Study of Iadademstat and Gilteritinib in Patients With R/R AML With FMS-like Tyrosine Kinase Mutation (FLT3 Mut+)

Study Overview
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Brief Summary
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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.

Detailed Description
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This is an escalation/expansion, open label, single arm, study to investigate the safety and the RP2D of the combination of iadademstat with gilteritinib in FLT3-mutated R/R AML. This study consists of 2 parts. A dose finding part to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and emerging activity of iadademstat and gilteritinib combination, and to determine the pharmacologically-active dose (i.e., the minimum safe and biologically active dose) of iadademstat in combination with gilteritinib, and an expansion part at the specific dose/s selected to evaluate the activity of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML.

Official Title
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An Escalation/Expansion, Open Label, Multicenter Study of Iadademstat and Gilteritinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) With FMS-like Tyrosine Kinase Mutation (FLT3 Mut+): The FRIDA Study

Conditions
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Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory

Intervention / Treatment
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* Drug: Iadademstat
* Drug: Gilteritinib Oral Tablet


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Diagnosis of primary AML or AML with myelodysplasia-related changes (AML-MRC) Patient is in first or second relapse or has refractory disease. Patients must have had histologic verification of AML at the original diagnosis. Patient must be positive for the following FLT3 mutations in bone marrow or PB: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD) D835 or I836 or FLT3-ITD and specified FLT3-TKD. ECOG performance status 0-2 Life expectancy of at least 3 months in the opinion of the investigator. Normal hepatic and renal function. Patient is able to swallow oral medications. Female patients are postmenopausal, documented as surgically sterile, use two methods of contraception or practice true abstinence and have a negative urine pregnancy test at screening. Male patients even if surgically sterilized agree to practice true abstinence or use highly effective barrier contraception. Main Exclusion Criteria: Diagnosis of acute promyelocytic leukemia. Known BCR-ABL-positive leukemia. AML secondary to prior chemotherapy for other neoplasms (except for MDS). AML that has relapsed after or is refractory to more than 2 lines of therapy. Clinically active central nervous system leukemia or prior history of NCI CTCAE Grade ≥ 3 drug-related CNS toxicity. Major surgery or radiation therapy within 4 weeks prior to the first study dose. Prior treatment with iadademstat or FLT3 inhibitors (except sorafenib or midostaurin used in first line as part of induction). Patients not eligible to receive gilteritinib per label. Prior treatment with 3 or more lines of AML therapy. Treatment with any investigational products within 3 weeks prior to first dose of study treatment. Uncontrolled hypertension or poorly controlled diabetes. Evidence of active uncontrolled viral, bacterial, or systemic fungal infection. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Escalation/extension open label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm<br>iadademstat and gilteritinib | Drug: Iadademstat<br>* iadademstat oral solution<br>* Other names: ORY-1001, RO7051790;Drug: Gilteritinib Oral Tablet<br>* 120 mg Gilteritinib<br>* Other names: XOSPATA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AE) | Number of participants with Adverse Events (AE) after treatment with iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. | Up to 18 months | 
| Laboratory value abnormalities and/or adverse events (AE) | Number of participants with laboratory value abnormalities and/or Adverse Events (AE) after treatment with iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. | Up to 18 months | 
| Vital sign abnormalities and/or adverse events (AEs) | Number of participants with vital signs abnormalities and/or Adverse Events (AE) after treatment with iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. | Up to 18 months | 
| Routine 12-lead electrocardiogram (ECG) abnormalities and/or Adverse Events (AEs) | Number of participants with Routine 12-lead electrocardiogram (ECG )abnormalities and/or Adverse Events (AE) after treatment with iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. | Up to 18 months | 
| Recommend Phase 2 dose (RP2D) | Determine the recommended Phase 2 dose (RP2D) of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R | Up to 18 months | 
| iadademstat tmax | Measurement of the time it takes for iadademstat to reach the maximum concentration (Cmax) in blood. | Up to 26 days | 
| Iadademstat Cmax | Measurement of the highest concentration of iadademstat in the blood after a dose is given. | Up to 26 days | 
| iadademstat Cmin | Measurement of the lowest concentration of iadademstat in the blood, after a dose is given. | Up to 26 days | 
| iadademstat AUC | Measurement of how much iadadmestat reaches a person's bloodstream in a given period of time after a dose is given. | Up to 26 days | 
| iadademstat Target Engagement (TE) | Percent of drug covalently bound to LSD1 molecule | Up to 26 days | 
| OR rate | Proportion of patients achieving complete remission (CR), CR with incomplete hematologic recovery (CRi), and partial remission (PR). | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from start of treatment to the time of death from any cause. | Up to 24 months | 
| Event-Free-Survival (EFS) | Time from start of treatment to the date of failure to achieve CR or CRi, relapse from CR/CRi, or death from any cause, whichever occurs first. | Up to 18 months | 
| Overall response rate | Percentage of patients with complete remission (CR), CR with incomplete blood count recovery (CRi), or PR. | Up to 6 months | 
| Time to Response (TTR) | Time from the date of initial dosing at RP2D/expansion dose to first documentation of either a type of CR or Partial Response (PR). | Up to 6 months | 
| Duration of Remission (DoR) | Time from the date of first documentation of any type of remission to the date of first documentation of progression of remission for remitters | Up to 18 months | 
| Transfusion independence rate | A patient is defined as red blood cell (RBC) and/or platelet-transfusion independent if he/she receives no RBC and/or platelet transfusions for a period of at least 8 weeks. Rate of transfusion independence is the percentage of patients who become RBC and/or platelet transfusion independent (from the number of patients transfusion dependent at baseline). | Up to 18 months | 
| Transplantation Rate Time Frame | Percentage of patients undergoing Hematopoietic Stem Cell Transplantation (HSCT) during the study period. | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, FLT3 mut