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Trial registered on ANZCTR


Registration number
ACTRN12623001006639
Ethics application status
Approved
Date submitted
3/08/2023
Date registered
15/09/2023
Date last updated
17/04/2024
Date data sharing statement initially provided
15/09/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
An Open-Label, Phase 1 Study to Characterize the Effects of a Moderate CYP3A4 and P-glycoprotein Inhibitor on the Pharmacokinetics of Bomedemstat (IMG-7289) in Healthy Participants
Scientific title
An Open-Label, Phase 1 Study to Characterize the Effects of a Moderate CYP3A4 and P-glycoprotein Inhibitor on the Pharmacokinetics of Bomedemstat (IMG-7289) in Healthy Participants
Secondary ID [1] 309966 0
IMG-7289-CTP-107
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 330454 0
Condition category
Condition code
Cancer 327302 327302 0 0
Myeloma
Blood 328031 328031 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Twenty (20) healthy male and female adult volunteers aged 18 to 65 years of age (inclusive) at the time of screening will be enrolled.

This study is to characterize the drug-drug interaction (DDI) potential of bomedemstat (also called IMG-7289) as a victim of CYP3A4 and P-gp inhibitors.

Investigational Product: bomedemstat (IMG-7289) 50 mg (free base; 2 x 25 mg strength capsules)
CYP3A4 and P-gp Inhibitor: diltiazem extended-release (XR) 240 mg capsule

For all participants:
• On Day 1, participants will receive a single oral capsule dose of bomedemstat 50 mg.
• On Day 5, participants will receive an oral capsule dose of diltiazem XR 240 mg.
• On Day 6, participants will receive an oral dose of diltiazem XR 240 mg coadministered with bomedemstat 50 mg.
• On Days 7 to 13, inclusive, participants will receive an oral dose of diltiazem XR 240 mg once daily.

The total maximum study duration for participants in this study is 73 days (approximately 10.5 weeks, including up to 28 days of screening and up to 45 days of clinical conduct, inclusive of visit windows).

For each participant enrolled in this study, there will be a domiciling period from Day -1 to Day 14.

Study drug adherence will be monitored by clinical facility staff who administer the study drug to participants. Administration of study drugs will be recorded in the appropriate drug accountability records and the eCRF. Administration of study drug will be verified by a second staff member.
Intervention code [1] 326380 0
Treatment: Drugs
Comparator / control treatment
Concomitant Administration with Diltiazem, a CYP3A4 and P-gp Inhibitor.
The commercially available concomitant diltiazem extended-release oral capsules at the dose strength of 240 mg co-administered with bomedemstat 50 mg on Day 6 will be used in this study.
Control group
Active

Outcomes
Primary outcome [1] 335169 0
To determine the pharmacokinetics (PK) of bomedemstat when coadministered with a moderate inhibitor of CYP3A4 and P-gp, diltiazem.

Plasma bomedemstat PK endpoints include (but are not limited to):
• Maximum observed concentration (Cmax)
• Time to Cmax (Tmax)
• Area under the concentration-time curve from time zero to 24 hour [AUC(0-24h)]
• Area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-last)]
• Area under the concentration-time curve from time zero extrapolated to infinity [AUC(0-inf)]
• Terminal elimination half-life (t1/2)
• Terminal elimination rate constant (lambda z)
• Apparent oral clearance (Cl/F)
• Apparent oral volume of distribution (Vd/F)
after dosing on Day 1 and then concomitant with the inhibitor.
Timepoint [1] 335169 0
PK blood plasma samples will be collected pre-first dose Day 1 then at 0.5, 1, 2, 3, 4, 6, 8, 24, 36, 48, 72 and 96 hours post-first dose. (The 96 h blood sample will be collected prior to administration of the first dose of diltiazem on Day 5.) Pre-second dose Day 6 then at 0.5, 1, 2, 3, 4, 6, 8, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-second dose.
Secondary outcome [1] 423382 0
To assess the safety and tolerability of bomedemstat when taken concomitantly with a moderate inhibitor of CYP3A4 and P-gp.

Safety and tolerability parameters including:
- adverse events (AEs)
- safety laboratory assessments
- electrocardiogram ECG
- physical examination
- body weight
- vital signs
Timepoint [1] 423382 0
Adverse events will be graded using the Common Terminology Criteria for Adverse Events [CTCAE] criteria and will be assessed as they are reported or observed and reviewed at Screening, Day -1 then daily on Day 1 to Day 5 pre and post-dose, Day 6 to Day 14 pre and post-dose and Day 27 post-dose (End of Study/Early Termination Visit) and Day 43 (Follow Up phone call).

Clinical lab samples (haematology, chemistry, coagulation) will be assessed at Screening, Day -1, Day 1 4 hrs post-dose, Day 5 within 1.5 hrs pre diltiazem dose, Day 6 4 hrs post-dose, Day 7 within 1.5 hrs pre diltiazem dose, Day 14 post-dose and Day 27 post-dose (End of Study/Early Termination Visit).

12-Lead ECG: ECG recordings will be obtained in triplicate at Screening then pre-dose Day 1 then 2 hrs post-dose, pre-dose Day 6, Day 7 24 hrs post-dose and Day 14.

Full physical examination at Screening will include, at a minimum, assessment of the following: general appearance, head, ears, eyes, nose and throat, neck (including thyroid and lymph nodes), respiratory system, cardiovascular system, gastrointestinal system, renal system, neurological condition, musculoskeletal system, skin and any other focused assessments suggested by the presence of specific symptoms.

Symptom-directed physical examination (focused assessments suggested by the presence of specific symptoms) to be performed if deemed required by a medically qualified staff member, in the case of participant-reported specific symptoms. And may be performed at any time on the scheduled day. Additional assessments may be performed at the discretion of the PI.

Weight to be recorded using digital scales at Screening, Day -1 and Day 14.

Vital Signs (blood pressure, pulse rate assessed using a sphygmomanometer, respiratory rate by manual breath count and body temperature by digital tympanic thermometer) will be assessed at Screening, Day -1, within 1.5 hrs pre-dose Day 1 and 6 hrs post-dose, then Days 2 - 5 pre-dose, within 1.5 hrs pre-dose Day 6 and 6 hrs post-dose, then Days 7 - 13 post-dose and Day 14 and Day 27 post-dose (End of Study/Early Termination Visit).
Secondary outcome [2] 423383 0
To determine the effect of bomedemstat on the electrocardiogram (ECG)

Changes in the measurements of ventricular heart rate (HR), respiratory rate (RR) and pulse rate (PR) intervals, QRS duration, QT interval, QTcF and QTcB of the ECGs
Timepoint [2] 423383 0
12-Lead ECG conducted on Day 1 (baseline) and 2 hrs post-dose after bomedemstat administration.

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 65 years of age (inclusive) at Screening Visit.
3. 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 greater than or equal to 55 and less than or equal to 100 kg at Screening Visit.
4. Be non-smokers (including tobacco, e-cigarettes or other nicotine containing products, and marijuana) for at least 1 month prior to first study drug administration and have a negative result of cotinine test at screening and on Day -1. In the event the cotinine test is positive, the test may be repeated once (at the discretion of the PI) to confirm eligibility.
5. No prior history of chronic alcohol abuse or excessive alcohol intake, at the discretion of the PI, within 12 weeks prior to screening. No alcohol is to be consumed for at least 48 hours prior to admission, with negative alcohol test results (at screening and on Day -1). In the event the alcohol breath test is positive, the test may be repeated once (at the discretion of the PI) to confirm eligibility. Excessive alcohol intake is defined as regular consumption of >12 standard units of alcohol per week, or more than 4 standard drinks on >3 days per week, 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]).
6. No prior history of substance abuse or drug addiction within 12 months prior to first study drug administration and negative urine drug screen results at screening and on Day -1. In the event the urinary drug test is positive, the test may be repeated once (at the discretion of the PI) to confirm eligibility.
7. No prior history of relevant drug hypersensitivity.
8. Medically healthy (in the opinion of the PI) as determined by pre-study medical history and without CS abnormalities at screening, and after check-in on Day -1, and prior to first dose administration on Day 1, including:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 100 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after 5 minutes in supine position;
c. Pulse rate (PR) in the range of 50 to 100 beats/minute after 5 minutes rest in supine position;
d. Body temperature (tympanic), between 35.5°C and 37.7°C;
e. A 12-lead ECG within normal range (QTcF males less than or equal to 450 ms; QTcF females less than or equal to 470 ms) or with abnormalities that are not hazardous to the participant according to the opinion of the PI;
f. No clinically relevant findings in clinical laboratory blood and urinalysis tests as judged by the PI;
g. ALT/AST less than or equal to 1.5 ULN, total bilirubin less than or equal to 1.5 x ULN and/or creatinine clearance greater than or equal to 80mL/min (calculated using Cockcroft & Gault formula).
NOTE: Laboratory results obtained during screening and prior to first dose administration on Day 1 should be used to determine eligibility criteria. In situations where laboratory results, vitals or ECGs are outside the permitted range, the Investigator may retest the participant once and the subsequent within range screening result may be used to determine the participant’s eligibility.
9. Participants with a history of Hepatitis B or C are eligible on the condition that participants have adequate liver function as defined by Inclusion Criterion #8 and are hepatitis B surface antigen (HBsAg) negative and/or have undetectable hepatitis C virus (HCV) RNA.
10. Female participants must:
a. Be of nonchildbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 months prior to dosing) or post-menopausal (where post-menopausal 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 child-bearing potential, must have a negative serum pregnancy test at screening and before the first study drug administration (Day -1, urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method from signing the consent form until at least 30 days after the last dose of study drug.
c. Must not be breast-feeding.
11. Male participants, if not surgically sterilised, must be willing not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must be willing to use a condom in addition to having the female partner use a highly effective contraceptive method from signing the consent form until at least 30 days after the last dose of study drug. Note that oral, injected or implanted hormonal methods of contraception must be established in the female partner who could become pregnant, and in use for at least a month prior to screening.
12. Have suitable venous access for blood sampling.
13. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Is pregnant or nursing.
2. Has an active or prior malignancy.
Exception: Participants who has been disease-free for 1 year, or a participant with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
3. Has thrombocytopenia, neutropenia, or anaemia, i.e., not within the normal range based on local lab references with a single repeat and minor aberrations allowable at the discretion of the PI, and any prior history of myeloid malignancies, including MDS.
4. Has had major surgery (in the opinion of the Investigator) within 3 months prior to enrollment.
5. Is unwilling to exclude grapefruit, grapefruit juice or products that contain grapefruit, star fruit, pomegranate, pomelo, tangelo or Seville orange-containing products from the diet and all foods that contain those fruits from time of enrolment until discharge from the clinical unit.
6. Has cardiovascular impairment, history of congestive heart failure greater than New York Heart Association Class II, arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of bomedemstat; or ventricular cardiac arrhythmia requiring medical treatment.
7. Participants taking medications that are known potent or moderate inducers or inhibitors of CYP3A4 (including St. John’s Wort).
8. Blood or plasma donation of >100 mL during the 4 weeks prior to Day -1.
9. Participation in another clinical trial of an investigational molecule (or medical device) within 30 days (or 5 half-lives of the drug, whichever is longer) prior to the start of IP administration on Day 1 (or within 6 months or 5 half-lives, whichever is longer, prior to the start of IP administration on Day 1 if the investigational drug was an immunosuppressive biologic).
10. Received treatment with immune-suppressive or immune-modulative medication (including topical, systemic and inhalant corticosteroids) or have received immunoglobulins and/or blood products within 4 months prior to the administration of the first dose of IP.
11. Exposure to any prescription medications (small molecules), topically or systemically administered over-the-counter drugs, dietary supplements, or herbal remedies (with the exception of aspirin) within 14 days or 5 half-lives (if known), (whichever is longer) prior to the start of IP administration on Day 1.
12. Has an active infection or recent history (<30 days before study drug administration) requiring systemic treatment.
13. Is immunocompromised (in the opinion of the Investigator), including participants with known HIV infection.
14. Has known hypersensitivity to any of the components of the IP.
15. Is unable to take oral medications, has a history of surgery that in the opinion of the PI would interfere with the administration or absorption of oral medication, has malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhoea or vomiting) that might impair the bioavailability of IP.
16. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness that would limit compliance with study requirements. At discretion of the PI, participants with any history of depression or suicidal ideation will be excluded and at a minimum, participants with a prior history should have stable mental state off medications for >6 months.
17. A history of bleeding (i.e., hemoptysis, hematuria, gastrointestinal blood loss, epistaxis, or others with greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 5.0) within 1 month prior to beginning therapy or any clinical indications of current active bleeding.
18. Individuals who have smoked cigarettes or tobacco within the 1 month prior to first study drug administration or have a positive urine cotinine result at Screening or Day -1.
19. Any other condition, which in the opinion of the PI precludes the participant’s participation in the clinical study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
The PK of bomedemstat will be assessed to characterize the DDI potential of bomedemstat as a victim of a CYP3A4 and P-gp inhibitor (diltiazem).
The number of participants (approximately n=20) is considered sufficient to achieve the PK objectives of the study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
13/09/2023
Date of last participant enrolment
Anticipated
4/10/2023
Actual
20/11/2023
Date of last data collection
Anticipated
15/11/2023
Actual
29/11/2023
Sample size
Target
20
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24979 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 40632 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 314139 0
Commercial sector/Industry
Name [1] 314139 0
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc.
Country [1] 314139 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc.
Address
126 East Lincoln AvenueP.O. Box 2000 Rahway, NJ 07065 USA
Country
United States of America
Secondary sponsor category [1] 316060 0
Commercial sector/Industry
Name [1] 316060 0
Avance Clinical Pty Ltd
Address [1] 316060 0
213 Glynburn Road, Firle, South Australia 5070
Country [1] 316060 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313275 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 313275 0
123 Glen Osmond Road,Eastwood SA 5063
Ethics committee country [1] 313275 0
Australia
Date submitted for ethics approval [1] 313275 0
28/06/2023
Approval date [1] 313275 0
14/08/2023
Ethics approval number [1] 313275 0
2023-06-772

Summary
Brief summary
This is a study to characterise the effects of a Moderate CYP3A4 and P-glycoprotein Inhibitor on the impact of Bomedemstat (IMG-7289) in healthy volunteers. IMG-7289 may be indicated for use in patients with cancer. A drug-drug interaction trial is needed to better understand how the body interacts with administered drugs throughout the entire duration of drug exposure.

Who is it for?

You may be eligible for this study if you are aged 18 to 65 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

This trial will take place over 73 days, where participants will be screened for 28 days, receive oral medication over a 13-day period, and will then be followed up. 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 whether Moderate CYP3A4 and P-glycoprotein Inhibitor have an effect on the reaction of volunteers to Bomedemstat (IMG-7289). Healthy participants in the current study will not receive any health benefit (beyond that of an assessment of their medical status) from participating in the study; however, data from this study will support the potential development of bomedemstat.
Trial website
Trial related presentations / publications
Public notes
Comparator / control treatment:
Concomitant Administration with Diltiazem
Anticipated DDIs would be those that significantly inhibit or induce CYP3A4 altering exposure to the freebase of bomedemstat. Inhibition of CYP3A4 by diltiazem may sufficiently inhibit this enzyme causing a rise in exposure to the free base of bomedemstat.

Contacts
Principal investigator
Name 127570 0
Dr Angela Rowland
Address 127570 0
CMAX Level 5,21-24 North Terrace Adelaide,SA 5000
Country 127570 0
Australia
Phone 127570 0
+61 04 3968 2089
Fax 127570 0
Email 127570 0
[email protected]
Contact person for public queries
Name 127571 0
Susi Lee
Address 127571 0
Merck & Co., Inc.126 East Lincoln AvenueP.O. Box 2000Rahway, NJ 07065 USA
Country 127571 0
United States of America
Phone 127571 0
+1 917 406 6559
Fax 127571 0
Email 127571 0
[email protected]
Contact person for scientific queries
Name 127572 0
Angela Rowland
Address 127572 0
CMAX Level 5,21-24 North Terrace Adelaide,SA 5000
Country 127572 0
Australia
Phone 127572 0
+61 04 3968 2089
Fax 127572 0
Email 127572 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
Privacy and intellectual property considerations


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.