AML With Gene MutationsPhase 1NCT06366789
Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated or Spliceosome Mutated Relapsed or Refractory Acute Myeloid Leukemia
A Phase 1 study testing ZE46-0134 in people with AML With Gene Mutations, run by Lomond Therapeutics Holdings, Inc. at 23 sites in 4 countries.
Trial summary
This is a clinical study aiming to assess pharmacokinetics, pharmacodynamics and preliminary efficacy of ZE46-0134 in patients with FLT3 and spliceosome mutated Relapsed or Refractory Acute Myeloid Leukemia Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- AML With Gene Mutations
- What is being tested?
- ZE46-0134
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 150 participants
- Where
- 23 sitesin 4 countries
- Study dates
- 29 May 2024to Dec 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written Informed Consent must be obtained from the patient or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
- Patient is ≥18 years of age at the time of obtaining informed consent.
- Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
- Group 1: Patient must have a confirmed FLT3-ITD or FLT3-TKD mutation by central laboratory testing. Group 2: Patient must have a documented SF3B1, SRSF2, U2AF1, or ZRSR2 pathogenic mutation by local lab sequencing.
- For Group 1 only: Patients must have previously been treated with Gilteritinib with failure to stop disease progression, or not met the criteria for treatment with Gilteritinib in the opinion of the Investigator, or chosen not to have treatment with Gilteritinib for social reasons.
- Patients have a life expectancy of at least 3 months in the opinion of the Investigator.
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- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
- Patient must meet the following criteria as indicated on the clinical laboratory tests:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN)
- Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease
- Estimated glomerular filtration (eGFR) rate of >50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
- Female patients:
- If of non-childbearing potential i.e., surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the Screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or
- If of childbearing potential, must:
- Have a negative serum pregnancy test at the Screening visit and urine pregnancy test on admission to the clinic on Day-1.
- Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 45 days after the last dose of study drug.
- Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception from Screening until at least 45 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle).
- Male patients and their female spouse/partners who are of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (at least 1of which must be a barrier method) starting at Screening and continue throughout the study period and for 45 days after the final study drug administration. Male patient must not donate sperm starting at Screening and throughout the study period and for 45 days after the final study drug administration.
Who cannot join
- Written Informed Consent must be obtained from the patient or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
- Patient is ≥18 years of age at the time of obtaining informed consent.
- Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
- Patient must have a confirmed FLT3 ITD, TKD or ITD-F691L mutation documented within the past 90 days in absence of therapy or within the Screening period 28 days) prior to study drug administration on C1D1 if therapy has been given.
- Patients must have previously been treated with Gilteritinib with failure to stop disease progression, or not met the criteria for treatment with Gilteritinib in the opinion of the Investigator, or chosen not to have treatment with Gilteritinib for social reasons.
- Patients have a life expectancy of at least 3 months in the opinion of the Investigator.
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- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
- Patient must meet the following criteria as indicated on the clinical laboratory tests:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN)
- Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease
- Estimated glomerular filtration (eGFR) rate of >50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
- Female patients:
- If of non-childbearing potential i.e., surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the Screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or
- If of childbearing potential, must:
- Have a negative serum pregnancy test at the Screening visit and urine pregnancy test on admission to the clinic on Day-1.
- Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 45 days after the last dose of study drug.
- Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception from Screening until at least 45 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle).
- Male patients and their female spouse/partners who are of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (at least 1of which must be a barrier method) starting at Screening and continue throughout the study period and for 45 days after the final study drug administration. Male patient must not donate sperm starting at Screening and throughout the study period and for 45 days after the final study drug administration.
- Diagnosis of isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML)
- Acute promyelocytic leukemia (FAB M3)
- Active central nervous system (CNS) involvement by AML
- Clinical signs/symptoms of leukostasis requiring urgent therapy
- Known active infection with Human Immunodeficiency Virus (HIV), hepatitis B or hepatitis C. Patients with a history of positive serology for hepatitis B or C require a negative Polymerase chain reaction (PCR) test for virus to go onto therapy
- Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs of thrombosis.
- Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent; if the half-life of the agent is unknown, patients must wait 1 week prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the local regulatory authority.
- Systemic antineoplastic therapy within 5 half-lives or radiation therapy within 1 week prior to starting protocol with the exception of hydroxyurea, which is allowed to control white blood cell counts.
- Female patients who are pregnant or lactating
- Patients with psychological, familial, social, or geographic factors, other significant medical condition, laboratory abnormality that otherwise preclude them from giving informed consent, following the protocol, potentially hamper compliance with study treatment and follow-up or would confound the interpretation of the results of the study.
- Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction with evidence of residual abnormalities within 6 months prior to enrollment (Troponin (regular or high sensitivity) leak alone not included if no residual dysfunction), New York Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
- Infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control in the opinion of the Investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
Trial locations and contacts
23 sites in 4 countries. Contact the study team or a site near you to ask about taking part.
23 sites in 4 countries
United States12 sites, 12 recruiting
- Recruiting
Emory University
Atlanta, Georgia, 30322
Blum
- Recruiting
University of North Carolina
Chapel Hill, North Carolina, 27514
Zeidner
- Recruiting
The University of Chicago
Chicago, Illinois, 60637
Stock
- Recruiting
University of Cincinnati
Cincinnati, Ohio, 45219
Curran
- Recruiting
University of Maryland
College Park, Maryland, 20742
Baer
- Recruiting
The Ohio State University
Columbus, Ohio, 43210
Handa
- Recruiting
The University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Madanat
- Recruiting
University of Kansas
Lawrence, Kansas, 66160
Lin
- Recruiting
University of California, Los Angeles
Los Angeles, California, 90095
Schiller
- Recruiting
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Stein
- Recruiting
Oregon Health & Science University
Portland, Oregon, 97239
Swords
- Recruiting
University of California, San Francisco
San Francisco, California, 94143
Olin
South Korea4 sites, 4 recruiting
- Not yet recruiting
Gachon University Gil Medical Center
Incheon, Gyeonggi-do, 21565
Kwai Han Yoo, 82-32-458-2752, khyoo@gilhospital.com
- Not yet recruiting
Korea University Anam Hospital
Seoul, 02841
Yong Park, 82-2-920-5981, paark76@hanmail.net
- Not yet recruiting
Seoul National University Hospital
Seoul, 03080
Dong-Yeop Shin, 82-2-2072-7209, shindongyeop@snu.ac.kr
- Not yet recruiting
The Catholic University of Korea Seoul St. Mary's Hospital
Seoul, 06591
Hee-Je Kim, 82-2-2258-6054, cumckim@catholic.ac.kr
Taiwan4 sites, 4 recruiting
- Not yet recruiting
Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare
New Taipei City, 235041
Yao-Yu Hsieh, 886-970-746-920, alecto39@gmail.com
- Not yet recruiting
China Medical University Hospital
Taichung, 404327
Su-Peng Yeh, 886-975-680-836, supengyeh@gmail.com
- Not yet recruiting
National Cheng Kung University Hospital
Tainan, 704302
Tsai-Yun Chen, 886-936-257-940, teresa@mail.ncku.edu.tw
- Not yet recruiting
Taichung Veterans General Hospital
Xitun, 407219
Po-Wei Liao, 886-988-063-468, rs60809st@hotmail.com
Australia3 sites, 3 recruiting
- Recruiting
The Alfred Hospital
Melbourne, Victoria, 3004
Shaun Fleming, Dr., +61 3 9076 3583, s.fleming2@alfred.org.au
- Recruiting
Eastern Health - Box Hill Hospital
Melbourne, Victoria, 3128
Tse-Chieh Teh, Dr., +61 425 326 804, t.teh@alfred.org.au
- Recruiting
Linear Clinical Research Ltd
Perth, Western Australia, 6009
Carolyn Grove, Prof
About this study
Official title: A Phase 1, Open-label, Dose Escalation and Dose Expansion, Multicenter Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ZE46-0134 in Adults With FLT3 Mutated or Spliceosome Mutated Relapsed or Refractory Acute Myeloid Leukemia (AML)
This is a clinical study aiming to assess pharmacokinetics, pharmacodynamics and preliminary efficacy of ZE46-0134 in patients with FLT3 and spliceosome mutated Relapsed or Refractory Acute Myeloid Leukemia
Read the detailed description
This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations and spliceosome mutations. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study.
The study will be run in 2 parts: Part 1 will be dose escalation and determination of MTD, and Part 2 will be dose expansion.
Part 1 of the study will have 2 groups. Group 1: 3 to 6 eligible patients with FLT3 mutation will be sequentially enrolled into each of 8 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of study treatment. For patients that continued to derive benefit after 24 cycles of treatment, continuation of ZE46-0134 therapy will be considered. Group 2: 3 to 6 eligible patients with spliceosome mutation will be sequentially enrolled into each of 4 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of study treatment. For patients that continued to derive benefit after 24 cycles of treatment, continuation of ZE46-0134 therapy will be considered.
In Part 2, the dose expansion phase will involve enrolling up to 30 patients across 2 dose cohorts (i.e., 15 patients per cohort) for Group 1 and up to 30 patients across 2 dose cohorts (i.e., 15 patients per cohort) for Group 2. ZE46-0134 will be dosed as described for Part 1 of the study. The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study.
Indication background information:
Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow (BM) and is the most commonly diagnosed adult leukemia with a median age at diagnosis is 68 years, with an overall survival (OS) rate of 29.8%. As patients age, there is a 10% decrease in 5-year OS for every additional decade of life, with a 5-year OS of 0.4% in patients age >85 years1. Furthermore, remission rates and OS depend on a number of other factors, including cytogenetics, previous BM disorders, and comorbidities.
FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed on immature hematopoietic progenitors and hematopoietic stem cells. FLT3 signaling is initiated when FLT3 ligand binds to FLT3, inducing the dimerization and activation of FLT3 via autophosphorylation. This then activates downstream signaling of phosphoinositide 3-kinase/protein kinase B (PI3K/PKB), mitogen-activated protein kinase (MAPK), and JAK2/STAT5 which leads to cell proliferation and suppression of apoptosis2.
FLT3 kinase is directly implicated in the pathogenesis of hematologic malignancies, particularly AML. FLT3 mutations are the most frequently identified mutations in AML patients. Activating mutations in FLT3, which are FLT3-internal tandom duplication (ITD) and FLT3 tyrosine kinase domain (TKD) mutations, account for 30% of all AML cases2. As a result of these mutations, the FLT3 receptor is continuously activated leading to the continuous activation of downstream signaling pathways, PI3K/AKT, MAPK, and signal transducer and activator of transcription (STAT5), resulting in increased cell proliferation and decreased apoptosis.
- Conditions
- AML With Gene Mutations
- Being tested
- ZE46-0134
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZE46-0134Drug
oral capsules QD
| Study group | Role | What they receive |
|---|---|---|
| ZE46-0134 Dose Level -1 | Experimental | Optional and would only be performed Dose Level 1 is poorly tolerated Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 1 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 2 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 3 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 4 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 5 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Selected dose 1 | Experimental | The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study and will not exceed a loading dose of 150 mg x 2 days and maintenance dose of 50 mg QD Receives: Drug: ZE46-0134 |
| ZE46-0134 Selected dose 2 | Experimental | The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study and will not exceed a loading dose of 150 mg x 2 days and maintenance dose of 50 mg QD Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 6 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 7 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE46-0134 Dose Level 8 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level -1 | Experimental | Optional and would only be performed Dose Level 1 is poorly tolerated Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 1 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 2 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 3 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 4 | Experimental | Not described Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Selected dose 1 | Experimental | The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study. Receives: Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Selected dose 2 | Experimental | The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study. Receives: Drug: ZE46-0134 |
What is being measured
The primary outcome is the main question the study is designed to answer.
The incidence of DLTs
To determine the maximum tolerated dose or biologically effective dose of ZE46-0134 in adults with FLT3 and spliceosome mutated relapsed and refractory AML.
Measured: From baseline to the End of Treatment (EOT) (Max 24 cycles, 28 days each)
Secondary outcomes (12)
Incidence of AE/SAE
Measured: From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of clinically significant abnormal laboratory results
Measured: From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of abnormal clinically significant ECG results
Measured: From baseline to the EOT (Max 24 cycles, 28 days each)
Number of patients with AEs of Grade ≥ 3
Measured: From baseline to the EOT (Max 24 cycles, 28 days each)
Number of treatment-related deaths
Number of deaths, deemed related to the study drug by the Investigator
Measured: From baseline to the EOT (Max 24 cycles, 28 days each)
Plasma Cmax
ZE46-0134 peak plasma concentration
Measured: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma Css
ZE46-0134 steady state plasma concentration
Measured: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma Cmin
Minimum ZE46-0134 plasma concentration reached during a dosing interval
Measured: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma AUC
Area under the ZE46-0134 plasma concentration-time curve during a dosing interval
Measured: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Number of patients attaining any type of Complete Remission (CR, CRh, CRi) by Cycle 6
Measured: Up to 6 cycles (168 days total)
Number of patients attaining CR by Cycle 6
Measured: Up to 6 cycles (168 days total)
Number of patients attaining response (CR, CRh, CRi, MLFS) by Cycle 6
Measured: Up to 6 cycles (168 days total)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2024
- Study start29 May 2024
- Primary completionJan 2026 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AML With Gene MutationsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- dose escalation and dose optimization study
- Masking
- None (open label)
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Lomond Therapeutics Holdings, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Carolyn Grove, Prof, Principal investigator, Linear Clinical Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06366789
- Sponsor's protocol ID
- ZE46-0134-0002
- Other IDs
- CT-2024-CTN-00161-1
- Status last verified
- Dec 2025
- First submitted
- 5 Apr 2024
- Last updated
- 31 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1, Open-label, Dose Escalation and Dose Expansion, Multicenter Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ZE46-0134 in Adults With FLT3 Mutated or Spliceosome Mutated Relapsed or Refractory Acute Myeloid Leukemia (AML)
- ClinicalTrials.gov ID
- NCT06366789
- Acronym / sponsor ID
- ZE46-0134-0002
- Conditions
- AML With Gene Mutations
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Lomond Therapeutics Holdings, Inc.Industry (pharma, biotech, devices)
- Study start
- 29 May 2024 (actual)
- Primary completion
- Jan 2026 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 16 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a clinical study aiming to assess pharmacokinetics, pharmacodynamics and preliminary efficacy of ZE46-0134 in patients with FLT3 and spliceosome mutated Relapsed or Refractory Acute Myeloid Leukemia
Detailed description
This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations and spliceosome mutations. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study.
The study will be run in 2 parts: Part 1 will be dose escalation and determination of MTD, and Part 2 will be dose expansion.
Part 1 of the study will have 2 groups. Group 1: 3 to 6 eligible patients with FLT3 mutation will be sequentially enrolled into each of 8 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of study treatment. For patients that continued to derive benefit after 24 cycles of treatment, continuation of ZE46-0134 therapy will be considered. Group 2: 3 to 6 eligible patients with spliceosome mutation will be sequentially enrolled into each of 4 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of study treatment. For patients that continued to derive benefit after 24 cycles of treatment, continuation of ZE46-0134 therapy will be considered.
In Part 2, the dose expansion phase will involve enrolling up to 30 patients across 2 dose cohorts (i.e., 15 patients per cohort) for Group 1 and up to 30 patients across 2 dose cohorts (i.e., 15 patients per cohort) for Group 2. ZE46-0134 will be dosed as described for Part 1 of the study. The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study.
Indication background information:
Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow (BM) and is the most commonly diagnosed adult leukemia with a median age at diagnosis is 68 years, with an overall survival (OS) rate of 29.8%. As patients age, there is a 10% decrease in 5-year OS for every additional decade of life, with a 5-year OS of 0.4% in patients age >85 years1. Furthermore, remission rates and OS depend on a number of other factors, including cytogenetics, previous BM disorders, and comorbidities.
FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed on immature hematopoietic progenitors and hematopoietic stem cells. FLT3 signaling is initiated when FLT3 ligand binds to FLT3, inducing the dimerization and activation of FLT3 via autophosphorylation. This then activates downstream signaling of phosphoinositide 3-kinase/protein kinase B (PI3K/PKB), mitogen-activated protein kinase (MAPK), and JAK2/STAT5 which leads to cell proliferation and suppression of apoptosis2.
FLT3 kinase is directly implicated in the pathogenesis of hematologic malignancies, particularly AML. FLT3 mutations are the most frequently identified mutations in AML patients. Activating mutations in FLT3, which are FLT3-internal tandom duplication (ITD) and FLT3 tyrosine kinase domain (TKD) mutations, account for 30% of all AML cases2. As a result of these mutations, the FLT3 receptor is continuously activated leading to the continuous activation of downstream signaling pathways, PI3K/AKT, MAPK, and signal transducer and activator of transcription (STAT5), resulting in increased cell proliferation and decreased apoptosis.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 18
- Model description
- dose escalation and dose optimization study
| Arm | Type | Receives |
|---|---|---|
| ZE46-0134 Dose Level -1 | Experimental | Drug: ZE46-0134Optional and would only be performed Dose Level 1 is poorly tolerated |
| ZE46-0134 Dose Level 1 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 2 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 3 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 4 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 5 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Selected dose 1 | Experimental | Drug: ZE46-0134The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study and will not exceed a loading dose of 150 mg x 2 days and maintenance dose of 50 mg QD |
| ZE46-0134 Selected dose 2 | Experimental | Drug: ZE46-0134The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study and will not exceed a loading dose of 150 mg x 2 days and maintenance dose of 50 mg QD |
| ZE46-0134 Dose Level 6 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 7 | Experimental | Drug: ZE46-0134 |
| ZE46-0134 Dose Level 8 | Experimental | Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level -1 | Experimental | Drug: ZE46-0134Optional and would only be performed Dose Level 1 is poorly tolerated |
| ZE50-0134 (Group 2) Dose Level 1 | Experimental | Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 2 | Experimental | Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 3 | Experimental | Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Dose Level 4 | Experimental | Drug: ZE46-0134 |
| ZE50-0134 (Group 2) Selected dose 1 | Experimental | Drug: ZE46-0134The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study. |
| ZE50-0134 (Group 2) Selected dose 2 | Experimental | Drug: ZE46-0134The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Written Informed Consent must be obtained from the patient or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
- Patient is ≥18 years of age at the time of obtaining informed consent.
- Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
- Group 1: Patient must have a confirmed FLT3-ITD or FLT3-TKD mutation by central laboratory testing. Group 2: Patient must have a documented SF3B1, SRSF2, U2AF1, or ZRSR2 pathogenic mutation by local lab sequencing.
- For Group 1 only: Patients must have previously been treated with Gilteritinib with failure to stop disease progression, or not met the criteria for treatment with Gilteritinib in the opinion of the Investigator, or chosen not to have treatment with Gilteritinib for social reasons.
Key exclusion criteria (30 listed)
- Written Informed Consent must be obtained from the patient or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
- Patient is ≥18 years of age at the time of obtaining informed consent.
- Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
- Patient must have a confirmed FLT3 ITD, TKD or ITD-F691L mutation documented within the past 90 days in absence of therapy or within the Screening period 28 days) prior to study drug administration on C1D1 if therapy has been given.
- Patients must have previously been treated with Gilteritinib with failure to stop disease progression, or not met the criteria for treatment with Gilteritinib in the opinion of the Investigator, or chosen not to have treatment with Gilteritinib for social reasons.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZE46-0134oral capsules QD | Drug | ZE46-0134 Dose Level -1, ZE46-0134 Dose Level 1, ZE46-0134 Dose Level 2, ZE46-0134 Dose Level 3, ZE46-0134 Dose Level 4, ZE46-0134 Dose Level 5, ZE46-0134 Dose Level 6, ZE46-0134 Dose Level 7, ZE46-0134 Dose Level 8, ZE46-0134 Selected dose 1, ZE46-0134 Selected dose 2, ZE50-0134 (Group 2) Dose Level -1, ZE50-0134 (Group 2) Dose Level 1, ZE50-0134 (Group 2) Dose Level 2, ZE50-0134 (Group 2) Dose Level 3, ZE50-0134 (Group 2) Dose Level 4, ZE50-0134 (Group 2) Selected dose 1, ZE50-0134 (Group 2) Selected dose 2 |
Primary outcome
The incidence of DLTs
Time frame: From baseline to the End of Treatment (EOT) (Max 24 cycles, 28 days each)
To determine the maximum tolerated dose or biologically effective dose of ZE46-0134 in adults with FLT3 and spliceosome mutated relapsed and refractory AML.
12 secondary outcomes
Incidence of AE/SAE
Time frame: From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of clinically significant abnormal laboratory results
Time frame: From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of abnormal clinically significant ECG results
Time frame: From baseline to the EOT (Max 24 cycles, 28 days each)
Number of patients with AEs of Grade ≥ 3
Time frame: From baseline to the EOT (Max 24 cycles, 28 days each)
Number of treatment-related deaths
Time frame: From baseline to the EOT (Max 24 cycles, 28 days each)
Plasma Cmax
Time frame: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma Css
Time frame: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma Cmin
Time frame: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma AUC
Time frame: PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Number of patients attaining any type of Complete Remission (CR, CRh, CRi) by Cycle 6
Time frame: Up to 6 cycles (168 days total)
Number of patients attaining CR by Cycle 6
Time frame: Up to 6 cycles (168 days total)
Number of patients attaining response (CR, CRh, CRi, MLFS) by Cycle 6
Time frame: Up to 6 cycles (168 days total)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Carolyn Grove, Prof principal investigator
Linear Clinical Research
23 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ZE46-0134 in people with AML With Gene Mutations, run by Lomond Therapeutics Holdings, Inc. at 23 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 31 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in United States, South Korea, Taiwan, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Kate Dokukina, PhD, MD (+38269728309, kdokukina@eileanther.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The incidence of DLTs (time frame: From baseline to the End of Treatment (EOT) (Max 24 cycles, 28 days each)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Dec 2025.