None listed
Conditions
Brief summary
This is A double-blind, placebo-controlled, First-in-Human Study study to assess the safety ofZE50-0134, and how this drug acts in the body in healthy volunteers. ZE50-0134 may be indicated for use in patients with chronic lymphocytic leukaemia (CLL), 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 dose of ZE50-0134 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 ZE50-0134 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 ZE50-0134 that can be administered safely without causing severe reactions. Once the dose of ZE50-0134 has been determined in healthy volunteers, a trial investigating the efficacy of ZE50-0134 as a treatment for patients with CLL may proceed.
Interventions
Single-ascending doses of ZE50-0134 soft gelatin capsules are to be administered orally with noncarbonated room temperature water to healthy participants.
A total of up to 104 healthy volunteers are planned to be enrolled in this study.
• Up to 5 dose escalation cohorts of 8 participants each (nominal Cohorts 1-5).
• Up to 5 additional optional cohort(s) of 8 participants each (may also be enrolled to investigate the effect of food on ZE50-0134 (nominal Cohorts 6-10).
• 1 additional cohort of
Single-ascending doses of ZE50-0134 soft gelatin capsules are to be administered orally with noncarbonated room temperature water to healthy participants. A total of up to 104 healthy volunteers are planned to be enrolled in this study. • Up to 5 dose escalation cohorts of 8 participants each (nominal Cohorts 1-5). • Up to 5 additional optional cohort(s) of 8 participants each (may also be enrolled to investigate the effect of food on ZE50-0134 (nominal Cohorts 6-10). • 1 additional cohort of 8 participants will be enrolled to investigate the effect of CYP3A4 inhibition on ZE50-0134 (nominal Cohort 11). • 1 additional cohort of 8 participants will be enrolled to evaluate twice per day (BID) dosing of ZE50-0134 (nominal Cohort 12). • 1 additional cohort of 8 participants will be enrolled to evaluate to investigate the effect of a proton pump inhibitor (PPI) (rabeprazole at 20 mg) on ZE50 0134 at a dose of 400 mg (nominal Cohort 13). 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 [BID] on Day -4 and once per day [QD] on Days -3 to 8, inclusive) Cohort 12: 400 mg BID (800 mg total daily dose) Cohort 13: 400 mg (to be administered in conjunction with rabeprazole [20 mg once daily (QD) on Day 1 and Day 2]) 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). Cohort 12: Single dose of ZE50-0134 administered BID (administered in the evening of Day 1, and the morning of Day 2). Cohort 13: Single dose of ZE50-0134 or placebo administered on Day 2. Cohort 13 will additionally receive rabeprazole (20 mg) QD on Day 1 and Day 2. 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. The effect of twice daily dosing will be evaluated in a single cohort. (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. Twice per day dosing (nominal Cohort 12): For each participant, the confinement period will commence on Day -1, with dosing in the evening of Day 1 and morning of Day 2. Participants will be discharged on Day 4 and will return to the clinic for their end of study (EoS) visit on Day 8. Effect of PPI (nominal Cohort 13): For each participant, the confinement period will commence on Day -1, with rabeprazole dosing on Day 1 and Day 2, and ZE50-0134 dosing on Day 2. Discharge will occur on Day 5. Participants will return to the clinic for their EoS visit on Day 9. Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Sponsors
Lomond Therapeutics AU Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
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. 27. 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). 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. Additional exclusion criteria for cohort evaluating the effect of proton pump inhibition only: 1. 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.
Outcome results
None listed