Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000180516p
Ethics application status
Submitted, not yet approved
Date submitted
12/02/2024
Date registered
26/02/2024
Date last updated
26/02/2024
Date data sharing statement initially provided
26/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
An Exploratory Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of ZE63-0302 in Healthy Volunteers
Scientific title
An Exploratory Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of ZE63-0302 in Healthy Volunteers
Secondary ID [1] 311470 0
ZE63-0302-0001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia (AML) 332785 0
Condition category
Condition code
Cancer 329502 329502 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a an exploratory Phase I, single dose escalation clinical trial conducted in healthy volunteers. The safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of ZE63-0302 following oral administration in healthy volunteers will be evaluated using a randomised, double-blind, placebo-controlled trial design.

A total of up to 40 healthy volunteers are planned to be enrolled into 5 cohorts (8 participants per cohort). Eligible participants will be randomised to receive a single dose of ZE63-0302 (6 participants) or placebo (2 participants) administered as an oral capsule under fasted conditions on Day 1.

The starting dose of ZE63-0302 will be 20 mg, with a planned dose range from 20 to 1200 mg to be evaluated across the 5 cohorts. 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).

The SRC may recommend an optional evaluation of food effect in Cohort 2, 3, 4 and/or 5 (i.e., dosing participants in a fed state instead of fasted state, using the same dose level used in a prior cohort).

Participants in the fed cohorts will be provided with a high-fat, high-caloric meal after a 10 hour fast overnight, consisting of the following: two eggs fried in butter, two rashers of bacon, two slices of toast with 16 g butter per slice, 125 g of hash brown potatoes and 240 mls of whole milk. ZE63-0302 or placebo will be administered following the consumption of the meal,

Adherence to the intervention will be done via supervised drug administration.
Intervention code [1] 327921 0
Treatment: Drugs
Comparator / control treatment
Placebo – Oral capsules containing microcrystalline cellulose instead of investigational product and identical in appearance will be used in this study.
Control group
Placebo

Outcomes
Primary outcome [1] 337301 0
To assess the PK, including plasma concentrations, of ZE63-0302 in plasma following administration of single oral doses in healthy adult volunteers.
Timepoint [1] 337301 0
Blood plasma samples will be collected as follows: Day 1 pre-dose, 0.25 hrs, 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs and 12 hrs post-dose, Day 2 24 hrs and 36 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose and Day 8 168 hrs post-dose.
Secondary outcome [1] 431398 0
To assess the safety and tolerability of single oral doses of ZE63-0302 in healthy adult volunteers.
Timepoint [1] 431398 0
Adverse events - The Investigator will make an assessment of severity for each AE and SAE reported during the study. The assessment will be based on the Investigator’s clinical judgment. The severity of each AE and SAE will be graded using the categories I (mild), II (moderate), III (severe), IV (life-threatening), V (death) and assessed continuously as they are reported or observed and reviewed daily for up to 8 days post-dose.

Body Weight - is measured using scales at Screening, Day -1, pre-dose Day 1, Day 2 post-dose, Day 3 post-dose, Day 4 post-dose and Day 8 post commencement of intervention.

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer, respiratory rate by manual breath count and temperature by thermometer. Measured from Screening, Day -1, Day 1 pre-dose,0.25 hrs, 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 6 hrs and 8 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose and Day 8 168 hrs post-dose.

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, 1 hr, 4 hrs, 8 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 4 post-dose and Day 8 post-dose.

Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected from Screening, Day -1, Day 1 6 hrs post-dose, Day 2 24 hrs post-dose, Day 4 72 hrs post-dose and Day 8 post-dose.
Secondary outcome [2] 431399 0
Exploratory Outcome: To assess the PD of single oral doses of ZE63-0302 and its relationship to drug concentrations.
Timepoint [2] 431399 0
Blood plasma samples will be collected as follows: pre-dose Day 1 2 hrs and 6 hrs post dose, Day 2 24 hrs post-dose,

Eligibility
Key inclusion 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 (BMI) 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 50.0 kg at screening.
4. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the screening visit and prior to dosing 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. HR in the range of 40 to 100 bpm after at least 5 minutes in a supine position
d. Body temperature (tympanic or oral) in the range 35.5°C to 37.5°C (inclusive).
e. No clinically significant findings in serum chemistry, haematology, coagulation and urinalysis tests as judged by the Investigator.
f. 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 non smokers (including tobacco, nicotine replacement therapy, e-cigarettes and marijuana) for at least 3 months prior to first study drug administration (self-reported to the Investigator) at screening visit 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 (FSH) 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 one month prior to screening until at least 30 days after the last dose of 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 one month prior to screening 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
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 or infestations within 4 weeks prior to dosing 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 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
5. Any screening laboratory result outside the normal laboratory reference range (as confirmed upon repeated testing) and deemed clinically significant by the PI. Participants who have Gilbert's syndrome, or who have hyperbilirubinaemia consistent with Gilbert's syndrome, will not be eligible.
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) within 5 half-lives of individual agent or within 28 days (whichever is longer) prior to dosing or during the study.
8. Use of or plans to use agents (e.g., grapefruit and grapefruit products) that have clinically significant interaction with CYP3A4 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 (whichever is longer) prior to dosing.
9. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or clinically significant 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 < 60 mL/min using the Cockcroft-Gault formula.
14. History of any drug or alcohol abuse in the past 2 years defined as >21 units of alcohol per week for males and >14 units of alcohol per week for females. Where 1 unit = 360 mL of beer, 150 mL wine, or 30 mL of spirits.
15. No alcohol consumption within 24 hours prior to check-in (Day -1).
16. Positive drugs of abuse, cotinine or alcohol breath test results at the screening visit or at check-in (Day -1).
17. Use of any prescription medications within 14 days or at least 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, including oral contraceptives and use of any over-the-counter medication (including herbal products, nutritional, diet aids, vitamin supplements, minerals and hormone supplements) within 7 days or at least 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, with the exception of the occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days).
18. 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.
19. Known hypersensitivity to any of the study drug ingredients.
20. 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) at check-in (Day -1).
21. Females who are breastfeeding or planning to breast feed at any time during the study.
22. 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.
23. Receiving an investigational drug in another clinical trial within 60 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration.
24. Any other condition or prior therapy that in the opinion of the Investigators 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.

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)
All study participants who sign an informed consent form (ICF) at screening will receive a unique sequential number (i.e., a Screening Number).
Participants who meet the study eligibility criteria will be assigned a randomisation number pre-dose on Day 1, which corresponds to a study treatment (ZE63-0302 or placebo). Sealed participant-specific code break envelopes will be produced by the unblinded statistician(s) and will be retained at the clinical facility in a secure, accessible location.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to ZE63-0302 or placebo will be performed using a block randomisation algorithm and will be documented in the study randomisation schedule. The randomisation schedule will be prepared by an unblinded statistician and maintained under controlled access.
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 FIH study with ZE63-0302 and as such no formal sample size calculation was performed. The chosen sample size chosen is deemed adequate to evaluate all study endpoints.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/02/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26145 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 42005 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 315755 0
Commercial sector/Industry
Name [1] 315755 0
Eilean Therapeutics AU Pty Ltd (A subsidiary of Eilean Therapeutics LLC)
Country [1] 315755 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Eilean Therapeutics AU Pty Ltd (A subsidiary of Eilean Therapeutics LLC)
Address
Country
Australia
Secondary sponsor category [1] 317869 0
Commercial sector/Industry
Name [1] 317869 0
Avance Clinical Pty Ltd
Address [1] 317869 0
Country [1] 317869 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314614 0
Bellberry Human Research Ethics Committee A
Ethics committee address [1] 314614 0
https://bellberry.com.au/
Ethics committee country [1] 314614 0
Australia
Date submitted for ethics approval [1] 314614 0
02/02/2024
Approval date [1] 314614 0
Ethics approval number [1] 314614 0

Summary
Brief summary
This is a double-blind, placebo-controlled, First-in-Human Study study to assess the safety of ZE63-0302 ,and how this drug acts in the body in healthy volunteers. ZE63-0302 may be indicated for use in patients with Acute Myeloid Leukaemia (AML), but a trial of the drug in healthy volunteers is needed before trials in AML 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. Participants with a prior cancer diagnosis are not eligible for inclusion in this study.

Study details
All healthy volunteer participants who choose to enrol in this study will be assigned by chance to receive a single dose of ZE63-0302 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.
It is hoped this research will determine the maximum dose of ZE63-0302 that can be administered safely without causing severe reactions. Once the dose of ZE63-0302 has been determined in healthy volunteers, a trial investigating the efficacy of ZE63-0302 as a treatment for patients with AML may proceed.
Trial website
Trial related presentations / publications
Public notes
Exclusion Criteria:
20. Use of any inactivated vaccinations within 14 days, or any live vaccinations within 30 days prior to the first study drug administration. Note: Subjects vaccinated for COVID-19 or influenza within at least 2 weeks prior to enrollment or earlier will be considered eligible for enrollment as long as they do not present with post-vaccination clinical symptoms, have a negative rapid antigen test (in the case of COVID-19), and are deemed otherwise healthy.
26. Any history of long COVID infection (defined by continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation).

Contacts
Principal investigator
Name 132178 0
Dr Peter Schrader
Address 132178 0
Linear Clinical Research - 1st Floor B-Block Hospital Avenue WA 6009
Country 132178 0
Australia
Phone 132178 0
+61 08 6382 5100
Fax 132178 0
Email 132178 0
pschrader@linear.org.au
Contact person for public queries
Name 132179 0
Peter Schrader
Address 132179 0
Linear Clinical Research - 1st Floor B-Block Hospital Avenue WA 6009
Country 132179 0
Australia
Phone 132179 0
+61 08 6382 5100
Fax 132179 0
Email 132179 0
pschrader@linear.org.au
Contact person for scientific queries
Name 132180 0
Peter Schrader
Address 132180 0
Linear Clinical Research - 1st Floor B-Block Hospital Avenue WA 6009
Country 132180 0
Australia
Phone 132180 0
+61 08 6382 5100
Fax 132180 0
Email 132180 0
pschrader@linear.org.au

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.