Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory
Conditions
Keywords
Acute Myeloid Leukemia, FLT3 mut
Brief summary
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
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.
Interventions
DRUGIadademstat
iadademstat oral solution
DRUGGilteritinib Oral Tablet
120 mg Gilteritinib
Sponsors
Oryzon Genomics S.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Escalation/extension open label study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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 is not allowed. Treatment with any other agents with KDM1A/LSD1 inhibitory activity is only allowed if treatment finalized at least 3 weeks prior to first dose on study. Previous treatment with FLT3 inhibitors is allowed in the following cases: midostaurin and sorafenib are allowed when used in first-line therapy regimen as part of induction, consolidation and/or maintenance: quizartinib and gilteritinib are allowed when used in first-line therapy regimen, as part of induction, consolidation and/or maintenance, ONLY if patients were not refractory to the drugs or if responding, relapse did not occur while on these drugs. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OR rate | Up to 18 months | Proportion of patients achieving complete remission (CR), CR with incomplete hematologic recovery (CRi), and partial remission (PR). |
| Routine 12-lead electrocardiogram (ECG) abnormalities and/or Adverse Events (AEs) | Up to 18 months | 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. |
| Recommend Phase 2 dose (RP2D) | Up to 18 months | Determine the recommended Phase 2 dose (RP2D) of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R |
| iadademstat tmax | Up to 26 days | Measurement of the time it takes for iadademstat to reach the maximum concentration (Cmax) in blood. |
| Iadademstat Cmax | Up to 26 days | Measurement of the highest concentration of iadademstat in the blood after a dose is given. |
| iadademstat Cmin | Up to 26 days | Measurement of the lowest concentration of iadademstat in the blood, after a dose is given. |
| iadademstat AUC | Up to 26 days | Measurement of how much iadadmestat reaches a person's bloodstream in a given period of time after a dose is given. |
| iadademstat Target Engagement (TE) | Up to 26 days | Percent of drug covalently bound to LSD1 molecule |
| Adverse Events (AE) | Up to 18 months | Number of participants with Adverse Events (AE) after treatment with iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. |
| Laboratory value abnormalities and/or adverse events (AE) | Up to 18 months | 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. |
| Vital sign abnormalities and/or adverse events (AEs) | Up to 18 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free-Survival (EFS) | Up to 18 months | 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. |
| Overall response rate | Up to 6 months | Percentage of patients with complete remission (CR), CR with incomplete blood count recovery (CRi), or PR. |
| Time to Response (TTR) | Up to 6 months | Time from the date of initial dosing at RP2D/expansion dose to first documentation of either a type of CR or Partial Response (PR). |
| Duration of Remission (DoR) | Up to 18 months | Time from the date of first documentation of any type of remission to the date of first documentation of progression of remission for remitters |
| Transfusion independence rate | Up to 18 months | 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). |
| Transplantation Rate Time Frame | Up to 18 months | Percentage of patients undergoing Hematopoietic Stem Cell Transplantation (HSCT) during the study period. |
| Overall Survival (OS) | Up to 24 months | Time from start of treatment to the time of death from any cause. |
Countries
United States
Contacts
Primary ContactMónica Reale-Vidal, MD
Backup ContactSonia Gutiérrez, MSc
Outcome results
None listed