. FMS-like tyrosine kinase 3 (FLT3) is a targetable mutation occurring in one third of AML patients. It contributes to increased tumor proliferation and decreased cellular differentiation, ultimately conferring a poor overall prognosis. Among patients with FLT3-positive relapsed/refractory AML, outcomes are particularly dismal. Gilteritinib is a novel, second-generation FLT3 inhibitor approved by the U.S. Food & Drug Administration (FDA) for the treatment of relapsed/refractory AML with an FLT3 mutation as detected by an FDA-approved test.
FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation. [2023]On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8-15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%-29%), median duration of CR + CRh was 4.6 months (range, 0.1-15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49-0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.
[Pharmacological and clinical profile of gilteritinib (Xospata® tablets 40 mg), a therapeutic agent for relapsed or refractory FLT3-mutated acute myeloid leukemia]. [2021]Gilteritinib fumarate (Xospata® tablets 40 mg) is a novel, highly selective, oral FMS-like tyrosine kinase 3 (FLT3) inhibitor used for the treatment of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), and it was approved in Japan in September 2018. Preclinical studies demonstrated that gilteritinib inhibited FLT3 and showed antiproliferative activity against Ba/F3 cells expressing mutated FLT3. In addition, gilteritinib inhibited tumor growth, induced tumor regression, and prolonged survival in mice xenografted with MV4-11 cells endogenously expressing FLT3-internal tandem duplication. In clinical trials conducted in the United States, Europe, and Japan, plasma concentrations after administration of gilteritinib 20 to 450 mg/day were generally dose proportional, and gilteritinib was well tolerated. Multiple clinical trials, including a global Phase III study, in patients with relapsed or refractory FLT3-mutated AML treated with gilteritinib demonstrated higher response rates of complete remission or complete remission with partial hematologic recovery and longer overall survival compared with patients treated with salvage chemotherapy. Some clinical trials are ongoing in patients with FLT3-mutated AML at various treatment stages, such as induction therapy, maintenance therapy, and treatment after hematopoietic stem cell transplantation. In conclusion, in vitro, in vivo, and clinical data indicate that gilteritinib fumarate is an effective treatment option in adult patients with relapsed or refractory FLT3-mutated AML in Japan.
Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML. [2023]Label="PURPOSE">Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML.
Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. [2023]Label="BACKGROUND">Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML.
Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. [2021]Gilteritinib (Xospata®), a next-generation tyrosine kinase inhibitor (TKI), is approved in several countries/regions worldwide for the treatment of relapsed or refractory acute myeloid leukaemia (AML) in adults with FMS-like tyrosine kinase 3 (FLT3) mutations. In this patient population, oral gilteritinib significantly improved overall survival (OS) and the response rate for complete remission with full or partial haematological recovery compared with salvage chemotherapy in the phase III ADMIRAL trial. In an integrated safety analysis of patients with relapsed or refractory AML, the most commonly reported grade ≥ 3 treatment-related adverse events (AEs) in gilteritinib recipients included anaemia, febrile neutropenia and thrombocytopenia. Clinically relevant AEs of special interest (AESIs) with gilteritinib therapy included differentiation syndrome, posterior reversible encephalopathy syndrome, QT interval prolongation and pancreatitis. AEs, including AESIs, were generally manageable with dose reduction, interruption or discontinuation. All patients of reproductive potential should use contraception during gilteritinib treatment due to the risk of embryo-foetal toxicity. Given its convenient oral regimen, along with the poor prognosis and paucity of treatment options for adults with relapsed or refractory FLT3-mutated AML, gilteritinib represents a valuable first-line targeted monotherapy in these patients.
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]On October 24, 2019, a marketing authorization valid through the European Union (EU) was issued for gilteritinib monotherapy for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication (ITD), FLT3 D835Y, and FLT3 ITD D835Y, and it induced apoptosis in leukemic cells expressing FLT3 ITD. The recommended starting dose of gilteritinib is 120 mg (three 40 mg tablets) once daily. Gilteritinib was evaluated in one, phase III, open-label, multicenter, randomized study of gilteritinib (n = 247, gilteritinib arm) versus salvage chemotherapy (n = 124, salvage chemotherapy arm) in patients with relapsed or refractory AML with FLT3 mutation. Overall survival (OS) was statistically significantly different between the two groups with a median OS of 9.3 months in the gilteritinib arm compared with 5.6 months for salvage chemotherapy (hazard ratio, 0.637; 95% confidence interval, 0.490-0.830; p = .0004 one-sided log-rank test). The most common adverse reactions with gilteritinib treatment were blood creatine phosphokinase increase, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, diarrhea, fatigue, nausea, constipation, cough, peripheral edema, dyspnea, dizziness, hypotension, pain in extremity, asthenia, arthralgia, and myalgia. The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Xospata was approved in the European Union as monotherapy for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib resulted in a clinically meaningful and statistically significant improvement of overall survival compared with salvage chemotherapy. At the time of the marketing authorization of gilteritinib, there were no approved standard therapies specifically for adult patients diagnosed with relapsed or refractory AML with FLT3 mutation. In terms of safety, the overall accepted safety profile was considered manageable.
Gilteritinib: First Global Approval. [2020]Gilteritinib (Xospata®) is an orally available small molecule receptor tyrosine kinase inhibitor developed by Astellas Pharma in collaboration with Kotobuki Pharmaceutical for the treatment of acute myeloid leukaemia (AML) harbouring FMS-like tyrosine kinase 3 (FLT3) mutations. Gilteritinib inhibits FLT3 (STK1 or FLK2), AXL (UFO or JTK11) and anaplastic lymphoma kinase (ALK or CD246). Gilteritinib inhibits FLT3 signalling in cells expressing FLT3 internal tandem duplication (ITD), tyrosine kinase domain mutation FLT3-D835Y and the double mutant FLT3-ITD-D835Y, thereby inducing apoptosis. Gilteritinib also binds to and inhibits the wild-type and mutated forms of ALK, resulting in reduced tumour cell proliferation in cancer cell types that overexpress the mutation. Gilteritinib is approved in Japan for the treatment of relapsed or refractory AML with FLT3 mutation. Recently, it was also approved in the USA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation, as detected by an FDA-approved test. Clinical development of gilteritinib is underway in several countries worldwide. Development for non-small cell lung cancer and solid tumours has been discontinued.
Gilteritinib (XOSPATA®) in Turkey: Early Access Program Results. [2023]Gilteritinib (XOSPATA®, Astellas) is a type I oral FLT3 inhibitor, a tyrosine kinase AXL inhibitor, involved in both c-Kit and FMS-like tyrosine kinase 3 (FLT3) resistance. In the phase 3 ADMIRAL trial, gilteritinib was compared with the standard of care in (R/R) acute myeloid leukemia (AML) patients who harbored any FLT3 mutation and showed superior efficacy with regard to response and survival.
Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy. [2022]Acute myeloid leukemia is a malignant disorder of the bone marrow, characterized by differentiation, clonal expansion, and uncontrolled proliferation of malignant myeloid progenitor cells and by several molecular and genetic abnormalities. A mutation of FMS-like tyrosine kinase 3 gene can be observed in about one-third of cases of acute myeloid leukemia. Two FLT3 inhibitors are actually approved for FLT3 mutated acute myeloid leukemia: midostaurin, a multikinase first generation inhibitor with lower affinity for FLT3 binding, and gilteritinib fumarate, a potent second-generation inhibitor of both FLT3-ITD and TKD. Gilteritinib is a new effective and well-tolerated drug for patients with relapsing or refractory FLT3-positive acute myeloid leukemia. Thanks to its efficacy, low toxicity, its good manageability (oral formulation), this drug is suitable for all the patients, including elderly frail patient with concomitant therapies or pre-existing or underlying diseases, and can be used also in the outpatient setting, reducing risks and costs related to the hospitalization. We report and discuss seven cases of different patients with FLT3 positive acute myeloid leukemia successfully managed with gilteritinib in the real clinical practice.