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Trial registered on ANZCTR


Registration number
ACTRN12618001070224
Ethics application status
Approved
Date submitted
19/06/2018
Date registered
27/06/2018
Date last updated
18/03/2020
Date data sharing statement initially provided
2/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 1 dose escalating study of ATX-101 given by intravenous infusion once every week in patients with advanced solid tumours.
Scientific title
A phase 1 dose escalating study to determine incidence of dose limiting toxicities of single agent ATX-101 given by intravenous infusion every week in patients with advanced solid tumours
Secondary ID [1] 295095 0
AM ATX101-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Tumors 308159 0
Condition category
Condition code
Cancer 307198 307198 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ATX-101 treatment will be administered weekly, as a single Intravenous Infusion (IV).
All subjects will receive mandated premedication with a corticosteroid, and H1 and H2 inhibitors 60 to 90 minutes prior to every dose of ATX-101 as follows:
• Dexamethasone 12 mg IV (or pharmacologically equivalent corticosteroid at an equivalent dose)
• Phenergan 12.5 mg IV (or pharmacologically alternative i.e. promethazine at recommended dose)
• Ranitidine 150 mg orally of Famotidine 20 mg orally
• Acetaminophen 1 g oral

Dosing will occur weekly for up to 2 cycles (i.e. 2 x 21 days = 6 weeks), on days 1, 8 and 15 (cycle 1) and days 22. 29 and 36 (cycle 2). Cohort 1 is to start at a dose level of 20mg/m2.
The dose escalation scheme, as overseen by a safety monitoring committee (SMC), will be followed, with up to 6 Cohorts expected. The SMC will provide expert recommendation on dose levels adjustments for subsequent cohorts. Current planned doses for subsequent cohorts:
Cohort 2: 30 mg/m2
Cohort 3: 45 mg/m2
Cohort 4: 60 mg/m2
Cohort 5: 90 mg/m2
Cohort 6: 135 mg/m2
Any additional cohort: TBD (up to 450 mg/m2)
After completion of the end of study visit, subjects without documented progressive disease may be approved to continue weekly treatment under as separate long term follow up protocol (AM ATX101-02). Under Protocol AM ATX-101-02, subjects are to be monitored by tumour imaging every 3 months (± 14 days) until documentation of progressive disease.
Intervention code [1] 301428 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306149 0
Composite Primary Outcome: To determine the maximum tolerated dose of ATX-101 following intravenous infusion once every week in subjects with advance solid tumours and identify candidate doses of ATX-101 for future Phase II studies in the target population To be assessed based on documented treatment-related toxicities, referred to as Dose limiting Toxicities (DLT's). Toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE4). The following adverse events will be assessed: - Non-haematologic - Heamatologic
Timepoint [1] 306149 0
Primary Timepoint: Weekly from Baseline (Day 1) to Day 21 of Cycle 1, to determine maximum tolerated dose. Additional timepoints added in week 1 (Day 2; 3)
Secondary Timepoint: Ongoing evaluation of Dose Limiting Toxicities (DLT's) occurring weekly from Baseline (Day 1) to End of Study Visit (2 x 21 day cycles).
Secondary outcome [1] 347734 0
To assess the safety and tolerability of ATX-101 following IV infusion once every week in subjects with advanced solid tumours. The following assessments will be used:
- Treatment exposure, by actual dose level
- Vital signs
- Electrocardiogram (ECG)
- Laboratory Parameters (Heamatology and Biochemistry)
- Urinalysis
- Physical Examination
- Adverse Events
Timepoint [1] 347734 0
Weekly from Baseline (Day 1) to End of Study (Day 43)
Secondary outcome [2] 347735 0
To characterise the plasma pharmacokinetic (PK) profile of ATX-101 following IV infusion once every week. Pharmacokinetic parameters will be computed from the individual plasma ATX-101 concentrations using a non-compartmental approach. The actual PK sampling time points will be used for the PK analysis. The following PK parameters will be assessed: Cmax, tmax, AUC0-inf, AUC0-t, CL, MRT, Vz, t1/2. Additional parameters may be calculated, as data allows.
Timepoint [2] 347735 0
Day 1 (Cycle 1) at pre-dose (within 30 minutes prior to dosing), when half of the planned dose has been administered, and 0, 5 (± 2), 10 (± 2), 20 (± 2), 30 (± 5), 60 (± 5), 90 (± 15), 120 (± 15), and 240 (± 15) minutes post-completion of infusion. Samples for PK will also be collected in Cycle 1 on Day 8 and Day 15 pre-dose (within 30 minutes prior to dosing), when half of the planned dose has been administered, and at end of infusion. On the final dosing day (Cycle 2, Day 36), blood samples for PK will be collected pre-dose (within 30 minutes prior to dosing), when half of the planned dose has been administered, and at the end of infusion. Trough PK samples will be collected on Day 3 (DLT follow up visit) and at the EOS/ET of treatment visit.

Eligibility
Key inclusion criteria
- Advanced disease (solid tumour) for which conventional anti-tumour treatment has been exhausted or has been refused
- Measurable or non-measurable (but radiologically evaluable) disease on CT/MRI scan
with at least one lesion outside previously irradiated areas
- Have an ECOG Performance status 0-2
- Life expectancy of at least 3 months
- Meet the following laboratory requirements:
Absolute lymphocyte count greater than or equal 0.8 x 109/L
Platelet count greater than or equal 75 x 109/L
Activated partial thromboplastin time (aPTT)/prothrombin time (PT) less than or equal to 1.5 x the upper limit of normal (ULN)
Total bilirubin level less than or equal to 1.5 x ULN
Aspartate transaminase (AST) and Alanine Aminotransferase (ALT) less than or equal to 2.5 x ULN
(less than or equal to 5 x ULN if liver metastasis present)
Creatinine less than or equal to 1.5 x ULN
Albumin greater than or equal to 30 g/L
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Have received an investigational drug within 4 weeks
2. Concurrent anticancer treatment within 21 days or 5x (five times) their half-lives (whichever is shorter) before the first dose of trial treatment
3. Use of hormonal agents within 7 days before start of trial treatment, except for subjects with castration-resistant prostate cancer (CRPC), who may remain on treatment with luteinizing hormone–releasing hormone agonists or antagonists
a. Note: Subjects receiving bisphosphonate or denosumab are eligible provided that treatment was initiated more or equal to 14 days before first dose of treatment.
4. Anticipated requirement for surgery or initiation of anti-cancer therapy during the study period
5. Have not recovered from AEs (more or equal to CTCAE Grade 2 other than alopecia) due to agent(s) administered more than 4 weeks earlier
6. Cardiac failure (per New York Heart Association [NYHA] functional classification) of more than Grade 2.
7. Evidence or history of clinically significant cardiac disease including congestive heart failure, unstable angina, acute myocardial infarction or cerebrovascular accident within the last six months, and symptomatic arrhythmia requiring therapy (with the exception of extra systoles or minor conduction abnormalities and controlled and well-treated chronic atrial fibrillation).
8. QTcF more than 460 ms
9. Active central nervous system (CNS) metastases. Subjects with known CNS metastases must have received previous radiotherapy or surgery at least two weeks prior to receiving ATX-101. Any residual neurological deficit must be stable off corticosteroids.
10. Lymphangitic carcinomatosis
11. Leptomeningeal involvement
12. Major surgery within 3 weeks of screening
13. Current acute or chronic disease, other than the study indication, that would increase the expected risk of exposure to the investigational product or would be expected to interfere with the planned evaluations, in the judgment of the Investigator
14. Breastfeeding or pregnant as confirmed by a positive serum beta human chorionic gonadotropin (ß-HCG) pregnancy test at screening or at subsequent clinic visits
15. Unwilling or unable to follow protocol requirements
16. Known positive status of Human immunodeficiency virus (HIV) and/or active Hepatitis B or C. In subjects with a history of Hepatitis B or Hepatitis C infection, resolution of infection must be demonstrated by negative serology for Hepatitis B surface antigen (HBsAg) and Hepatitis C virus (HCV) ribonucleic acid (RNA) must be demonstrated at least 6 weeks following antiviral therapy.
17. History of severe allergy (requiring hospital care), severe reaction to any drug, or any known or suspected allergies or sensitivities to the study drug constituents.
18. Inadequate venous access to allow collection of blood samples.

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



Intervention assignment
Other
Other design features
Up to 6 cohorts is expected to be enrolled. Additional cohorts may be added if recommended by the SMC. A minimum of three subjects will e enrolled at each dose level, and up to six in the event of Dose Limiting Toxicity (DLT) in the first treatment cycle (21 days). A safety monitoring committee (SMC) will convene at completion of each cohort to provide recommendations on safety signals deemed clinically significant, determine dose limiting toxicity (DLT) and review dose escalation/cohort progression. The dose escalation scheme is planned as follows:
Cohort 1: 20 mg/m2
Cohort 2: 30 mg/m2
Cohort 3: 45 mg/m2
Cohort 4: 60mg/m2
Cohort 5: 90 mg/m2
Cohort 6: 135 mg/m2
Any additional cohort (up to 450mg/m2)
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The total sample size is expected to be up to 36 subjects. No sample size calculation was
performed.
Data will be summarised using descriptive statistics (continuous data) and/or frequency
tabulations with counts and percentages (categorical data) for demographic and baseline
characteristics, efficacy measurements, safety measurements, and all relevant PK measurements.
Details of the statistical analysis, analysis populations, and data reporting will be provided in the Statistical Analysis Plan (SAP) to be finalised prior to database lock.
An interim analysis of all available safety data will be conducted at the time that the last subject completes the first treatment cycle in the MTD cohort.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/11/2018
Actual
15/10/2018
Date of last participant enrolment
Anticipated
30/04/2020
Actual
Date of last data collection
Anticipated
8/07/2020
Actual
Sample size
Target
36
Accrual to date
14
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Recruitment hospital [1] 11071 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment hospital [2] 11072 0
Linear Clinical Research - Nedlands
Recruitment hospital [3] 11073 0
Scientia Clinical Research - Randwick
Recruitment hospital [4] 16141 0
Flinders Private Hospital - Bedford Park
Recruitment postcode(s) [1] 22876 0
2031 - Randwick
Recruitment postcode(s) [2] 22874 0
5000 - Adelaide
Recruitment postcode(s) [3] 29670 0
5042 - Bedford Park
Recruitment postcode(s) [4] 22875 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 299677 0
Commercial sector/Industry
Name [1] 299677 0
Therapim Pty Ltd
Country [1] 299677 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Therapim Pty Ltd
Address
COHORT, Health & Knowledge Precinct, 16 Nexus Way, Southport QLD 4215, Australia
Country
Australia
Secondary sponsor category [1] 299013 0
None
Name [1] 299013 0
Address [1] 299013 0
Country [1] 299013 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300576 0
Bellberry Human Research Ethics Committee H [EC00459)
Ethics committee address [1] 300576 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 300576 0
Australia
Date submitted for ethics approval [1] 300576 0
23/05/2018
Approval date [1] 300576 0
09/07/2018
Ethics approval number [1] 300576 0

Summary
Brief summary
This is a Phase I, open-label, single arm, safety and tolerability study which will evaluate escalating dose cohorts of ATX-101 to determine the maximum tolerated dose in subjects with advanced solid tumours.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, have advanced solid tumours for which conventional anti-tumour treatment has been exhausted or has been refused

Study details
The study is designed to systematically assess safety and tolerability, and to identify the maximum tolerated dose (MTD) for ATX-101. Dose escalation will be determined based on recommendations from a Safety Review Committee and is expected to occur over a total of 6 cohorts.

Potential study subjects who provide voluntary written informed consent will undergo screening evaluations to determine eligibility within 28 days prior to enrolment and the start of treatment (Day 1). Eligible subjects will be admitted to the study centre on Day 1 for the first dose of study drug to be administered by IV infusion. Prior to each treatment infusion the subject will receive mandated pre-medication. Treatment will be administered weekly in cycles of 21-day duration, with a single IV infusion of ATX-101 on Day 1, 8 and 15. Dosing of subjects will occur weekly for up to two cycles (i.e. 2 x 21 days = 6 weeks), or until criteria for early termination is met.

After completion of the end of study visit, subjects without documented progressive disease may be approved to continue weekly treatment under a separate long term follow up protocol (AM ATX101-02). Under Protocol AM ATX-101-02, subjects are to be monitored by tumour imaging every 3 months (± 14 days) until documentation of progressive disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84106 0
Dr Michael Millward
Address 84106 0
Linear Clinical Research, 1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009
Country 84106 0
Australia
Phone 84106 0
+61 1300 546 327
Fax 84106 0
Email 84106 0
contactus@linear.org.au
Contact person for public queries
Name 84107 0
Dr Michael Millward
Address 84107 0
Linear Clinical Research, 1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009
Country 84107 0
Australia
Phone 84107 0
+61 1300 546 327
Fax 84107 0
Email 84107 0
contactus@linear.org.au
Contact person for scientific queries
Name 84108 0
Dr Michael Millward
Address 84108 0
Linear Clinical Research, 1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009
Country 84108 0
Australia
Phone 84108 0
+61 1300 546 327
Fax 84108 0
Email 84108 0
contactus@linear.org.au

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.