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, 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

Study Overview

• Status: Recruiting
• Conditions: AML With Gene Mutations
• Intervention / Treatment: Drug: ZE46-0134

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 Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kate Dokukina, PhD, MD; Phone Number: +38269728309; Email: kdokukina@eileanther.com

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred Hospital
      • Contact: Shaun Fleming, Dr.; Phone Number: +61 3 9076 3583; Email: s.fleming2@alfred.org.au
    • Melbourne, Victoria, Australia, 3128
      • Recruiting
      • Eastern Health - Box Hill Hospital
      • Contact: Tse-Chieh Teh, Dr.; Phone Number: +61 425 326 804; Email: t.teh@alfred.org.au
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Recruiting
      • Linear Clinical Research Ltd
      • Contact: Carolyn Grove, Prof
• South Korea
  • Seoul, South Korea, 03080
    • Not yet recruiting
    • Seoul National University Hospital
    • Contact: Dong-Yeop Shin; Phone Number: 82-2-2072-7209; Email: shindongyeop@snu.ac.kr
  • Seoul, South Korea, 02841
    • Not yet recruiting
    • Korea University Anam Hospital
    • Contact: Yong Park; Phone Number: 82-2-920-5981; Email: paark76@hanmail.net
  • Seoul, South Korea, 06591
    • Not yet recruiting
    • The Catholic University of Korea Seoul St. Mary'S Hospital
    • Contact: Hee-Je Kim; Phone Number: 82-2-2258-6054; Email: cumckim@catholic.ac.kr
  • Gyeonggi-do
    • Incheon, Gyeonggi-do, South Korea, 21565
      • Not yet recruiting
      • Gachon University Gil Medical Center
      • Contact: Kwai Han Yoo; Phone Number: 82-32-458-2752; Email: khyoo@gilhospital.com
• Taiwan
  • New Taipei City, Taiwan, 235041
    • Not yet recruiting
    • Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare
    • Contact: Yao-Yu Hsieh; Phone Number: 886-970-746-920; Email: alecto39@gmail.com
  • Taichung, Taiwan, 404327
    • Not yet recruiting
    • China Medical University Hospital
    • Contact: Su-Peng Yeh; Phone Number: 886-975-680-836; Email: supengyeh@gmail.com
  • Tainan, Taiwan, 704302
    • Not yet recruiting
    • National Cheng Kung University Hospital
    • Contact: Tsai-Yun Chen; Phone Number: 886-936-257-940; Email: teresa@mail.ncku.edu.tw
  • Xitun, Taiwan, 407219
    • Not yet recruiting
    • Taichung Veterans General Hospital
    • Contact: Po-Wei Liao; Phone Number: 886-988-063-468; Email: rs60809st@hotmail.com
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
      • Contact: Schiller
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Olin
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Blum
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • The University of Chicago
      • Contact: Stock
  • Kansas
    • Lawrence, Kansas, United States, 66160
      • Recruiting
      • University of Kansas
      • Contact: Lin
  • Maryland
    • College Park, Maryland, United States, 20742
      • Recruiting
      • University of Maryland
      • Contact: Baer
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Stein
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • University of North Carolina
      • Contact: Zeidner
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • University of Cincinnati
      • Contact: Curran
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • The Ohio State University
      • Contact: Handa
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health & Science University
      • Contact: Swords
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • The University of Texas Southwestern Medical Center
      • Contact: Madanat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. Patient is ≥18 years of age at the time of obtaining informed consent.
3. Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
4. 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.
5. 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.
6. Patients have a life expectancy of at least 3 months in the opinion of the Investigator.
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

8. Patient must meet the following criteria as indicated on the clinical laboratory tests:

   1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN)
   2. Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease
   3. Estimated glomerular filtration (eGFR) rate of >50 mL/min as calculated by the Modification of Diet in Renal Disease equation.

9. Female patients:

   1. 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
   2. If of childbearing potential, must:

   i. Have a negative serum pregnancy test at the Screening visit and urine pregnancy test on admission to the clinic on Day-1.

   ii. 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.

   iii. 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).

10. 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.

Exclusion Criteria:

1. 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).
2. Patient is ≥18 years of age at the time of obtaining informed consent.
3. Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
4. 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.
5. 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.
6. Patients have a life expectancy of at least 3 months in the opinion of the Investigator.
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

8. Patient must meet the following criteria as indicated on the clinical laboratory tests:

   1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN)
   2. Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease
   3. Estimated glomerular filtration (eGFR) rate of >50 mL/min as calculated by the Modification of Diet in Renal Disease equation.

9. Female patients:

   1. 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
   2. If of childbearing potential, must:

   i. Have a negative serum pregnancy test at the Screening visit and urine pregnancy test on admission to the clinic on Day-1.

   ii. 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.

   iii. 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).

10. 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.

Exclusion criteria

1. Diagnosis of isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML)
2. Acute promyelocytic leukemia (FAB M3)
3. Active central nervous system (CNS) involvement by AML
4. Clinical signs/symptoms of leukostasis requiring urgent therapy
5. 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
6. Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs of thrombosis.
7. 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.
8. 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.
9. Female patients who are pregnant or lactating
10. 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.
11. 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.
12. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

18

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZE46-0134 Dose Level -1; Optional and would only be performed Dose Level 1 is poorly tolerated	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 1	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 2	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 3	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 4	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 5	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Selected dose 1; 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	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Selected dose 2; 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	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 6	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 7	Drug: ZE46-0134; oral capsules QD
Experimental: ZE46-0134 Dose Level 8	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Dose Level -1; Optional and would only be performed Dose Level 1 is poorly tolerated	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Dose Level 1	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Dose Level 2	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Dose Level 3	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Dose Level 4	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Selected dose 1; The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study.	Drug: ZE46-0134; oral capsules QD
Experimental: ZE50-0134 (Group 2) Selected dose 2; The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study.	Drug: ZE46-0134; oral capsules QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline to the End of Treatment (EOT) (Max 24 cycles, 28 days each)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AE/SAE		From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of clinically significant abnormal laboratory results		From baseline to the EOT (Max 24 cycles, 28 days each)
Incidence of abnormal clinically significant ECG results		From baseline to the EOT (Max 24 cycles, 28 days each)
Number of patients with AEs of Grade ≥ 3		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	From baseline to the EOT (Max 24 cycles, 28 days each)
Plasma Cmax	ZE46-0134 peak plasma concentration	PK samples will be collected throughout Cycles 1 and 2 (28 days each)
Plasma Css	ZE46-0134 steady state plasma concentration	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	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	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		Up to 6 cycles (168 days total)
Number of patients attaining CR by Cycle 6		Up to 6 cycles (168 days total)
Number of patients attaining response (CR, CRh, CRi, MLFS) by Cycle 6		Up to 6 cycles (168 days total)

Other Outcome Measures

Outcome Measure	Time Frame
Proportion of patients who became FLT3 ITD and TKD undetectable	During 6 Cycles of treatment (28 days each)
Number of patients with Genomic or proteomic abnormalities	From baseline to the EOT (Max 24 cycles, 28 days each)

Collaborators and Investigators

• Sponsor: Lomond Therapeutics Holdings, Inc.
• Investigators: Principal Investigator: Carolyn Grove, Prof, Linear Clinical Research

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: April 5, 2024
• First Submitted That Met QC Criteria: April 10, 2024
• First Posted (Actual): April 16, 2024

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 24, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Leukemia, Myeloid, Acute
• Other Study ID Numbers: ZE46-0134-0002; CT-2024-CTN-00161-1 (Other Identifier: Therapeutic Goods Administration)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No