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Trial registered on ANZCTR


Registration number
ACTRN12623001265662
Ethics application status
Approved
Date submitted
19/10/2023
Date registered
6/12/2023
Date last updated
6/12/2023
Date data sharing statement initially provided
6/12/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of PLX-4545 in Healthy Volunteers
Scientific title
A Phase 1, Randomized, Placebo-Controlled, Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of PLX-4545 in Healthy Subjects
Secondary ID [1] 310455 0
PLX-4545-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumours 331246 0
Condition category
Condition code
Cancer 328004 328004 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is designed to evaluate the safety, pharmacokinetics and pharmacodynamics in healthy adult participants after administration of increasing doses of PLX-4545. The study consists of 3 parts (unique participants will only be enrolled in each part):
- Part 1: Single Ascending Dose (SAD): participants will receive a single oral dose of PLX-4545 (2.5 mg up to 200 mg) or placebo. Dosing will occur in the clinic.
- Part 2: Multiple Ascending Dose (MAD): participants will receive a single oral dose of PLX-4545 (10 mg up to 200 mg) or placebo daily for 14 days. Part 2 will commence after at least 3 cohorts have completed Part 1. Dosing will occur in the clinic.
- Part 3: Food Effect (FE): participants will receive a single dose of PLX-4545 under fed (consumption of breakfast comprising 507g fat, 139 g protein, 284g carbohydrate) and fasted (minimum 10 hours with water permitted) conditions. A 7-day washout is required between dosing in the fasting and fed conditions. Part 3 will commence after completion of Part 1. Dosing will occur in the clinic.
Intervention code [1] 326854 0
Treatment: Drugs
Comparator / control treatment
Participants allocated to placebo will receive matching capsules (microcrystalline cellulose) containing no active ingredients.
Control group
Placebo

Outcomes
Primary outcome [1] 335867 0
To assess the safety and tolerability of single and multiple doses of PLX-4545 in healthy subjects. This will be done by investigator assessment of the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
Adverse events will be assessed as defined by CTCAE, Version 5.0. Potential adverse events that may be encountered include changes in kidney function (assessed via blood/urine laboratory tests), deterioration of the lining of the nerves in the body (assessed via neurological examinations) and skin irritation/damage after sun exposure (assessed via physical examinations).
Timepoint [1] 335867 0
Adverse events are assessed at screening, on the day prior to first dose (Day -1), then daily while the participant is admitted in the clinical research unit and at the end of study visit (Day 7, Day 24 or Day 14 post-first dose depending on the group participants are enrolled in).
Secondary outcome [1] 425935 0
To characterize the human pharmacokinetics (PK) (Cmax, Ctrough, tmax, AUC0-tau, AUC0-inf, AUC0-t, t½, Vz/F, CL/F, and Rac, as applicable) profile of single and multiple doses of PLX-4545 in healthy subjects.
Timepoint [1] 425935 0
Blood PK samples will be collected as follows:
- Part 1: pre-dose on Day 1, then post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours, and at the end of study visit (Day 14)
- Part 2: pre-dose on Days 1, 4, 7 and 14, then post-dose (Day 1 and Day 14) at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours, and at the end of study visit (Day 24)
Secondary outcome [2] 425936 0
To evaluate the effect of food on the PK (Cmax, Ctrough, tmax, AUC0-tau, AUC0-inf, AUC0-t, t½, Vz/F, CL/F, and Rac, as applicable) of orally administered PLX-4545 in healthy adult subjects following a single dose.
Timepoint [2] 425936 0
Blood PK samples will be collected pre-dose on Day 1, then post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours, then pre-dose Day 8, then post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours and at the end of study visit (Day 14).
Secondary outcome [3] 425937 0
To evaluate the pharmacodynamic effect of single and multiple doses of PLX-4545 for target degradation (IKZF2) in peripheral blood. This will be assessed by review of IKZF2 protein levels in peripheral blood mononuclear cells (PBMCs) isolated from whole blood and measured by flow cytometry.
Timepoint [3] 425937 0
Blood samples will be collected for pharmacodynamic analysis as follows:
- Part 1: pre-dose Day 1, then at 2, 24, 48, 72 and 144 hours post-dose.
- Part 2: pre-dose Day 1, then 2 hours post-dose on Day 1, Day 7 and 14.

Eligibility
Key inclusion criteria
A participant is eligible for inclusion in this study if all of the following criteria are met:
- Male or female subjects 18 years to 65 years old at the time of informed consent.
- Must have a body mass index of 18.5 to 32.0 kg/m2, inclusive, and weigh at least 50 kg at Screening.
- Must be otherwise healthy and free from illness or disease as determined by medical history, vital signs, physical examinations, ECGs, laboratory studies, and/or other tests performed within 28 days prior to drug administration, as judged by the Investigator.
- Must be able to swallow capsules.
- Must be willing and able to understand the study procedures and comply with all aspects of the protocol and confinement periods.
- Must be able to give signed informed consent and any locally required authorization prior to any protocol-related procedures.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants are not eligible for this study if any of the following criteria apply:
- Has presence or history of hypersensitivity to murine proteins or any drug or other allergies which are considered, in the opinion of the Investigator, to contraindicate study participation.
- Has recently received any vaccination within 12 weeks prior to randomization, or who intends to receive a live vaccination during the study.
- Is known to be seropositive for human immunodeficiency virus (HIV).
- Has a positive result for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, or antibody to hepatitis C virus (HCV).
- Use of any investigational drug or product, or participation in an investigational drug study within 30 days prior to dosing or 5 half-lives of the drug (whichever is longest).
- Has previous exposure to antibody therapies within 6 months or administration of immunoglobulins within 6 months prior to study drug administration.
- Has a history of donating 1 unit of blood (450 mL) in the 3 months prior to study drug administration or who intends to donate within 3 months of their last scheduled study visit.
- Has a history of hypertension or a blood pressure >160/90 mmHg at Screening or a history of recurrent hypotensive events considered as clinically relevant or a blood pressure <95/50 mmHg at Screening.
- Is currently taking or who has taken any prescription or non-prescription medication within 7 days of study drug administration including aspirin, dietary or mega dose vitamin supplements, and herbal preparations (except paracetamol, hormone replacement therapies, and/or hormonal contraceptives).
- Active smoker and/or user of nicotine-containing products unless the participant agrees to discontinue smoking/use of nicotine-containing products from 2 weeks before first study drug administration through to study completion, including the Follow-up period.
- Has a history of febrile illness within 5 days prior to the first dose or symptoms of and active infection within 14 days prior to first dose.
- Unable to adhere to the required dietary restrictions
- Criteria, that in the opinion of the investigator, would interfere with the subject's participation in the study.

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)
In each cohort, participants will be randomly assigned by computer to receive PLX-4545 or placebo in a ratio of 3:1.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This study will be implementing simple randomisation (with fixed blocks), using randomisation tables created by computer software (SAS).
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
After at least 3 Part 1/SAD cohorts have completed and have been reviewed by the Safety Review Committee (SRC), the Part 2/MAD portion of the study will begin. Part 3/FE will consist of 8 participants who will receive a single dose of PLX-4545 in the fasted and subsequently in the fed state. The dose of PLX-4545 used in Part 3/FE will be 1 dose lower than the highest dose successfully completed in Part 1/SAD at that time, as assessed by the SRC. All participants will receive PLX-4545 under non-randomised conditions in Part 3/FE.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
No formal sample size calculations have been performed for this study. The sample size chosen is based on experience from previous studies of a similar nature.
PK parameters will be summarized in tabular and graphic format. Results of exploratory analyses will be summarized by dose level. A detailed Statistical Analysis Plan (SAP) will be developed prior to hard lock of the study database. The SAP will contain the planned analyses in more detail and will include specifications for all tables, listings, and figures. Summary statistics will be provided for safety analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
21/11/2023
Date of last participant enrolment
Anticipated
29/01/2024
Actual
Date of last data collection
Anticipated
6/03/2024
Actual
Sample size
Target
96
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 25449 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 41199 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 314663 0
Commercial sector/Industry
Name [1] 314663 0
Plexium Australia Pty Ltd
Country [1] 314663 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Plexium Australia Pty Ltd
Address
Level 1, 1805 Gold Coast HwyBurleigh Heads, QLD 4220
Country
Australia
Secondary sponsor category [1] 316634 0
None
Name [1] 316634 0
None
Address [1] 316634 0
None
Country [1] 316634 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313682 0
Bellberry Limited
Ethics committee address [1] 313682 0
123 Glen Osmond Road, Eastwood, South Australia, 5063
Ethics committee country [1] 313682 0
Australia
Date submitted for ethics approval [1] 313682 0
30/08/2023
Approval date [1] 313682 0
03/10/2023
Ethics approval number [1] 313682 0

Summary
Brief summary
The purpose of this study is to assess the safety, tolerability (how well an individual can tolerate a drug), pharmacokinetics (how a drug moves into, through and out of the body) and pharmacodynamics (the effect of a drug on the body) of single and multiple ascending doses of PLX-4545 in healthy volunteers. PLX-4545 may be indicated for use in patients with cancer that present as solid tumours, 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 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 be conducted across three parts. In the first study (Part 1), healthy volunteer participants will be assigned by chance to receive either a single dose of PLX-4545 or placebo, to be taken after a fasting period. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood samples for testing. If the drug appears safe, additional participants will be assigned by chance to receive a larger single dose of PLX-4545 or placebo, followed by blood testing. This will continue until a maximum safe dose is determined.
In the second study (Part 2), healthy volunteer participants will be assigned by chance to receive either multiple doses of PLX-4545 or placebo to be taken once per day for 14 days. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood samples for testing. If the drug appears safe, additional participants will be assigned by chance to receive a larger daily dose of PLX-4545 or placebo for 14 days, followed by blood testing. This will continue until a maximum safe dose is determined.
In the third study (Part 3), healthy volunteer participants will be assigned by chance to receive either a single dose of PLX-4545 after fasting conditions or immediately after a high fat meal. All participants will have their vital signs checked and will provide blood samples for testing to determine the effect of food on PLX-4545. Once participants have completed their first dose, they will be asked to take another dose either after fasting or a meal, whichever they did not do for the first dose round.

It is hoped this research will determine the maximum dose of PLX-4545 that can be administered safely without causing severe reactions. The healthy volunteer study will help define the starting doses of PLX-4545 to be evaluated in a subsequent Phase 1 clinical trial in cancer patients for determining the recommended dose to support a Phase 2 clinical study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128994 0
Dr Jonathan Newchurch
Address 128994 0
CMAX Clinical Research 21-24 North Terrace, Adelaide SA 5000
Country 128994 0
Australia
Phone 128994 0
+61 08 7088 7900
Fax 128994 0
Email 128994 0
[email protected]
Contact person for public queries
Name 128995 0
Greg Plunkett
Address 128995 0
Accelagen Pty Ltd Suite 2.02 / 785 Toorak Road, Hawthorn East, Victoria, 3123
Country 128995 0
Australia
Phone 128995 0
+61 03 9114 2270
Fax 128995 0
Email 128995 0
[email protected]
Contact person for scientific queries
Name 128996 0
Jonathan Newchurch
Address 128996 0
CMAX Clinical Research21-24 North Terrace, Adelaide SA 5000
Country 128996 0
Australia
Phone 128996 0
+61 08 7088 7900
Fax 128996 0
Email 128996 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
The Sponsor and site (CMAX Clinical Research) will not be sharing data with anyone outside of Plexium Australia Pty Ltd and the CRO (Accelagen) involved in the study.


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.