Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000725561
Ethics application status
Approved
Date submitted
20/05/2024
Date registered
13/06/2024
Date last updated
28/07/2024
Date data sharing statement initially provided
13/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-in-Human Safety Trial of MTX-474
Scientific title
A Phase 1 Randomized, Double-Blind, Dose- Escalating Study to assess the Safety, Tolerability, and Pharmacokinetics of MTX-474 in Healthy Adults
Secondary ID [1] 312142 0
MTX-474-S101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Systemic Sclerosis 333789 0
Condition category
Condition code
Inflammatory and Immune System 330460 330460 0 0
Connective tissue diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, and PK of single and multiple ascending doses of MTX-474 administered by a qualified designee of the study doctor intravenously over 60 minutes in healthy adults. The SAD portion of the study will consist of 6 planned dosing cohorts each comprising 8 healthy participants. The starting dose will be 0.125mg/kg (Cohort 1) with subsequent planned doses of 0.25 mg/kg (Cohort 2), 0.5 mg/kg (Cohort 3), 1 mg/kg (Cohort 4), 2 mg/kg (Cohort 5), and 4 mg/kg (Cohort 6). Within each cohort, participants will be randomly assigned to receive MTX-474 or matched placebo. The MAD portion of the study will consist of 4 planned dosing cohorts administered once weekly (QW) for 4 infusions. Each cohort will comprise 8 healthy participants (n=6 MTX-474; n=2 placebo). The starting dose will be 0.5 mg/kg (Cohort 1) with subsequent planned doses of 1 mg/kg (Cohort 2), 2 mg/kg (Cohort 3), and 4 mg/kg (Cohort 4). Planned doses may be adjusted in response to the data. Additional cohorts may be added as long as no Dose-Limiting Toxicity (DLT) emerges. A cumulative review of safety and tolerability of MTX-474 will be conducted by the study Investigator, Medical Monitor, and Sponsor's Responsible Medical Officer (SRMO) to inform dose escalation decisions for the next dose cohort. The Investigator, Medical Monitor, and SRMO will also verify that none of the stopping criteria for safety parameters was met before proceeding.
Intervention code [1] 328577 0
Treatment: Drugs
Comparator / control treatment
Placebo (NaCl solution) which will be administered via intravenous infusion over 60 minutes and be identical in appearance to the prepared solution of MTX-474.
Control group
Placebo

Outcomes
Primary outcome [1] 338229 0
To assess the safety and tolerability of MTX-474 in healthy adult participants.
Timepoint [1] 338229 0
SAD Cohorts:
Clinical Laboratory Tests: Blood samples will be collected during the Screening, Day -1, Day 2, Day 3, Day 5, Day 8, Day 15, Day 22, and End of Study visits
Urinalysis: Urine samples will be collected at Screening, Day -1, Day 8, Day 15, Day 22, and End of Study visits for analysis.
ECGs: Triplicate ECGs will be performed at Screening, Day -1, Day 1 (pre-dose, 1-hour post-dose, 6-hours post-dose), Day 2, Day 8, Day 22, and End of Study visits
Physical Examination: A full Physical Examination will be performed at screening and Day -1. visits. A symptom-directed Physical Exam will be performed at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 15, Day 22, and End of Study visits, as warranted.

MAD Cohorts:
Clinical Laboratory Tests: Blood samples will be collected during the Screening, Day -1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 14, Day 16, Day 21, Day 23, Day 24 Day 26, Day 29, and End of Study visits
Urinalysis: Urine samples will be collected at Screening, Day -1, Day 7, Day 14, Day 21, Day 29, and End of Study visits for analysis.
ECGs: Triplicate ECGs will be performed at Screening, Day -1, Day 1, Day 2, Day 8, Day 9, Day 15, Day 16, Day 22, Day 23, Day 29, and End of Study visits. On dosing days (Day 1, 8, 15, and 22) ECGs will be performed pre-dose, 1-hour post-dose, and 6-hours post-dose.
Physical Examination: A full Physical Examination will be performed at screening and Day -1. visits. A symptom-directed Physical Exam will be performed at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 15, Day 22, and End of Study visits, as warranted.
Primary outcome [2] 338230 0
To characterize the pharmacokinetics (PK) of MTX-474 in healthy adult participants.
Timepoint [2] 338230 0
SAD: PK samples will be collected pre-dose on Day 1 (within 2 hr before dosing) and 1 hr (±15 min), 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), 168 hr (±6 hr), 336 hr (±1 day), 504 hr (±1 day) post-dose, and Day 29 (±1 day) (EOS/ET). The post-dose PK sampling timepoints will be calculated relative to the end of infusion.
MAD: PK samples will be collected at pre-dose (within 2 hr before dosing) on Day 1, Day 8, Day 15, and Day 22; 1 hr (±15 min), 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), and 168 hr (±6 hr) post-dose on Days 1 and 22; and Day 50 (±1 day) (EOS/ET). The 168-hr post-dose measurement can be same as the subsequent dosing day pre-dose measurement. The post-dose PK sampling timepoints will be calculated relative to the end of infusion.
Primary outcome [3] 338231 0
To characterize the immunogenicity of MTX-474 via assessment of anti-drug antibodies (ADA) in healthy adult participants
Timepoint [3] 338231 0
SAD: ADA samples will be collected pre-dose on Day 1 (within 2 hr before dosing), at 504 hr (±1 day) (ie, Day 22) post-dose, and Day 29 (±1 day) (EOS/ET). The post-dose ADA sampling timepoints will be calculated relative to the end of infusion.
MAD: ADA samples will be collected at pre-dose (within 2 hr before dosing) on Day 1 and Day 22, Day 29 (±1 day), and Day 50 (±1 day) (EOS/ET). The post-dose ADA sampling timepoint will be calculated relative to the end of infusion.
Secondary outcome [1] 435057 0
To assess the target engagement of MTX-474 in healthy adult participants. This will be assessed as a composite outcome.
Timepoint [1] 435057 0
SAD Cohort: Samples for target engagement will be collected pre-dose on Day 1 (within 2 hr before dosing), and 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), 168 hr (±6 hr), 336 hr (±1 day), 504 hr (±1 day) post-dose, and Day 29 (±1 day) (EOS/ET). The post-dose sampling timepoint will be calculated relative to the end of infusion.
MAD Cohort: Samples for target engagement and biomarker assessment will be collected pre-dose (within 2 hr before dosing on each day) on Day 1, Day 8, Day 15, and Day 22; 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr) and 168 hr (±6 hr) post-dose on Days 1 and 22; Day 16;and Day 50 (±1 day) (EOS/ET). In addition, samples for target engagement will be collected at pre-dose on day 1 (within 2 hr before dosing) and 168 hr (±6 hr) post-dose on Day 22. The 168-hr post-dose measurement can be same as the subsequent pre-dose measurement. The post-dose sampling timepoints for target engagement and biomarker assessment will be calculated relative to the end of infusion.

Eligibility
Key inclusion criteria
- All genders, ages 18 to 60 years, inclusive

- Consumption of not more than 5 cigarettes or other cotinine-containing products (including tobacco, nicotine gum, patches, and e-cigarettes) per week as long as they are willing to abstain nicotine use approximately 5 days prior to admission and during inpatient stays

- Willing to refrain from marijuana- or cannabinol-containing products for 30 days before Screening and until the last study visit

- Willing to refrain from ingestion of alcohol from 7 days before Screening until the last study visit

- Agrees to not donate egg or sperm (if applicable) from the time of first infusion until 125 days after the final dose; additionally agrees to not donate blood from 56 days prior to the time of first infusion until 90 days after the last study visit, or platelets/plasma 14 days prior to the time of first infusion until 90 days after the last study visit.

- All participants assigned female at birth must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline.

- Participants are required to follow specific contraception measures as follows:

Participants assigned male at birth must use a condom (even if vasectomized) at the time of Screening and for 125 days after the final dose.

Participants assigned female at birth must be of non-childbearing potential (defined as either at least 6 months surgically sterilized or at least 1 year postmenopausal and confirmed by FSH (Follicle Stimulating Hormone) level >40U/L) OR, if of childbearing potential (defined as not sterilized via bilateral oophorectomy, or hysterectomy, ; still menstruating; or <1 year has passed since the last menses, if menopausal), must use a combination of 1 highly effective method of contraception and 1 effective method of contraception . This contraceptive practice should begin at least 28 days before the first dose of study drug, continue during the study, and persist for 65 days after the final dose of study drug, if applicable.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Any concurrent active medical condition determined clinically significant by the Investigator

- Body mass index (BMI) >32 kg/m2.

- Use of any systemic immunosuppressant medications, medications to treat diabetes, antipsychotics, anticoagulants, or other prescription medications other than oral contraceptives within 90 days of Screening that, as determined by the Investigator, could confound their participation in the study

- Cancer or a history of cancer or lymphoproliferative disorder within 5 years of Screening other than adequately treated non-melanomatous skin cancers or cervical carcinoma in situ

- Current infection with hepatitis B, positive hepatitis B core antibody (HBcAb), hepatitis C, or human immunodeficiency virus (HIV) as evidenced by a positive hepatitis B surface antigen (HbsAg) at Screening or a positive HIV test at Screening. For hepatitis C, a positive hepatitis C antibody (anti-HCV) test is exclusionary unless the participant has previously been treated for hepatitis C, in which case they would be eligible with a negative HCV RNA.

- Currently pregnant, lactating, or planning to conceive or contribute to pregnancy during the trial and up to 28 days after the participant’s last dose of study drug, if applicable

- History of severe depression, psychosis, or suicidal ideation, as determined by the Investigator, within 5 years of Screening

-History of anaphylaxis or other significant allergies in the opinion of the Investigator.

- History of substance use disorder as specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within 1 year of Screening

- Positive screen for drugs of abuse or alcohol intake at Screening or admission to the CRU (Day -1).

- Donation of blood within 28 days of Screening.

- Any clinically significant disease or laboratory abnormality detected at Screening that might interfere with a participant’s ability to complete the study, on-study evaluations, or participant safety, including the following:

Hemoglobin outside of the normal range for the study laboratory
Absolute neutrophils outside of the normal range for the study laboratory
White blood cells outside of the normal range for the study laboratory
Platelet count outside of the normal range for the study laboratory

- Any clinically significant abnormality on any of the screening ECGs

- Alanine aminotransferase or aspartate aminotransferase up to 1.2 times the upper limit of normal

- Any surgical procedure, including planned procedures within 12 weeks of Screening

- Participation in another research study of an investigational agent within 30 days of Screening or 5 half-lives of the agent, whichever is longer

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/07/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 316502 0
Commercial sector/Industry
Name [1] 316502 0
Mediar Therapeutics
Country [1] 316502 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Mediar Therapeutics
Address
Country
United States of America
Secondary sponsor category [1] 318681 0
None
Name [1] 318681 0
Address [1] 318681 0
Country [1] 318681 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315298 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315298 0
Ethics committee country [1] 315298 0
Australia
Date submitted for ethics approval [1] 315298 0
27/05/2024
Approval date [1] 315298 0
04/07/2024
Ethics approval number [1] 315298 0

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

Contacts
Principal investigator
Name 134258 0
Dr Gloria Wong
Address 134258 0
Level 5 Clive Berghofer Cancer Research Centre (CBRC Building) 300C Herston Rd Herston, Queensland, 4006 Australia
Country 134258 0
Australia
Phone 134258 0
+61 07 3707 2720
Fax 134258 0
Email 134258 0
[email protected]
Contact person for public queries
Name 134259 0
Colleen Graham
Address 134259 0
Mediar Therapeutics, 20 Overland St., Suite 520, Boston, MA, 02215
Country 134259 0
United States of America
Phone 134259 0
+16174681770
Fax 134259 0
Email 134259 0
[email protected]
Contact person for scientific queries
Name 134260 0
Jeffrey Bornstein
Address 134260 0
Mediar Therapeutics, 20 Overland St., Suite 520, Boston, MA
Country 134260 0
United States of America
Phone 134260 0
+16174681770
Fax 134260 0
Email 134260 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


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.