A Phase 1b Study of Lonitoclax + Azacitidine in Acute Myeloid Leukemia Patients

A Phase 1b Study of Lonitoclax + Azacitidine (Aza) in Acute Myeloid Leukemia (AML) Patients

This is a clinical study aiming to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ZE50-0134 in relapsed and refractory Acute Myeloid Leukemia patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacitidine Days 1-7; Drug: ZE 50-0134; Drug: ZE50-0134

Detailed Description

It is an open-label Phase 1b clinical study of Lonitoclax + Aza in relapsed/refractory AML patients. The study is an open-label, with 2 parts.

The phase 1b dose escalation portion would include relapsed/refractory patients, as well as in the expansion group. Once the phase 1b dose and schedule of Lonitoclax + Aza is defined in the 3 + 3 design with biologically effective dose assessment, an amendment will be filed with the Regulatory Authorities and expansion cohort of 30 relapsed and refractory AML patients would be enrolled at two different doses (15 patients per dose) to determine the RP2D; the first dosing will be at the presumed potential phase 2 dose combination and the second dosing will be below this.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ekaterina Dokukina; Phone Number: +38269728309; Email: kdokukina@eilenther.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients must be able to understand and provide written informed consent. 2. AML patients: For the dose escalation and expansion, patients aged 18 and older with relapsed and/or refractory AML would be eligible. Prior treatment with a hypomethylating agent or Venetoclax is allowed.

3. At the time of Lonitoclax initiation, white blood count (WBC) needs to be < 25 × 109/L: Hydroxyurea can be used to achieve that level.

4. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 5. Adequate organ function as defined by the following:

1. Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if thought to be secondary to leukemia.
2. Total bilirubin ≤ 1.5 x ULN (patients with known Gilbert's syndrome may enroll if direct bilirubin is ≤ 3 x ULN) for the local laboratory.

3. Estimated Glomerular Filtration Rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CDK-EPI) ≥ 60 mL/min/1.73m2 for the local laboratory.

   6. Female patients of childbearing potential must agree to use a highly effective method of contraception from screening visit until 120 days following the last dose of study treatment. Highly effective methods of contraception include sexual abstinence, bilateral tubal ligation, tricycle combined (estrogen and progestogen containing) oral or transdermal hormonal contraceptives, intrauterine devices and vasectomized partner. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

   7. Male patients capable of having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use highly effective contraception from the screening visit until 120 days until the last dose of study treatment, and themselves use barrier contraception (i.e., condoms). They must also refrain from sperm donation from the screening visit until 120 days following the last dose of study treatment. Should his partner become pregnant or suspect she is pregnant while he is participating in this study, he should inform his treating physician immediately.

   8. Patients must be able to take oral medications. Exclusion Criteria

   1. 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 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 Regulatory Authorities.
   8. Systemic antineoplastic therapy within 1 week (or 5 half-lives of drug received, whichever is shorter) or radiation therapy within 1 week prior to starting protocol except for 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 trial.
   11. Concomitant medications that are strong CYP3A4 inducers.
   12. Patients with QTcF > 470 msec that cannot be corrected with electrolyte replacement, hydration, or medication modifications. This does not apply to patients with a pacemaker as measurement of QTc is not accurate under such conditions and bears no risk to patients since they are being medically paced by their device.
   13. 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 leak alone not included if no residual dysfunction), familial QT prolongation, known potassium wasting syndrome (Bartter syndrome, Gitelman syndrome, and Liddle syndrome), New York Heart Association (NYHA) Class III or IV heart failure, 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.
   14. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.

   Exclusion Criteria:

   1. 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 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 Regulatory Authorities.
   8. Systemic antineoplastic therapy within 1 week (or 5 half-lives of drug received, whichever is shorter) or radiation therapy within 1 week prior to starting protocol except for 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 trial.
   11. Concomitant medications that are strong CYP3A4 inducers.
   12. Patients with QTcF > 470 msec that cannot be corrected with electrolyte replacement, hydration, or medication modifications. This does not apply to patients with a pacemaker as measurement of QTc is not accurate under such conditions and bears no risk to patients since they are being medically paced by their device.
   13. 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 leak alone not included if no residual dysfunction), familial QT prolongation, known potassium wasting syndrome (Bartter syndrome, Gitelman syndrome, and Liddle syndrome), New York Heart Association (NYHA) Class III or IV heart failure, 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.
   14. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. 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

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZE50-0134 + Azacitidine Dose Level -1; Optional and would only be performed Dose Level 1 is poorly tolerated.	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE 50-0134; Oral capsules QD
Experimental: ZE50-0134 + Azacitidine Dose Level 1	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine Dose Level 2	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine Dose Level 3	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine Dose Level 4	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine Dose Level 5	Drug: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine 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: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID
Experimental: ZE50-0134 + Azacitidine 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: Azacitidine Days 1-7; 75 mg/m2 daily, days 1-7; Drug: ZE50-0134; Oral capsules BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the RP2D and expansion cohort enrollment	To determine the recommended phase 2 (RP2D) dose using a 28-day schedule in relapsed and refractory (R/R) AML followed by an expansion cohort.	Up to 24 cycles, 4 weeks each

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite response rate	Composite response rate will be defined as the proportion of efficacy-evaluable patients who achieve CR, CRi, CRh, or MLFS.	Up to 24 cycles, 4 weeks each
To determine the time to neutrophil and platelet recovery in patients receiving Lonitoclax + Aza	Monitoring of neutrophil and platelet counts	Up to 24 cycles, 4 weeks each
Overall incidence of treatment-related and non-treatment-related toxicities	To determine the overall incidence of treatment-related and non-treatment-related toxicities.	Up to 24 cycles, 4 weeks each
Event-free survival	Event-free survival will be measured from start of the treatment to the first of failure to achieve a CR/CRi/CRh/MLFS, or relapse, or death due to any cause, with patients last known to be alive and event-free censored at the date of last contact.	Up to 24 cycles, 4 weeks each
Duration of remission	Duration of remission is defined in responders as the time from documentation of remission to the date of disease progression.	Up to 24 cycles, 4 weeks each

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of patients that undergo hematopoietic stem cell transplant (HSCT)	To determine the percentage of patients that undergo hematopoietic stem cell transplant (HSCT).	Up to 24 cycles, 4 weeks each
Peak plasma concentration of Lonitoclax	To determine peak plasma concentration of Lonitoclax when dosed in combination with Aza and its interaction with strong CYP3A4 inhibitors used in this disease	3 cycles, 4 weeks each
Investigating the baseline properties of leukemia cells	To examine the baseline properties of leukemia cells that respond versus those that do not respond to initial therapy.	Up to 24 cycles, 4 weeks each
Serial properties of AML cells	To determine the serial properties of AML cells that respond and then become resistant to this novel combination.	Up to 24 cycles, 4 weeks each
Minimal Residual Disease (MRD) and immune effects	A BM aspirate and biopsy will be performed at time of count recovery or day 42 (whichever occurs first) after 3 and 6 total cycles of therapy (induction + continuation therapy cycles) and for MRD assessment done by a central lab.	3 and 6 cycles, 4 weeks each
Time to maximum concentration of Lonitoclax	To determin time to maximum concentration of Lonitoclax when dosed in combination with Aza and its interaction with strong CYP3A4 inhibitors used in this disease	3 cycles, 4 weeks each
Area Under the Curve	To determine Area Under the Curve of Lonitoclax when dosed in combination with Aza and its interaction with strong CYP3A4 inhibitors used in this disease	3 cycles, 4 weeks each
The half-life of Lonitoclax	To determine the half-life of Lonitoclax when dosed in combination with Aza and its interaction with strong CYP3A4 inhibitors used in this disease	3 cycles, 4 weeks each

Collaborators and Investigators

• Sponsor: Lomond Therapeutics Holdings, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): January 10, 2026
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: December 5, 2025
• First Submitted That Met QC Criteria: December 18, 2025
• First Posted (Actual): December 26, 2025

Study Record Updates

• Last Update Posted (Actual): December 26, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute
• Other Study ID Numbers: ZE50-0134-0004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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