Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000956606
Ethics application status
Approved
Date submitted
25/07/2023
Date registered
4/09/2023
Date last updated
9/02/2024
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacology, and Preliminary Efficacy of AT-0174 in Subjects with Advanced Solid Malignancies
Scientific title
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacology, and Preliminary Efficacy of AT-0174 in Subjects with Advanced Solid Malignancies
Secondary ID [1] 310192 0
Antido Therapeutics (Australia) Protocol No. AT-0174-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Locally Advanced Solid Tumours 330860 0
Condition category
Condition code
Cancer 327659 327659 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment cycles will be 28 days in duration and may continue as long as the participant agrees and is tolerating treatment, and if there is potential clinical benefit as determined by the Investigator. Each cohort will be assessed for dose-limiting toxicities during the first 28 days before enrolment commences in the next cohort. Separate participants will be enrolled into each cohort but may escalate to the next dosing duration or level if it is found to be safe and at Investigator's discretion. Treatment adherence will be assessed using daily dosing diaries and the return of unused capsules after each cycle.

In Part 1, AT-0174 will be administered orally, once daily at a dose of 50 mg once daily for 7 days followed by a 21-day safety observation or follow-up period (Cohort 1). The duration of AT-0174 (50 mg) treatment will then be prolonged to 14 consecutive days (Cohort 2) and then 28 consecutive days (Cohort 3) in each 28-day cycle.

In Part 2, AT-0174 will be administered once daily as an oral capsule for 28 consecutive days of each 28-day cycle. The dose level will be escalated across up to 3 cohorts in Part 2, with the exact dose in each cohort to be selected based on the safety and tolerability of AT-0174 in previous cohorts. Enrolment into Part 2 will commence following the safety review of Cohort 3 data.

Intervention code [1] 326589 0
Treatment: Drugs
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335462 0
Safety and Tolerability Assessments, as measured by adverse events (AEs), serious AEs (SAEs), physical examinations, vital sign measurements, clinical laboratory evaluations, and reasons for treatment discontinuation due to toxicity.

As this is a first-in-human study, adverse events cannot be predicted with certainty. Based on studies in animals and from studies of similar drugs in people, possible adverse events may include (but not be limited to): Tiredness/Drowsiness/Sleepiness; Lightheadedness; Confusion; Mood swings; Difficulty concentrating; Difficulty performing complex tasks; Insomnia; Headache; Dryness in mouth; Nausea, vomiting; Diarrhea; Joint pain/discomfort; Skin rash; Muscle cramps; Muscle weakness; Sexual dysfunction; Visual blurring; Seizures; Low blood pressure; Low sodium in blood; Itching.

Adverse events will be assessed via participant report, physical examinations, and laboratory testing.

Vital sign measurements will include temperature, pulse rate, respiratory rate, and blood pressure using standard vital signs monitoring equipment.

Clinical laboratory evaluations will include haematology, blood chemistry, coagulation, and urinalysis. Blood and urine samples will be collected.
Timepoint [1] 335462 0
AEs/SAEs will be assessed at least weekly during treatment, and at End of Treatment (30 days post-last dose)

Safety assessments will be performed throughout each treatment cycle at the following timepoints, where Day 1 is the first day of treatment administration in each cycle, and Pre-treatment assessments may be performed within 2 days prior to Day 1 of each cycle. Physical examinations will be performed at the following timepoints for each cycle: Pre-treatment, Day 7, and Day 14. Vital signs will be assessed at Screening and the following timepoints for each cycle: Day 1, Day 7, Day 14, and Day 21. Clinical laboratory evaluations will be performed at Screening and the following timepoints for each cycle: Pre-treatment, Day 7, Day 14, and Day 21
Primary outcome [2] 335463 0
Recommendation of a dose for subsequent studies of AT-0174 (Recommended Phase II dose [RP2D]) administered on a 28-day oral once-daily schedule repeated every 4 weeks, which maximally inhibits Indoleamine 2,3-dioxygenase/tryptophan (TRP) 2,3-dioxygenase (IDO/TDO), as assessed by measurements of plasma concentrations of kynurenine (KYN) pathway constituents, particularly KYN and TRP, and is safe and tolerable as determined by a review of adverse events as documented in study-specific logs.
Timepoint [2] 335463 0
The RP2D will be determined by the Safety Review Committee based on a thorough data review throughout the course of the study. The Safety Review Committee will meet to review the study data after each cohort has completed Day 29 post-commencement of intervention dosing.
Secondary outcome [1] 424734 0
Pharmacokinetic (PK) profile: parameters including but not limited to Cmax, AUC, t½, CL, and Vd. PK analysis will be performed on plasma samples.
Timepoint [1] 424734 0
PK sampling will be performed at the following timepoints in Cycle 1:
Cohort 1 (50 mg, 7 days):
• Day 1: Pre-treatment and post-dose at t = 15 and 30 minutes, and 1, 2, 4, and 6 hours.
• Day 2: Pre-dose on Day 2, and post-dose at t = 30 minutes, and 1, 2, 4, and 6 hours.
• Day 7: Pre-dose on Day 7 and post-dose at t = 1, 2, 4, and 6 hours.
Cohort 2 (50 mg, 14 days):
• Day 1: Pre-treatment and post-dose at t = 15 and 30 minutes, and 1, 2, 4, 6, and 24 hours (pre-dose on Day 2).
• Day 14: Pre-dose on Day 14 and post-dose at t = 1, 2, 4, and 6 hours.
Cohort 3 (50 mg, 28 days):
• Day 1: Pre-treatment and post-dose at t = 15 and 30 minutes, and 1, 2, 4, 6, and 24 hours (pre-dose on Day 2).
• Day 28: Pre-dose on Day 28 and post-dose at t = 1, 2, 4 and 6 hours.
Cohorts 4+ (Dose TBD, 28 days):
• Day 1: Pre-treatment and post-dose at t = 15 and 30 minutes, and 1, 2, 4, 6, and 24 hours.
• Days 7, 14, 28: Pre-treatment and post-dose at t = 1, 2, 4, and 6 hours.
For all cohorts, PK sampling will be performed at the following timepoints in Cycles 2-4:
• Any treatment day: Pre-dose and post-dose at t = 1, 2, 4, and 6 hours. There is flexibility in the day these samples may be collected, based on participant availability and site logistics, as long as it is a day that AT-0174 is administered.
Secondary outcome [2] 424735 0
Pharmacodynamic (PD) profile: measurement of plasma concentrations of constituents of the KYN pathway: tryptophan (TRP), kynurenine (KYN), and serotonin.
Timepoint [2] 424735 0
PD sampling will be performed at the following timepoints in Cycle 1:
• Pre-treatment Day -1 (no treatment given): 3 samples, each taken 2 hours apart, on the day preceding treatment, to provide an extended baseline (i.e. at 8 am, 10 am, 12 noon ± 30 min)
• Day 1: two samples taken before treatment (within 1 h prior to dosing) and at t = 0.5, 1, 2, 4, and 6 hours post-dose
• Day 7, 14, or 28 (i.e. Day 7 for Cohort 1, Day 14 for Cohort 2, Day 28 for cohorts 3+): two samples taken before treatment (within 1 h prior to dosing) and at t = 0.5, 1, 2, 4, and 6 hours post-dose
PD sampling will be performed at the following timepoints in Cycles 2-4:
• Any treatment day: Pre-dose and post-dose at t = 1, 2, 4, and 6 hours. There is flexibility in the day these samples may be collected, based on participant availability and site logistics, as long as it is a day that AT-0174 is administered.
Following discontinuation of study treatment, where possible, blood sampling will occur at the following times on Day 1 and Day 8 ± 1 day after their final dose:
• 3 timepoints over a 6-hour period (i.e. at 8 am, 10 am, 12 noon ± 30 min).


Secondary outcome [3] 424736 0
Disease assessed using RECIST v1.1, RANO-HGG or RANO-LGG criteria.

Response will be assessed based on imaging assessments (CT or MRI or CT/PET). The same imaging procedure (i.e., CT or MRI or CT/PET) should be used for all scheduled tumour assessments and measurements in any individual patient.
Timepoint [3] 424736 0
Tumour assessments will be performed pre-treatment (i.e., within 21 days prior to treatment) and between Days 21-28 post-first dose for every second treatment cycle (i.e. during the last week of cycles 2, 4, 6, and so on). Tumour assessments will continue until the patient discontinues the study drug or study completion/study closure, whichever occurs first.

Eligibility
Key inclusion criteria
- Able to understand, sign, and commit to informed consent and to all study procedures
- Histological/cytological evidence of one of the following unresectable locally advanced or metastatic solid cancers:
a. Non-small cell lung carcinoma
b. Small cell lung carcinoma
c. Triple-negative breast carcinoma
d. Malignant melanoma
e. Gastric carcinoma/gastroesophageal junction carcinoma/esophageal adenocarcinoma
f. Squamous cell carcinoma of the esophagus
g. Colorectal carcinoma
h. Pancreatic ductal adenocarcinoma
i. Epithelial ovarian carcinoma (fallopian, ovarian, primary peritoneal carcinoma)
j. Endometrial carcinoma
k. Thyroid carcinoma (non-medullary)
l. Moderate-high grade astrocytoma (oligodendroglioma, astrocytoma, or anaplastic astrocytoma [Grade 2 or 3] and glioblastoma multiforme [Grade 4])
m. Other cancers based on the Investigator’s discretion with Sponsor Medical Monitor’s approval.
- Locally advanced unresectable or metastatic disease that is refractory to standard therapy, or for whom no standard therapy exists, and where standard therapy is contraindicated or has been declined by the patient
- Measurable or evaluable disease per RECIST v1.1, or Grades 2-4 astrocytoma as per RANO-HGG or RANO-LGG criteria, that was not in a prior radiation or other locally treated area unless imaging-based progression has been clearly documented following radiation or other local therapy
- Eastern Cooperative Oncology (ECOG) performance status less than or equal to 1
- Life expectancy greater than or equal to 3 months
- Adhere to contraception requirements where applicable
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Prior radiotherapy within two weeks of treatment
- Treatment with anticancer therapies including cytotoxic chemotherapy, monoclonal antibodies (mAbs), and/or small molecule tyrosine kinase inhibitors within 14 days prior to study therapy administration, or 5 half-lives, whichever is shorter (42 days for prior nitrosourea or mitomycin-C)
- Major surgery within 28 days of the Screening visit
- Therapeutic radiopharmaceuticals within 8 weeks of treatment
- Systemic treatment with either corticosteroids (> 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days before the planned first dose of study drug
- Clinically significant gastrointestinal disorder that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
- Evidence or history of uncontrolled, clinically significant haematological, renal, hepatic, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, coagulation neurologic, dermatologic, autoimmune, or allergic disease
- Additional active malignancy that is progressing or has required active treatment within the past 3 years
- Known active CNS metastases and/or carcinomatous meningitis

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
Single group
Other design features
Open label, dose escalation, sequential allocation to cohorts
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Listings and tabulation of safety and efficacy variables
Pharmacokinetic and pharmacodynamic analysis and modeling to estimate and visualize standard parameters
Sample size is based on customary practice in Phase 1 oncology clinical studies.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
16/10/2023
Actual
15/11/2023
Date of last participant enrolment
Anticipated
13/07/2024
Actual
Date of last data collection
Anticipated
2/12/2024
Actual
Sample size
Target
33
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 25250 0
Sunshine Coast University Private Hospital - Birtinya
Recruitment hospital [2] 25251 0
Southside Cancer Care Centre - Miranda
Recruitment hospital [3] 25252 0
Ballarat Health Services (Base Hospital) - Ballarat Central
Recruitment hospital [4] 25253 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [5] 25254 0
Cancer Research SA - Adelaide
Recruitment postcode(s) [1] 40923 0
4575 - Birtinya
Recruitment postcode(s) [2] 40924 0
2228 - Miranda
Recruitment postcode(s) [3] 40925 0
3350 - Ballarat Central
Recruitment postcode(s) [4] 40926 0
3065 - Fitzroy
Recruitment postcode(s) [5] 40927 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 314362 0
Commercial sector/Industry
Name [1] 314362 0
Antido Therapeutics (Australia) Pty Ltd
Country [1] 314362 0
Australia
Funding source category [2] 314363 0
Other Collaborative groups
Name [2] 314363 0
George Clinical Pty Ltd
Country [2] 314363 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Antido Therapeutics (Australia) Pty Ltd
Address
Level 7, 616 St Kilda Road
Melbourne, VIC 3004
Country
Australia
Secondary sponsor category [1] 316310 0
None
Name [1] 316310 0
Address [1] 316310 0
Country [1] 316310 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313455 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 313455 0
Ethics committee country [1] 313455 0
Australia
Date submitted for ethics approval [1] 313455 0
01/08/2023
Approval date [1] 313455 0
30/09/2023
Ethics approval number [1] 313455 0
2023-06-732
Ethics committee name [2] 313456 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [2] 313456 0
Ethics committee country [2] 313456 0
Australia
Date submitted for ethics approval [2] 313456 0
31/07/2023
Approval date [2] 313456 0
Ethics approval number [2] 313456 0

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

Contacts
Principal investigator
Name 128222 0
Dr Dr Jeremy Long
Address 128222 0
Sunshine Coast University Private Hospital
3 Doherty St
Birtinya QLD 4575
Country 128222 0
Australia
Phone 128222 0
+61 428 190 959
Fax 128222 0
Email 128222 0
[email protected]
Contact person for public queries
Name 128223 0
Kristi Villagonzalo
Address 128223 0
George Clinical Pty Ltd
Level 5, 1 King St
Newtown, NSW 2042
Country 128223 0
Australia
Phone 128223 0
+61 493 494 739
Fax 128223 0
Email 128223 0
[email protected]
Contact person for scientific queries
Name 128224 0
Eric Rowinsky
Address 128224 0
Antido Therapeutics (Australia) Pty Ltd
Level 7, 616 St Kilda Road
Melbourne, VIC 3004
Country 128224 0
Australia
Phone 128224 0
+61 493 494 739
Fax 128224 0
Email 128224 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.