Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000652673
Ethics application status
Approved
Date submitted
5/04/2023
Date registered
16/06/2023
Date last updated
16/06/2023
Date data sharing statement initially provided
16/06/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Study of ELVN-002 in Healthy Adult Volunteers: Part C
Scientific title
A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ELVN-002 in Healthy Adult Volunteers: Part C Open-label Drug-Drug Interaction
Secondary ID [1] 309386 0
ELVN-002-002
Universal Trial Number (UTN)
Trial acronym
Linked study record
The study consist of three parts. Part A, Part B and Part C.
- Part B of the study is registered ACTRN12623000431628

Health condition
Health condition(s) or problem(s) studied:
Non-small Cell lung cancer 329615 0
Condition category
Condition code
Cancer 326540 326540 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational Product (IP): ELVN-002
Dosage Form: Capsule
Mode of Administration: Oral
Part C (DDI): This part of study includes two arm.
CYP3A4 inhibitor arm: The participants will be admitted to the study site on Day -1 and will fast for at least 10 hours before dosing. On dosing day (Day 1), participants will take ELVN-002 90 mg orally with240 mL of water and remain fasting for 4 hours after dosing (water intake will be permitted 1 hour after dosing). Participants will then consume a standard meal within 30 minutes. From Day 4 to Day 9 (6 days), participants will receive itraconazole 200 mg once daily in the morning after consuming a standard meal.
On Day 6, participants will fast for at least 10 hours before the 2nd dose of ELVN-002. On dosing day (Day7), participants will take ELVN-002 90 mg orally and remain fasting for 4 hours after dosing (water intake will be permitted 1 hour after dosing). Participants will then consume a standard meal and then immediately receive itraconazole 200 mg.
Please note for CYP3A4 inhibitor arm, it is recommended to take itraconazole with food.
Standard meal provided by site.

CYP3A4 inducer arm: Twelve eligible participants will be admitted to the study site on Day -1 and will fast for at least 10 hours before dosing. On dosing day (Day 1), participants will take ELVN-002 360 mg orally with 240 mL of water and will remain fasting for 4 hours after dosing (water intake will be permitted 1 hour after dosing). From Day 3 to Day 19 (17 days), participants will receive phenytoin 3 times daily (100mg each dose) for a total daily dose of 300 mg.
On Day 16, participants will fast for at least 10 hours before the 2nd dose of ELVN-002. On dosing day (Day17), participants will take ELVN-002 360 mg orally, and then receive 100 mg of phenytoin 2 hours after dosing (allowed window: ± 5 minutes). It is okay to dose phenytoin without food. Food is not required for phenytoin dose administration.
Participants will receive 100 mg of phenytoin 3 times daily after meals for a total daily dose of 300 mg.
Please note for CYP3A4 inhibitor arm, it is recommended to take itraconazole with food.
The Phenytoin and Itraconazole will be administered in Capsule form.


Intervention code [1] 325822 0
Treatment: Drugs
Comparator / control treatment
Comparator

The effect of itraconazole or phenytoin on ELVN-002 will be separately evaluated. There is no comparison between results from the CYP3A4 inhibitor arm to the CYP3A4 inducer arm.

In both the itraconazole-treated (inhibitor arm) or phenytoin-treated (inducer arm), participants will fast for 10 hours before ELVN-002 administration. Except during the fasting period, participants in both arms will consume standard meals provided by the study site during the study period.
Site will provide standard meal as per FDA guidance. The FDA recommends that individuals consume an average of 2000 calories a day (depending on age and level of activity), so 3 meals within this 500-800 calorie range will add up to this total amount.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334378 0
Part C: The effect of itraconazole on the PK profile of ELVN-002 in healthy volunteers.
Blood sample will be collected for Pharmacokinetic assessment.
Pharmacokinetic (PK) Parameters:
- Maximum concentration (Cmax)
- Time to maximum concentration (Tmax)
- Area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-last)
- AUC from time 0 to infi nity
- Half-life (t½)
- Apparent oral body clearance (CL/F)
- Apparent volume of distribution (Vz/F)
Timepoint [1] 334378 0
Part C inhibitor arm: PK blood samples will be collected pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48hours post-dose (Day 1 to Day 3 and Day 7 to Day 9)
Primary outcome [2] 334531 0
Part C: The effect of phenytoin on the PK profile of ELVN-002 in healthy volunteers.
Blood sample will be collected for Pharmacokinetic assessment.
Pharmacokinetic (PK) Parameters:
- Maximum concentration (Cmax)
- Time to maximum concentration (Tmax)
- Area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-last)
- AUC from time 0 to infi nity
- Half-life (t½)
- Apparent oral body clearance (CL/F)
- Apparent volume of distribution (Vz/F)
Timepoint [2] 334531 0
Part C inducer arm: PK blood samples will be collected pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48hours post-dose (Day 1 to Day 3 and Day 17 and Day 19)
Secondary outcome [1] 420438 0
Part C: The safety and tolerability profile of ELVN-002 and itraconazole in healthy volunteers.
- The incidence of adverse events (AEs) and serious adverse events (SAEs) will be coded using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA)
- Vital signs (systolic and diastolic blood pressure assessed using a digital sphygmomanometer, heart rate assessed using a pulse oximeter, respiratory rate, and body temperature)
- Laboratory test results (including haematology, biochemistry, coagulation, urinalysis, and serology)
- Physical examination
Timepoint [1] 420438 0
Adverse events (AEs) and serious adverse events (SAEs):
Part C Inhibitor Arm: Daily from Screening to Day 10 post-dose administration

Vital signs:
Part C Inhibitor Arm: Daily from Screening to Day 10 post-dose administration

Laboratory test:
Part C Inhibitor Arm: Screening, Day -1, Day 3, 6, 8, 10

Physical examination:
Part C Inhibitor Arm: Screening, Day -1, Day 2, 6, 8, 9, 10
Secondary outcome [2] 420439 0
Part C: Plasma PK profile of ELV-2228, a major metabolite of ELVN-002, in healthy volunteers who have also been administered itraconazole
Pharmacokinetic Parameters:
- Maximum concentration (Cmax)
- Time to maximum concentration (Tmax)
- Area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-last)
- AUC from time 0 to infinity
- Half-time (t½)
- Metabolite-to-parent AUC and Cmax ratios
Timepoint [2] 420439 0
Part C inhibitor arm: PK blood samples will be collected pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 and 48hours post-dose (Day 1 to Day 3 and Day 7 to Day 9)
Secondary outcome [3] 421014 0
Part C: The safety and tolerability profile of ELVN-002 and phenytoin in healthy volunteers.
- The incidence of adverse events (AEs) and serious adverse events (SAEs) will be coded using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA)
- Vital signs (systolic and diastolic blood pressure assessed using a digital sphygmomanometer, heart rate assessed using a pulse oximeter, respiratory rate, and body temperature)
- Laboratory test results (including haematology, biochemistry, coagulation, urinalysis, and serology)
- Physical examination
Timepoint [3] 421014 0
Adverse events (AEs) and serious adverse events (SAEs):
Part C Inducer Arm: Daily from Screening to Day 20 post-dose administration

Vital signs:
Part C Inducer Arm: Daily from Screening to Day 20 post-dose administration

Laboratory test:
Part C Inducer Arm: Screening, Day -1, 3, 4 to 16, 18, 20

Physical examination:
Part C Inducer Arm: Screening; an abbreviated physical examination will be performed on Day -1, 2, 6, 16,18, and 19; a symptom directed physical examination will be performed on Day 20.
Secondary outcome [4] 421015 0
Part C: Plasma PK profile of ELV-2228, a major metabolite of ELVN-002, in healthy volunteers who have also been administered phenytoin
Pharmacokinetic Parameters:
- Maximum concentration (Cmax)
- Time to maximum concentration (Tmax)
- Area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-last)
- AUC from time 0 to infinity
- Half-time (t½)
- Metabolite-to-parent AUC and Cmax ratios
Timepoint [4] 421015 0
Part C inducer arm: PK blood samples will be collected pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 and 48hours post-dose (Day 1 to Day 3 and Day 17 to Day 19

Eligibility
Key inclusion criteria
1. Male or female, aged more than 18 to less than 60 years old (both inclusive at the time of informed consent).
2. In good general health, with no significant medical history, and no clinically significant abnormalities on physical examination at Screening and/or before the first administration of IP at the discretion of the PI or designee.
3. Body mass index (BMI) greater than 18 and less than 32.0 kg/m2 at Screening and weight more than 50 kg.
4. Non-smoker (has not used any tobacco products). A participant who smokes less than 2 cigarettes or equivalent (eg, cigars, vaping, nicotine patches) per week within 3 months prior to Screening can be included in the study if willing and able to stop smoking for the duration of the study, at the discretion of the PI or designee.
5. Clinical laboratory values at Screening (including haematology, biochemistry, coagulation, and urinalysis) within normal range as specified by the testing laboratory, unless deemed not clinically significant by the PI or designee.
6. Acceptable estimated glomerular filtration rate (eGFR) for the study using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation: greater than 89 mL/min/1.73 for participants 18 to 59 years old, or greater than 84 mL/min/1.73 for participants 60 years old).
7. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Day -1 and be willing to have additional pregnancy tests as required throughout the study.
8. Female participants who meet 1 of the following criteria will be included.
a. Female participants must not be pregnant or lactating, and must use acceptable, highly effective double contraception from Screening until 90 days after the last study procedure is completed. Females with same-sex partners (abstinence from penile-vaginal intercourse) or who are abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle. Effective forms of contraception include:
• Simultaneous use of intrauterine device (IUD) (non-hormonal) and condom for the male partner.
• Simultaneous use of diaphragm or cervical cap and male condom for the male partner.
• Sterile male partner (vasectomized since at least 6 months prior to first IP administration).
• True abstinence, defined as no sexual intercourse (heterosexual couples). Periodic abstinence and withdrawal are not acceptable methods.
b. Women of non-childbearing potential (WONCBP), defined as postmenopausal for at least more than 12 months, confirmed by follicle stimulating hormone (FSH) levels greater than 40 IU/L, or judged by the Investigator.
9. Male participants must be surgically sterile (more than 90 days since vasectomy with no sperm on sperm analysis; verbal report allowed), or if engaged in sexual relations with a WOCBP, either his partner must be surgically sterile (eg, tubal occlusion, tubal ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or an acceptable, highly effective contraceptive method must be used from Screening until 90 days after the last study procedure is completed. Effective forms of contraception are shown in Inclusion criterion 7.
Males with same-sex partners (abstinence from penile-vaginal intercourse) or are abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle. Males must not donate sperm from the first dose of IP until at least 90 days after the last dose of IP.
10. Able and willing to comply with the study procedure and the restriction specified in the protocol.
11. Able and willing to provide written informed consent after the nature of the study and the potential risk related to participating in the study have been explained and prior to the commencement of any study procedures.
12. Systolic blood pressure of 90 to 140 mmHg and diastolic blood pressure of 40 to 90 mmHg.
13. Resting heart rate of 40 to 100 beats per minute (bpm).
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has participated in previous studies of ELVN-002.
2. Underlying physical or psychological medical condition that, in the opinion of the PI, could impact on the participant’s safety, participant involvement in the study, or data integrity.
3. History or surgical records of any clinically significant renal, cardiovascular, hepatic, hematopoietic, neurological, pulmonary, or gastrointestinal pathology, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of the IP, as determined by the PI or designee.
4. History of severe allergic or anaphylactic reactions, or sensitivity to ELVN-002, itraconazole, and phenytoin, or their constituents.
5. History of malignancy, except for non-melanoma skin cancer, excised more than 2 years ago and cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening (a general practitioner [GP] letter or biopsy report for confirmation required).
6. History of symptomatic bacterial or viral infection within 2 weeks prior to Screening.
7. Abnormal ECG findings at Screening or Day -1 (eg, repeated demonstration of a QTc interval greater than 450 ms (male) or greater than 470 ms (female) corrected by Fridericia's formula [QTcF] or Bazett's formula [QTcB]) that are considered by the PI or designee to be clinically significant.
8. History of clinically significant arrhythmia, cardiac conditions, or risk factors for Torsades de Pointes (eg, heart failure, current hypokalaemia, and family history of long QT syndrome).
9. Clinically significant findings in transthoracic echocardiogram at Screening, including less than normal left ventricular ejection fraction (LVEF).
10. Blood donation or significant blood loss (greater than 500 mL) within 60 days prior to the first administration of IP.
11. Plasma donation within 30 days prior to the first administration of IP.
12. Poor pill swallowing ability.
13. Vaccination with a live vaccine within 1 month prior to the first administration of ELVN-002.
14. Participants who do not have suitable veins for multiple venepunctures/cannulations, as assessed by the Investigator at Screening.
15. Positive test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or human immunodeficiency virus (HIV) antibody at Screening.
16. Known or suspected history of drug, alcohol, or other substrate abuse within 6 months prior to Screening (verbal confirmation is acceptable).
Regular alcohol consumption defined as greater than 21 units per week for males or greater than 14 units per week for females (where 1 unit equal to 285 mL of beer, 30 mL of spirit, or a 150 mL glass of wine).
17. Positive drugs of abuse screening panel (urine test including but not limited to amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ecstasy (methylenedioxymethamphetamine [MDMA]), methadone, methamphetamines, phencyclidine, opiates, and tetrahydrocannabinol [THC]), or alcohol breath test.
18. Participant is unwilling to abstain from alcohol beginning 48 hours prior to the first administration of ELVN-002.
19. Use of IP or investigational medical device other than the ELVN-002, itraconazole, and phenytoin in this study within 30 days prior to Screening, or 5 half-lives of the product (whichever is the longest).
20. Use of (or anticipated use of) any prescription drugs or the medication leading to prolong the QT/QTc interval for 2 weeks prior to dosing, over-the-counter (OTC) medication, herbal remedies, supplements, or vitamins for 7 days prior to dosing, and during the study without prior approval of the PI and designee. Simple analgesia (paracetamol up to 4 g daily, ibuprofen or nonsteroidal anti-inflammatory drug [NSAID] up to 1200 mg daily) may be permitted at the discretion of the PI.
21. Intake of caffeine- or xanthine-containing products 48 hours before the first administration of IP.
22. Any intake of grapefruit, Seville oranges, pomelos, or other products containing the above-mentioned fruits within 7 days of the first administration of ELVN-002, itraconazole, and phenytoin.
23. Anything that the PI considers would jeopardise the safety of the participant, prevent complete participation in the study, or compromise interpretation of study data.

Additional exclusion criteria in Part C portion (DDI).
A participant in the DDI cohorts who meets any of the following exclusion criteria must be excluded:
1. History of significant hypersensitivity or idiosyncratic reaction to itraconazole and phenytoin or related drugs, as judged by the PI.
2. Only for participants in the phenytoin arm: history of seizures (excluding simple febrile seizures), epilepsy, severe head injury, multiple sclerosis, or other known neurological conditions considered clinically significant by the PI.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
2/05/2023
Date of last participant enrolment
Anticipated
19/07/2023
Actual
Date of last data collection
Anticipated
8/10/2023
Actual
Sample size
Target
24
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 24474 0
Linear Clinical Research - Nedlands
Recruitment hospital [2] 24475 0
Linear Clinical Research - Joondalup - Joondalup
Recruitment postcode(s) [1] 40058 0
6009 - Nedlands
Recruitment postcode(s) [2] 40059 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 313581 0
Commercial sector/Industry
Name [1] 313581 0
Enliven Therapeutics, Inc.
Country [1] 313581 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Enliven Therapeutics, Inc.
Address
6200 Lookout Road, Boulder, CO 80301, US
Country
United States of America
Secondary sponsor category [1] 315367 0
None
Name [1] 315367 0
Address [1] 315367 0
Country [1] 315367 0
Other collaborator category [1] 282613 0
Commercial sector/Industry
Name [1] 282613 0
Novotech (Australia) Pty Limited
Address [1] 282613 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 282613 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312761 0
Bellberry HREC B
Ethics committee address [1] 312761 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 312761 0
Australia
Date submitted for ethics approval [1] 312761 0
01/03/2023
Approval date [1] 312761 0
03/04/2023
Ethics approval number [1] 312761 0

Summary
Brief summary
This study is investigating a new cancer treatment drug, ELVN-002, that may be used for patients with lung cancer.

Who is it for?
You may be eligible for this study if you are a healthy adult aged 18 to 60 years old. Please note that this study will not be enrolling patients with lung cancer.

Study details
This registration is for Part C of a 3-part study investigating ELVN-002. There are two arms in Part C of the study.
Participants enrolled into the CYP3A4 Inhibitor Arm will receive two single dose of ELVN-002 (in capsule form) on separate days. First dose on Day 1 and second dose on Day 7. Participants will also be asked to take a daily dose of itraconazole for 7 days (from Day 4- Day 10).
Participants enrolled into the CYP3A4 Inducer Arm will receive two single dose of ELVN-002 (in capsule form) on separate days. First dose on Day 1 and second dose on Day 17. Participants will also be asked to take phenytoin 3 times daily for 17 days (from Day 3- Day 19).

Total participation will last up to 10 days for CYP3A4 Inhibitor Arm and 20 days for CYP3A4 Inducer Arm to the clinic for physical examination and vitals assessments and to collect blood and urine samples.

It is hoped that this research will help determine the dose that ELVN-002 can be safely given to patients with lung cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125814 0
Dr Ana Sun
Address 125814 0
Linear Clinical Research, Level 1, B Block Hospital Avenue Nedlands, WA 6009 Australia
Country 125814 0
Australia
Phone 125814 0
+61 414 801 448
Fax 125814 0
Email 125814 0
asun@linear.org.au
Contact person for public queries
Name 125815 0
Mr Qi Wang
Address 125815 0
Enliven Therapeutics, Inc.
6200 Lookout Road, Boulder, CO 80301, US
Country 125815 0
United States of America
Phone 125815 0
+1 609 651 2686
Fax 125815 0
Email 125815 0
qi.wang@enliventherapeutics.com
Contact person for scientific queries
Name 125816 0
Ms Helen Collins
Address 125816 0
Enliven Therapeutics, Inc.
6200 Lookout Road, Boulder, CO 80301, US
Country 125816 0
United States of America
Phone 125816 0
+1 707 799 3272
Fax 125816 0
Email 125816 0
helen.collins@enliventherapeutics.com

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.