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Trial registered on ANZCTR


Registration number
ACTRN12624000093583
Ethics application status
Approved
Date submitted
21/12/2023
Date registered
1/02/2024
Date last updated
17/11/2024
Date data sharing statement initially provided
1/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZE50 0134 in Healthy Volunteers
Scientific title
A Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZE50 0134 in Healthy Volunteers
Secondary ID [1] 311180 0
ZE50-0134-0001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic lymphocytic leukemia (CLL) 332358 0
Condition category
Condition code
Cancer 329066 329066 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single-ascending doses of ZE50-0134 soft gelatin capsules are to be administered orally with noncarbonated room temperature water to healthy participants.

• Up to 5 dose escalation cohorts of 8 participants each.
• Up to 5 additional optional cohort(s) of 8 participants each (may also be enrolled to investigate the effect of food on ZE50-0134.
• 1 additional cohort of 8 participants will be enrolled to investigate the effect of CYP3A4 inhibition on ZE50-0134.


Cohort 1: 100 mg
Cohort 2: 200 mg
Cohort 3: 400 mg
Cohort 4: 800 mg
Cohort 5: 1600 mg
Cohort 6-10 (optional): food effect (FE) cohort(s)
Cohort 11: 200 mg fasted (to be administered in conjunction with itraconazole [200 mg itraconazole to be administered twice per day [BID] on Day -4 and once per day [QD] on Days -3 to 8, inclusive)


For fasted administration: Soft gelatin capsules of matching appearance and formulation to the investigational product, however without the ZE50-0134 active ingredient, will be administered as placebo in this study. Participants will receive a single dose of either investigational product or placebo on Day 1 under fasted conditions.

Cohorts 1-5: Participants will administer ZE50-0134 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. Water will not be restricted.
Up to 5 additional optional cohort(s) of 8 participants may also be enrolled to investigate the effect of food on ZE50-0134.
Cohorts 6-10: Doses to be confirmed (the dose level of the optional food effect cohorts will be a dose level already evaluated in a preceding cohort).
In the case that the optional food effect cohort is enrolled, the food effect on the PK of ZE50-0134 will be calculated as fed/fasted ratios for Cmax, AUC0-last and AUC0-inf. Point estimates and 90% confidence interval (CI) for the food effect of ZE50-0134 will be calculated as fed/fasted ratios for AUC0-inf, AUC0-last and Cmax.
Cohorts 6-10 are optional in study design and will only proceed based on results of cohorts 1-5.
Cohort 11 will additionally receive itraconazole (200 mg) twice daily onBID Day -4, and once daily QD on Days -3 – 8 (inclusive).

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 blinded safety data and available pharmacokinetics (PK) data of each cohort by the Safety Review Committee (SRC).

All participants will attend the clinic for a screening visit.

Dose escalation and food effect cohorts (nominal Cohorts 1-10):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.

Effect of CYP3A4 inhibition (nominal Cohort 11): Participants will attend the clinic on Day -4 to receive itraconazole for at home dosing, and will return on Day -1 where they will be confined to the clinic until discharge on Day 8. Participants will return to the clinic for their end of study (EoS) visit on Day 11. In addition, participants will also receive a daily telephone call (check-in) from clinic staff on Day -4 (PM), Day -1 and from Day 5 to Day 8 to remind participants of itraconazole self-administration at home and accurate study diary completion. It is noted that the telephone check-in on Day -1 and Day 8 may not be required if the participant administers the itraconazole dose at the clinical facility under the supervision of site staff.

Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Intervention code [1] 327626 0
Treatment: Drugs
Comparator / control treatment
Capsules of matching appearance and formulation to the investigational product without the ZE50-0134 active ingredient, will be administered as placebo in this study.

Placebo – soft gelatin capsules to match
Control group
Placebo

Outcomes
Primary outcome [1] 336871 0
To assess the PK of ZE50-0134 in plasma following administration of single oral doses in healthy adult volunteers.
Timepoint [1] 336871 0
Blood 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.
Secondary outcome [1] 429982 0
To assess the safety and tolerability of single oral doses of ZE50-0134 in healthy adult volunteers
Timepoint [1] 429982 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 11 days post-dose EOS/ETV (End of Study/Early Termination Visit). Body Weight - is measured using scales at Screening, Day -1 and Day 11 post commencement of intervention EOS/ETV (End of Study/Early Termination Visit). 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, 0.25hrs, 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs, and 8hrs post-dose, Day 2 24hrs post-dose, Day 3 48hrs post-dose, Day 4 72hrs post-dose and Day 11 post-dose EOS/ETV (End of Study/Early Termination Visit). 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, Day 4 post-dose and Day 11 post-dose EOS/ETV (End of Study/Early Termination Visit). Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected from Screening, Day -1, Day 1 6hrs post-dose, Day 2 24hrs post-dose, Day 3 48hrs post-dose, Day 8 post-dose and Day 11 post-dose EOS/ETV (End of Study/Early Termination Visit).

Eligibility
Key inclusion criteria
1. Adult males and females, 18 to 55 years of age (inclusive) at screening.
2. Body mass index (BMI) greater than or equal to 18.0 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 (males) or greater than or equal to 45.0 kg (females) at screening.
3. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the screening visit and prior to dosing at the timepoints indicated in the Schedule of Assessments (SoA), including:
a. Physical examination without any clinically significant findings .
b. Systolic blood pressure in the range of 90 mm Hg to 160 mm Hg; diastolic blood pressure in the range of 40 mm Hg to 95 mm Hg.
c. Heart rate (HR) in the range of 40 to 100 bpm after 5 minutes in a supine or semi-supine position
d. Body temperature (tympanic or oral) in the range 35.5°C to 37.75°C (inclusive).
e. No clinically significant findings in serum chemistry, haematology, coagulation and urinalysis tests as judged by the Investigator, including the following specific findings:
i. Haemoglobin, platelet count, WBC count, lymphocyte count, and neutrophil count within normal ranges (as per local laboratory standard ranges), WBC count (> 3.0 x 109/L), lymphocyte count (> 1.0 x 109/L), and neutrophil count (> 1.5 x 109/L)
ii. AST, ALT and total bilirubin < 1.5 x ULN (note: for participants with Gilbert’s syndrome, ULN is considered to be 2.9 mg/ml).
iiii. Additional inclusion criterion for cohort evaluating effect of CYP3A4 inhibition only: ALT, AST, ALP and gamma-glutamyltransferase (GGT) must be normal (within reference range).f. Triplicate 12-lead ECG (taken after the volunteer has been semi-supine for at least 10 minutes) with average 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.
4. 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 signing the consent form until at least 30 days after the last dose of the study drug.
5. 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.
6. Have suitable venous access for blood sampling.
7. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
8. 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.
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. Note: participants with a history of fully resolved childhood asthma are permitted.
2. Acute infections within 4 weeks prior to Day -1 (nominal Cohorts 1-10) or Day -4 (nominal Cohort 11), 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. Note: participants with Gilbert’s syndrome may be permitted, at the discretion of the PI (or delegate). Participants with a history of cholecystectomy may be permitted at the discretion of the PI (or delegate).
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.
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 (whichever is longer) prior to first study drug administration.
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 first study drug administration. Note: timeframe = 3 days for grapefruit and grapefruit products or other foods/drinks (e.g. pomelo) that may have a clinically significant interaction with CYP3A4.
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 EoS 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, or tuberculosis (TB) at the screening visit.
12. History of latent or active TB infection, or signs or symptoms suggestive of active TB infection upon medical history and/or physical examination.
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. History of alcohol consumption in the 4 days prior to dosing.
16. Positive drugs of abuse, or alcohol breath test results at the screening visit, Day -4 prior to itraconazole administration (nominal Cohort 11 only), or at check-in (Day -1).
17. Volunteer smokes more than 5 cigarettes or equivalent per week, and/or volunteer is unwilling to abstain from smoking (including use of all tobacco products or nicotine-containing products, and smoking cessation aids such as gum or patches) for 72 hours prior to Day -4 (nominal Cohort 11 only) or check-in on Day -1 and throughout the confinement period at the study site.
18. 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 supplements, 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 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 inactivated vaccinations within 14 days, or any live vaccinations within 30 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 prior to itraconazole administration (nominal Cohort 11 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. Receiving an investigational drug in another clinical trial within 30 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 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.

Additional exclusion criteria for cohort evaluating the effect of CYP3A4 inhibition only:
1. History or presence of clinically significant hypersensitivity or idiosyncratic reaction to itraconazole or other azole compounds, or any inactive ingredients.
2. History or presence of clinically significant liver disease.
3. Creatinine kinase more than 1.5 x ULN at Screening or Day -1.

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 ZE50-0134 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 (ZE50-0134 or placebo). The allocation to ZE50-0134 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 FIH study with ZE50-0134 and as such no formal sample size calculation was performed. The 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 study drug (ZE50-0134 or placebo). Participants will be analysed according to treatment received.

The PK Analysis Set will include all participants in the Safety Analysis Set who have sufficient data to reliably calculate at least 1 PK parameter.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/05/2024
Actual
21/05/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
88
Accrual to date
31
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26559 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 42601 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 315438 0
Commercial sector/Industry
Name [1] 315438 0
Eilean Therapeutics AU Pty Ltd (A subsidiary of Eilean Therapeutics LLC)
Country [1] 315438 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Eilean Therapeutics AU Pty Ltd (A subsidiary of Eilean Therapeutics LLC)
Address
Level 5, 63 Pirie Street Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 317507 0
Commercial sector/Industry
Name [1] 317507 0
Avance Clinical Pty Ltd
Address [1] 317507 0
213 Glynburn Road, Firle, South Australia, 5070
Country [1] 317507 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314350 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 314350 0
Ethics committee country [1] 314350 0
Australia
Date submitted for ethics approval [1] 314350 0
19/12/2023
Approval date [1] 314350 0
19/04/2024
Ethics approval number [1] 314350 0
2023-11-1476-AA

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131274 0
Dr Christopher Argent
Address 131274 0
Scientia Clinical Research Ltd, The Bright Building, Level 5, Corner High & Avoca Streets, Randwick NSW 2031, Australia
Country 131274 0
Australia
Phone 131274 0
+61 2 9382 5844
Fax 131274 0
Email 131274 0
christopher.argent@scientiaclinicalresearch.com.au
Contact person for public queries
Name 131275 0
Christopher Argent
Address 131275 0
Scientia Clinical Research Ltd, The Bright Building, Level 5, Corner High & Avoca Streets, Randwick NSW 2031, Australia
Country 131275 0
Australia
Phone 131275 0
+61 2 9382 5844
Fax 131275 0
Email 131275 0
christopher.argent@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 131276 0
Christopher Argent
Address 131276 0
Scientia Clinical Research Ltd, The Bright Building, Level 5, Corner High & Avoca Streets, Randwick NSW 2031, Australia
Country 131276 0
Australia
Phone 131276 0
+61 2 9382 5844
Fax 131276 0
Email 131276 0
christopher.argent@scientiaclinicalresearch.com.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.