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Trial registered on ANZCTR


Registration number
ACTRN12623000871640
Ethics application status
Approved
Date submitted
25/07/2023
Date registered
15/08/2023
Date last updated
29/10/2024
Date data sharing statement initially provided
15/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of ZE46 0134 in Healthy Volunteers
Scientific title
A Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of ZE46 0134 in Healthy Volunteers
Secondary ID [1] 310149 0
ZE46-0134-0001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 330720 0
Condition category
Condition code
Cancer 327560 327560 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single and multiple-ascending doses of ZE46-0134 will be administered orally to healthy participants.

Part A (SAD) single-ascending dose: Up to 8 planned dose levels of ZE46-0134, 8 participants each, randomised (ZE46-0134: placebo) as follows:

SAD Cohort 1: 2 mg (fasted)
SAD Cohort 2: 10 mg (fasted)
SAD Cohort 3: 50 mg (fasted)
SAD Cohort 4: 10 mg (fed)
SAD Cohort 5: 100 mg (fasted)
SAD Cohort 6: 50 mg (fasted)
SAD Cohort 7 (optional): 200 mg (fasted)
SAD Cohort 8: 200 mg total dose - two doses of 100 mg each, 12 hours (± 5 minutes) apart between doses

The potential effect of CYP3A4 inhibition will be evaluated in SAD Cohort 6 with participants randomised to receive a single dose of ZE46-0134 or placebo under fasted conditions, in conjunction with itraconazole 100 mg tablet (taken as 200 mg oral dose twice daily on Day -4 and once daily on Days -3 to 8).

For fasted administration (SAD Cohorts 1 to 7 and first dose of SAD Cohort 8): participants will be administered ZE46-0134 or placebo on an empty stomach (at least 10 hours after the last meal). No food will be allowed for at least 4 hours after study drug administration.

For fasted administration (second dose of SAD Cohort 8): participants will be administered ZE46-0134 or placebo at least 2 hours after the last meal. No food will be allowed for at least 2 hours after study drug administration. Water will not be restricted.

For ZE46-0134 administration under fed conditions, following an overnight fast of at least 10 hours, participants will be served a high fat/high calorie breakfast in the clinic approximately 30 minutes before taking their dose of study medication.
A standard high fat, high calorie meal includes:
1. Two eggs fried in butter
2. Two rashers of bacon
3. Two slices of toast with 16 g butter per slice
4. 125 g of hash browns
5. 240 mL of full cream milk
Participants must consume the meal within 20 minutes. The study drug will be administered following consumption of the meal and within 30 minutes after the start of consumption of the meal.

Part B (MAD) multiple-ascending dose: Up to 3 planned dose levels of ZE46-0134, 8 participants each, randomised (ZE46-0134: placebo) as follows:

MAD Cohort 1: 50 mg Day 1, followed by 10 mg Day 2 to 7
MAD Cohort 2: 50 mg Day 1, followed by 10 mg Day 2 to 7 (rabeprazole administration is optional and will be conducted at the ZE46-0134 dose level of preceding cohort)
MAD Cohort 3: 100 mg Day 1, followed by single daily dose of 20 mg from Day 2 to 7

Rabeprazole oral tablets, a protein pump inhibitor (PPI) may be co-administered in Part B of the study to investigate its impact on the absorption of the ZE46-0134.

Participants will only be able to enrol in one dose cohort.

The decision to escalate between dose levels will be based upon review of the safety data and available PK data of each cohort by the Safety Review Committee (SRC).

Part A Cohort 1 to 5, 7 and 8: For each participant, the confinement period will commence on Day -1, with dosing on Day 1 and discharge on Day 4. Participants will return to the clinic for their end of study (EoS) visit on Day 8 (±1 day).

Part A Cohort 6: Participants will visit the clinic on Day -4 to commence itraconazole administration. All participants will return to the clinic on Day -1 and commence a confinement period until Day 4, with dosing (ZE46-0134 or placebo) on Day 1. Participants will return to the clinic on Day 8 for a follow-up visit and on Day 11 (±1 day) for their EoS visit.

Part B: For each participant, the confinement period will commence on Day -1, with dosing commencing on Day 1 and continuing to Day 7 and discharge on Day 10. Participants will return to the clinic for an outpatient follow-up visit on Day 14 (±1 day) and for their EoS visit on Day 21 (± 2 days).

Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Intervention code [1] 326547 0
Treatment: Drugs
Comparator / control treatment
Single-ascending doses of comparator placebo will be administered orally to healthy participants and contain an inactive compendial grade excipient microcrystalline cellulose (MCC) only.
Control group
Placebo

Outcomes
Primary outcome [1] 335408 0
To assess the pharmacokinetics (PK), including plasma concentrations, of ZE46-0134 in plasma following administration of single oral doses in healthy adult volunteers.

Parameters to be examined include: Cmax, Tmax, AUC0-last, AUC0-24, AUC0-inf, t1/2, Lambda z, CL/F and Vz/F.
Timepoint [1] 335408 0
Plasma samples will be collected as follows: Day 1 pre-dose, 0.25hrs, 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-dose, Day 2 24hrs and 36hrs post-dose, Day 3 48hrs post-dose, Day 4 72hrs post-dose and Day 8 168hrs post-dose. PK on Day 8 for Cohorts 3, 4, 5 and 6 only.
Primary outcome [2] 337501 0
To assess the PK, including plasma concentrations, of ZE46-0134 in plasma following administration of multiple oral doses in healthy adult volunteers.

Parameters to be examined include: Cmax, Tmax, Trough concentrations, AUC0-last, AUC0-24, AUC0-inf, t1/2, Lambda z, CL/F and Vz/F.
Timepoint [2] 337501 0
Plasma samples will be collected as follows: pre-dose Day 1 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs post-commencement of intervention.
Primary outcome [3] 337502 0
To assess the PK, including plasma concentrations, of ZE46-0134 in plasma following administration of multiple oral doses in healthy adult volunteers.

Parameters to be examined include: Cmax, Tmax, Trough concentrations, AUC0-last, AUC0-24, AUC0-inf, t1/2, Lambda z, CL/F and Vz/F.
Timepoint [3] 337502 0
Plasma samples will be collected as follows: pre-dose Day 1 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs post-commencement of intervention.
Primary outcome [4] 337503 0
To evaluate and compare the PK profile of ZE46-0134 after multiple dose administration with and without rabeprazole (PPI) pre-dosing in healthy adult volunteers (Optional, Part B only).

Parameters to be examined include: Cmax (with/without), AUC0-inf (with/without), AUC0-last (with/without)
Timepoint [4] 337503 0
Plasma samples will be collected as follows: pre-dose Day 1 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs post-commencement of intervention.
Primary outcome [5] 337504 0
To evaluate and compare the PK profile of ZE46-0134 after multiple dose administration with and without rabeprazole (PPI) pre-dosing in healthy adult volunteers (Optional, Part B only).

Parameters to be examined include: Cmax (with/without), AUC0-inf (with/without), AUC0-last (with/without)
Timepoint [5] 337504 0
Plasma samples will be collected as follows: pre-dose Day 1 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 12hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs post-commencement of intervention.
Secondary outcome [1] 424728 0
To assess the safety and tolerability of single oral doses of ZE46-0134 in healthy adult volunteers
Timepoint [1] 424728 0
Adverse events - will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily for up to 8 days post commencement of intervention. For Cohort 6 - Adverse events will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily for up to 8 days post commencement of intervention and Day 11 End of Study/Early Termination Visit (EoS/ETV). Body Weight - is measured using scales daily from screening up to 8 days post commencement of intervention. For Cohort 6 - Body Weight is measured using scales at screening, Day 2, 3 and Day 4 post commencement of intervention and Day 11 End of Study/Early Termination Visit (EoS/ETV). Vital signs - Blood pressure and heart rate is measured using sphygomomanometer respiratory rate by manual breath count and temperature by thermometer. Measured daily from screening up to 8 days post commencement of intervention. For Cohort 6 - Vital signs - Blood pressure and heart rate is measured using sphygomomanometer respiratory rate by manual breath count and temperature by thermometer. Measured daily from screening, Day 1, 2, 3 and Day 4 post commencement of intervention and Day 11 End of Study/Early Termination Visit (EoS/ETV). up to 8 days post commencement of intervention. Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at screening, single recordings will be obtained daily from screening up to 8 days post commencement of intervention (excluding Day 3). For Cohort 6 - Electrocardiogram (ECG) 12-lead ECG recordings will be obtained in triplicate at screening, single recordings will be obtained daily from screening, Day -1, Day 1, 2 and Day 4 post commencement of intervention and Day 11 End of Study/Early Termination Visit (EoS/ETV). Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected at daily from screening up to 8 days post commencement of intervention (excluding Day 4). For Cohort 6 - Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) blood and urine samples will be collected from screening, Day -1, Day 1, 2 and Day 4 post commencement of intervention and Day 11 End of Study/Early Termination Visit (EoS/ETV).
Secondary outcome [2] 432138 0
To assess the safety and tolerability multiple oral doses of ZE46-0134 in healthy adult volunteers.

Safety endpoints include:
• Incidence, severity and relationship of adverse events (AEs)//serious AEs (SAEs) (including withdrawals due to AEs)
• Change from baseline in body weight
• Change from baseline in vital signs
• Change from baseline in electrocardiogram (ECG) parameters
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis)
Timepoint [2] 432138 0
Adverse events - will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily for up to 21 days post commencement of intervention. Body Weight - is measured using scales from daily from screening, Day -1, Day 1 pre-dose, Day 7 pre-second dose, Day 14 and Day 21 post commencement of intervention. Vital signs - Blood pressure and heart rate is measured using sphygomomanometer, respiratory rate by manual breath count and temperature by thermometer. Measured daily from screening, Day -1, pre-dose Day 1 0.08 hr, 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.08hr, 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs and Day 21 336hrs post-commencement of intervention. Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at screening, single recordings will be obtained from screening, Day -1, pre-dose Day 1 1hr and 6hrs post-dose, Day 2 24hrs post-dose, pre-second dose Day 4 1hr and 6hrs post-second dose pre-third dose Day 7 1hr and 6hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs and Day 21 336hrs post-commencement of intervention. Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected at daily from screening, Day -1, Day 1 6hrs post-dose, Day 3 post-dose, Day 5 24hrs post-second dose, Day 8 24hrs post-third dose, Day 14 and Day 21 post-commencement of intervention.
Secondary outcome [3] 432139 0
To assess the safety and tolerability multiple oral doses of ZE46-0134 in healthy adult volunteers.

Safety endpoints include:
• Incidence, severity and relationship of adverse events (AEs)//serious AEs (SAEs) (including withdrawals due to AEs)
• Change from baseline in body weight
• Change from baseline in vital signs
• Change from baseline in electrocardiogram (ECG) parameters
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis)
Timepoint [3] 432139 0
Adverse events - will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily for up to 21 days post commencement of intervention.

Body Weight - is measured using scales from daily from screening, Day -1, Day 1 pre-dose, Day 7 pre-second dose, Day 14 and Day 21 post commencement of intervention.

Vital signs - Blood pressure and heart rate is measured using sphygomomanometer, respiratory rate by manual breath count and temperature by thermometer. Measured daily from screening, Day -1, pre-dose Day 1 0.08 hr, 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-dose, Day 2 24hrs post-dose, Day 3 post-dose, pre-dose Day 4 0.08hr, 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-second dose, Day 5 24hrs post-second dose, Day 6 post-second dose, pre-third dose Day 7 0.25hr, 0.5hr, 1hr, 2hrs, 4hrs, 6hrs and 8hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs and Day 21 336hrs post-commencement of intervention.

Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at screening, single recordings will be obtained from screening, Day -1, pre-dose Day 1 1hr and 6hrs post-dose, Day 2 24hrs post-dose, pre-second dose Day 4 1hr and 6hrs post-second dose pre-third dose Day 7 1hr and 6hrs post-third dose, Day 8 24hrs post-third dose, Day 9 48hrs post-third dose, Day 10 72hrs post-third dose, Day 14 168hrs and Day 21 336hrs post-commencement of intervention.

Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected at daily from screening, Day -1, Day 1 6hrs post-dose, Day 3 post-dose, Day 5 24hrs post-second dose, Day 8 24hrs post-third dose, Day 14 and Day 21 post-commencement of intervention.

Eligibility
Key inclusion criteria
Healthy volunteers will be included in Part A and Part B of the study if they satisfy all of the following criteria:
1. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
2. Adult males and females, 18 to 55 years of age (inclusive) at screening.
3. Body mass index greater than or equal to 18.5 and less than or equal to 32.0 kg/m2, with a body weight (to 1 decimal place) greater than or equal to 50 kg at screening.
4. Medically healthy without clinically significant abnormalities (in the opinion of the PI) at the screening visit and prior to dosing at the timepoints indicated, including:
a. Physical examination without any clinically significant findings.
b. Systolic blood pressure in the range of 90 mm Hg to 140 mm Hg; diastolic blood pressure in the range of 40 mm Hg to 90 mm Hg.
c. Heart rate in the range of 40 to 100 bpm after 5 minutes in a supine position
d. Body temperature (tympanic or oral) in the range 35.5°C to 37.5°C (inclusive).
e. Serum chemistry, haematology, coagulation and urinalysis tests within normal ranges at screening.
f. Additional inclusion criteria for study Part A (Itraconazole administration in SAD Cohort 6 only): ALT, AST, ALP and gamma-glutamyltransferase (GGT) must be normal (within reference range).
g. Triplicate 12-lead ECG (taken after the volunteer has been supine for at least 5 minutes) with a QTcF less than or equal to 450 msec for males and less than or equal to 470 msec for females and no clinically significant abnormalities.
5. Be nonsmokers (including tobacco, e-cigarettes and marijuana) for at least 3 months prior to first study drug administration (self-reported to investigator) at screening visit, on Day -4 (SAD Cohort 6 only) and at check-in on Day -1.
6. Female volunteers must:
a. Be of nonchildbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone level >40 IU/L at the screening visit), or
b. If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception from signing the consent form until at least 30 days after the last dose of the study drug.
7. Male volunteers must agree not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception from signing the consent form until at least 90 days after the last dose of study drug.
8. Have suitable venous access for blood sampling.
9. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers will be excluded from Part A or Part B of this study if there is evidence of any of the following at the screening visit or prior to dosing:
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI to be clinically significant.
2. Acute infections within 4 weeks prior to the screening or current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
3. Presence or history of any abnormality or illness, including gastrointestinal surgery, which in the opinion of the PI may affect absorption, distribution, metabolism or elimination of the study drug.
4. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
5. Any screening laboratory result outside the normal laboratory reference range and as confirmed upon repeated testing, and deemed clinically significant by the PI.
6. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
7. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids by any route, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 5 half-lives of individual agent or within 28 days prior to enrolment.
8. Use of or plans to use agents that have clinically significant interaction with cytochrome P450 3A4 or the use of any medications that could have a significantly impact on organ function (e.g., barbiturates, omeprazole, cimetidine) during the study or within 5 half-lives of individual agent or within 28 days prior to enrolment.
9. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
10. Participant is planning to have surgery between Screening and the end of study visit.
11. Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies at the screening visit.
12. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
13. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula.
14. Creatine kinase >1.5 x ULN at screening visit (SAD Cohort 6 only) or on Day -1.
15. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) within 12 weeks prior to the screening visit.
16. History of alcohol consumption in the 4 days prior to Screening.
17. Positive drugs of abuse, cotinine or alcohol breath test results at the screening visit, on Day -4 (SAD Cohort 6 only) or at check-in (Day -1).
18. Use of any prescription or over-the-counter medication (including herbal products, diet aids, and hormone supplements) within 14 days prior to the first study drug administration, including oral contraceptives (with the exception of the occasional use of paracetamol [no more than 2 g per day on no more than 3 days in one week]).
19. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial.
20. Known hypersensitivity to any of the study drug ingredients.
21. Use of any vaccinations within 14 days prior to the first study drug administration.
22. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) on Day -4 (SAD Cohort 6 only) or at check-in (Day -1).
23. Females who are breastfeeding or planning to breast feed at any time during the study.
24. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration.
25. Participation in another clinical trial of an investigational drug within 60 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration.
26. Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
27. Any history of prolonged COVID infection (>2 months).
Additional exclusion criteria for study Part A (Itraconazole administration in SAD Cohort 6 only):
28. History or presence of clinically significant hypersensitivity or idiosyncratic reaction to itraconazole or other azole compounds, or any inactive ingredients.
29. History or presence of clinically significant liver disease.

Additional exclusion criteria for study Part B (Optional Rabeprazole administration in MAD Cohort 2):
30. History or presence of clinically significant hypersensitivity or idiosyncratic reaction to rabeprazole or related compounds (e.g., substituted benzimidazoles, other azole compounds), or any inactive ingredients.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomized to receive ZE46-0134 or Placebo according to the randomisation schedule and plan prepared prior to study start. Code-break tamper-evident envelopes containing treatment allocation per participant will be provided to the study site for emergency unblinding if required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants who meet the study eligibility criteria will be assigned a randomisation number
pre-dose on Day 1, which corresponds to a study treatment (ZE46-0134 or placebo). The
allocation to ZE46-0134 or placebo will be performed using a block randomisation algorithm
and will be documented in the study randomisation schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This study is the First in Human (FIH) study with ZE46-0134 and as such no formal sample size calculation was performed. The chosen sample size chosen is deemed adequate to evaluate all study endpoints.

The Full Analysis Set (FAS) will include all randomised participants and will be based on the
randomised treatment regardless of which treatment the participants actually received.

The Safety Analysis Set (SS) will include all participants who receive at least 1 dose of study
drug (ZE46-0134 placebo or rabeprazole). Participants will be analysed according to treatments received.

The PK Analysis Set (PKS) will include all participants in the Safety Analysis Set who have sufficient data to reliably derive at least one PK parameter using non-compartmental analysis and have no other events, or protocol violations that would adversely affect results.

The Pharmacodynamic (PD) Analysis Set will include all participants in the Safety Analysis Set who at least one post dose PD parameter.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/08/2023
Actual
21/08/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
88
Accrual to date
80
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 25210 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 40880 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 314311 0
Commercial sector/Industry
Name [1] 314311 0
Eilean Therapeutics AU Pty Ltd
Country [1] 314311 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Eilean Therapeutics
Address
Level 5, 63 Pirie Street,
Adelaide SA 5000, AUS
Country
Australia
Secondary sponsor category [1] 316258 0
Commercial sector/Industry
Name [1] 316258 0
Avance Clinical Pty Ltd
Address [1] 316258 0
213 Glynburn Road,
Firle, SA 5031 AUS
Country [1] 316258 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313421 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 313421 0
123 Glen Osmond Road,
Eastwood, South Australia, 5063
Ethics committee country [1] 313421 0
Australia
Date submitted for ethics approval [1] 313421 0
28/06/2023
Approval date [1] 313421 0
28/07/2023
Ethics approval number [1] 313421 0
2023-06-774

Summary
Brief summary
This is a single-centre, randomised, double blind, single and multiple ascending dose study to assess the safety of ZE46-0134, and how this drug acts in the body in healthy volunteers. ZE46-0134 may be indicated for use in patients with leukaemia, but a trial of the drug in healthy volunteers is needed before trials in cancer patients can proceed.

Who is it for?
You may be eligible for this study if you are aged 18 to 55 years and are in good general health without a clinically significant medical history. People who have been diagnosed with cancer will not be eligible for this study.

Study details
All healthy volunteer participants who choose to enrol in this study will be assigned by chance to receive either a single or double dose of ZE46-0134 or placebo. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing. If the drug appears safe, additional participants will be assigned by chance to receive a larger single dose of ZE46-0134 or placebo, followed by blood and urine testing. This will continue until a maximum safe dose is determined.

It is hoped this research will determine the maximum dose of ZE46-0134 that can be administered safely without causing severe reactions. Once the dose of ZE46-0134 has been determined in healthy volunteers, a trial investigating the efficacy of ZE46-0134 as a treatment for patients with leukaemia may proceed.
Trial website
Trial related presentations / publications
Public notes
Note: Subjects fully vaccinated for COVID-19 within at least 2 weeks prior to enrollment or earlier will be considered eligible for enrollment as long as they have negative antigen test, do not present with post-vaccination clinical symptoms, if any, and are deemed otherwise healthy

Contacts
Principal investigator
Name 128102 0
Dr Peter Schrader
Address 128102 0
Linear Clinical Research - B Block
1st Floor, B-Block, Hospital Avenue
Nedlands, WA, 6009
Country 128102 0
Australia
Phone 128102 0
+61 8 63825100
Fax 128102 0
Email 128102 0
[email protected]
Contact person for public queries
Name 128103 0
Peter Schrader
Address 128103 0
Linear Clinical Research - B Block
1st Floor, B-Block, Hospital Avenue
Nedlands, WA, 6009
Country 128103 0
Australia
Phone 128103 0
+61 8 63825100
Fax 128103 0
Email 128103 0
[email protected]
Contact person for scientific queries
Name 128104 0
Peter Schrader
Address 128104 0
Linear Clinical Research - B Block
1st Floor, B-Block, Hospital Avenue
Nedlands, WA, 6009
Country 128104 0
Australia
Phone 128104 0
+61 8 63825100
Fax 128104 0
Email 128104 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.