Dose escalation and expansion of ZE46-0134 for 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 trial tests whether ZE46-0134 is safe and can help adults with relapsed or refractory AML who have FLT3 or spliceosome gene mutations.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 150 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Lomond Therapeutics Holdings, Inc. (Industry-sponsored)
• Drugs / interventions: Gilteritinib, radiation
• Locations: 23 sites (Los Angeles, California and 22 other locations)
• Trial ID: NCT06366789 on ClinicalTrials.gov

What this trial studies

This is a Phase 1, open‑label, multicenter dose‑escalation and dose‑expansion trial studying ZE46‑0134 in adults with relapsed or refractory AML carrying FLT3 or defined spliceosome mutations. Part 1 enrolls two parallel dose‑escalation cohorts (FLT3-mutated and spliceosome‑mutated) to determine the maximum tolerated dose and characterize safety, pharmacokinetics, and pharmacodynamics, with patients treated in 28‑day cycles for up to 24 cycles. Part 2 is a dose‑expansion phase that will enroll additional patients into selected dose cohorts to gather more safety and preliminary efficacy data. Key outcomes include tolerability, PK/PD profiles, and early signals of anti‑leukemia activity.

Who should consider this trial

Good fit: Adults (≥18 years) with relapsed or refractory AML and a confirmed FLT3‑ITD or FLT3‑TKD mutation (Group 1) or a documented SF3B1, SRSF2, U2AF1, or ZRSR2 spliceosome mutation (Group 2), meeting baseline safety and life‑expectancy criteria and, for FLT3 patients, having failed or not being a candidate for gilteritinib.

Not a fit: Patients who lack the specified FLT3 or spliceosome mutations, those responding to standard frontline therapies, or those with very limited life expectancy or poor organ function are unlikely to benefit from this early‑phase investigational therapy.

Why it matters

Potential benefit: If successful, ZE46‑0134 could offer a new targeted treatment option that controls disease or delays progression for patients with these specific mutations.

How similar studies have performed: Approved FLT3 inhibitors such as gilteritinib and midostaurin have demonstrated benefit in FLT3‑mutated AML, whereas direct targeting of spliceosome mutations is less established and remains an area of active early‑phase research.

Eligibility criteria

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.

Where this trial is running

Los Angeles, California and 22 other locations

• University of California, Los Angeles — Los Angeles, California, United States (Recruiting)
• University of California, San Francisco — San Francisco, California, United States (Recruiting)
• Emory University — Atlanta, Georgia, United States (Recruiting)
• The University of Chicago — Chicago, Illinois, United States (Recruiting)
• University of Kansas — Lawrence, Kansas, United States (Recruiting)
• University of Maryland — College Park, Maryland, United States (Recruiting)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (Recruiting)
• University of North Carolina — Chapel Hill, North Carolina, United States (Recruiting)
• University of Cincinnati — Cincinnati, Ohio, United States (Recruiting)
• The Ohio State University — Columbus, Ohio, United States (Recruiting)
• Oregon Health & Science University — Portland, Oregon, United States (Recruiting)
• The University of Texas Southwestern Medical Center — Dallas, Texas, United States (Recruiting)
• The Alfred Hospital — Melbourne, Victoria, Australia (Recruiting)
• Eastern Health - Box Hill Hospital — Melbourne, Victoria, Australia (Recruiting)
• Linear Clinical Research Ltd — Perth, Western Australia, Australia (Recruiting)
• Gachon University Gil Medical Center — Incheon, Gyeonggi-do, South Korea (Not_yet_recruiting)
• Korea University Anam Hospital — Seoul, South Korea (Not_yet_recruiting)
• Seoul National University Hospital — Seoul, South Korea (Not_yet_recruiting)
• The Catholic University of Korea Seoul St. Mary's Hospital — Seoul, South Korea (Not_yet_recruiting)
• Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare — New Taipei City, Taiwan (Not_yet_recruiting)
• China Medical University Hospital — Taichung, Taiwan (Not_yet_recruiting)
• National Cheng Kung University Hospital — Tainan, Taiwan (Not_yet_recruiting)
• Taichung Veterans General Hospital — Xitun, Taiwan (Not_yet_recruiting)

Study contacts

• Principal investigator: Carolyn Grove, Prof — Linear Clinical Research
• Study coordinator: Kate Dokukina, PhD, MD

Conditions AML With Gene Mutations