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Trial registered on ANZCTR


Registration number
ACTRN12620000583943
Ethics application status
Approved
Date submitted
29/01/2020
Date registered
20/05/2020
Date last updated
20/02/2023
Date data sharing statement initially provided
20/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and anti-tumour activity of once-daily oral treatment with EO1001 in patients with advanced cancer.
Scientific title
An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and anti-tumour activity of once-daily oral treatment with EO1001 in patients with advanced cancer.
Secondary ID [1] 300386 0
EOHC-1001-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ErbB-1(EGFR) positive cancer 316008 0
ErbB-2(HER2) positive cancer 317132 0
ERbB-4 (HER4) positive cancer 317133 0
Condition category
Condition code
Cancer 314282 314282 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tier 1a and 1b (Dose Escalation):

Patients enrolled in the study will receive one oral dose of EO1001. Up to eight dose escalation cohorts are planned at the following incremental single-daily dose levels:
Cohort 1 = 2.5 mg q.d;
Cohort 2 = 10 mg q.d;
Cohort 3 = 20 mg q.d;
Cohort 4 = 30 mg q.d.;
Cohort 5 = 50 mg q.d.;
Cohort 6 = 70 mg q.d.;
Cohort 7 = 90 mg q.d.;
Cohort 8 = 120 mg q.d.;
Cohort 9 = 160 mg q.d..

All patients will start on Tier 1a, the dose at which they will be treated will depend on which dose cohort they are allocated to. Cohort 1 patients will receive 2.5mg once daily, when the patient has received 28 days of treatment and the Safety Review Committee have cleared the dose, the next dose cohort will be open ie 10mg once daily and so only until the maximum tolerated dose is reached.

Cycle 1: Patients will receive a single dose of oral EO1001 on day 1 and single dose pharmacokinetics will be performed at nominated time points for 7 days. Beginning on day 8, oral EO1001 will be administered once daily for 21 days. Multi-dose pharmacokinetics will be performed at the nominated time points.
Cycles 2-6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. Multi-dose pharmacokinetics will be performed at the nominated time points. Following Cycle 6, participants without DLT or disease progression may be offered continued treatment in an extension protocol upon recommendation of the principal investigator.

Tier 2 (MTD Expansion):
When the Safety Review Committee state that maximum tolerated dose (MTD) is reached additional patients will be recruited to the MTD dose.

Oral EO1001 will be administered once daily in continuous 28 day cycles for up to 6 cycles (24 weeks). Multi-dose pharmacokinetics will be performed at the nominated time points. Following Cycle 6, participants without DLT or disease progression may be offered continued treatment in an extension protocol upon recommendation of the principal investigator

Adherence to investigational product treatment will be monitored by the study coordinator by counting the tablets returned to the unit and reviewing the participant diary.
Intervention code [1] 316668 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322671 0
To examine the safety and tolerability of EO1001 in participants with metastatic or advanced stage ErbB-1(EGFR), ErbB-2(HER2) and/or ERbB-4 (HER4) positive cancer..

Safety and tolerability will be measured by serum blood tests and patient feedback. All adverse events will be captured in the patient files and the EDC.
Timepoint [1] 322671 0
Safety and tolerability for cycle 1 will be assessed daily for 7 days and then weekly until day 28. For Cycle 2 to Cycle 6 safety and tolerability will be assessed every 28 days.

Overall Safety and tolerability will be assessed at the end of study visit iie 26 weeks post enrolment.
Secondary outcome [1] 379248 0
To define a safe Recommended Phase II dose level (RP2D) for testing in subsequent Phase II clinical trials. This will be done in the following way:
Patients enrolled in the study will receive EO1001 at a nominated dose. Up to eight dose levels are planned to be tested during this study.
The study will start at the lowest dose, that is, patients will receive 10mg once daily, When the patients have received 28 days of of treatment the Safety Review Committee will review the patients safety data to ensure that no dose limiting toxicities occurred and the dose is safe and will then clear the dose. The Safety Review Committee will then allow the next dose cohort will be open ie 20mg. This will continue until such time as the Safety Review Committee assess that the dose level is not safe for the patients, that is, that dose limiting toxicities occurred or until the top dose is cleared. The Maximum Tolerated Dose (MTD) is defined as the dose below which the dose limiting toxicities occurred.

When the Safety Review Committee state that the MTD is reached additional patients will be recruited to the MTD dose.level to confirm the safety profile.
Timepoint [1] 379248 0
The Safety Review Committee (SRC) will review the patients safety data to ensure that no dose limiting toxicities occurred within 28 days from the patients first dose. If the SRC deems the dose safe then the next dose cohort will be open. Patients safety data will be reviewed by the SRC within 28 days of the first dose for all dose level cohorts to ensure that no dose limiting toxicities occurred within 28 days from first dose..

first dose, this will continue until such time as the SRC assess that the dose level is not safe for the patients, that is, that dose limiting toxicities occurred or until the top dose is cleared.
Secondary outcome [2] 382177 0
Blood samples will be collected from patients at various time-points to assess the pharmacokinetic profile of EO1001. The parameters that will be assessed include Tmax,,Cmax, Cmin, AUC and T1/2. Serum assays will be conducted at the completion of patient treatment is at 26 weeks.
Timepoint [2] 382177 0
Serum assays will be conducted at the completion of patient treatment ,(26 weeks). on pharmacokinetic samples collected on:
Cycle 1 day 1: 0( predose), 30min, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr and 24hr post dose
Cycle 2 - 6:: day 1: 0 (predose), 30min, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr and 24hr post dose and predose on the following days Day 28, Day 56, Day 84, Day 112, Day 140, day 168
will be conducted at the completion of patient treatment is at 26 weeks..
Secondary outcome [3] 382178 0
To assess preliminary efficacy outcomes according to RECIST 1.1
Timepoint [3] 382178 0
After 26 weeks of treatment

Eligibility
Key inclusion criteria
• Male or female >= 18 years of age participants with confirmed diagnosis of metastatic or advanced stage ErbB-1 (EGFR), ErbB-2 (HER2) and/or ERbB-4 (HER4) positive cancer who have relapsed after treatment with approved therapies and are unsuitable for further treatment with approved therapies or declined further treatment with approved therapies.
• Participants must sign informed consent.
• Participants must have measurable disease, defined as at least 1 unidimensional measurable lesion on an imaging scan as defined by RECIST 1.1.
• Life expectancy of greater than 3 months.
• Acceptable organ function, as evidenced by the following laboratory data during screening period:
• Adequate hepatic function as defined by bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x ULN. Serum bilirubin must be less than or equal to 2.5 mg/dL when increase is clearly documented as due to Gilbert’s syndrome.
• Adequate renal function, with serum creatinine less than or equal to 1.5 x ULN or MDRD greater than or equal to 60 mL/min (CKD EPI Creatinine Equation).
o CNS metastases that have been treated by complete resection and/or radiotherapy demonstrating stability or improvement may be enrolled provided they are stable as shown by CT/MRI scan at least 4 weeks before screening without evidence of cerebral oedema.
o Patients with CNS metastases requiring corticosteroids or anticonvulsants must be on a stable or declining dose for a minimum of 10 days prior to cycle 1 day 1
o Patients with leptomeningeal disease may be allowed in the study in agreement with sponsor and medical monitor.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Active infection requiring systemic treatment, defined as requiring antimicrobial, antifungal, or antiviral agents.
• Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
• Untreated or symptomatic brain metastases. Participants with treated or untreated brain metastases are NOT eligible if there has been a change in brain disease status in the 8 weeks prior to screening. This includes evidence of radiological progression, clinical decline and increasing steroid dose.
• Current or recent (within 10 days of Cycle 1 Day 1) use of full dose oral or parenteral anticoagulants or other thrombolytic agents for therapeutic (as opposed to prophylactic) purposes, clinically serious non-healing wounds, or incompletely healed bone fracture.
• Participants on > 2mg dexamethasone (or steroid equivalent).
• Ventriculoperitoneal (VP) shunts.
• Renal compromised or renal failure.
• Hepatic compromised or hepatic failure.
• Bullous and exfoliative skin disorders.
• Interstitial lung disease (ILD)
• Participants with adequate cardiac function ( less than or equal to NYHA class II) or normal cardiac function with left ventricular ejection fraction (LVEF) less than or equal to 50% at screening.
• Anticancer therapy within 4 weeks, or a minimum of 5 half-lives whichever is longer.
• Pregnancy or breast-feeding.
• Inability to swallow oral medications or having malabsorption syndrome.
• Unresolved adverse reactions to prior treatments NCI CTCAEv5 > Grade 1.
• Any serious medical or psychiatric conditions which the Investigator feels may interfere with the patient’s ability to give informed consent or participate in the procedures or evaluations of the study.
• Abnormal coagulation not corrected by plasma infusion (APTT > ULN or INR> 1.2).
• Participants of childbearing potential who do not agree to use at least 2 effective contraceptive methods throughout the study and for 6 months following completion of treatment.
• Female participants who are pregnant or lactating.
• Unstable angina or acute myocardial infarction less than or equal to 6 months prior to starting study treatment.
• Baseline QTc greater than or equal to 470 msec
• Cardiomyopathy.
• Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

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
Other design features
This is a 2-stage, Phase I-IIa (initial dose escalation followed by an expansion phase), open label, multi-centre study.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Statistical methods / analysis
The statistical package SAS will be used to produce all summary tables and listings. In general terms, categorical data will be presented using counts and percentages, whilst continuous variables will be presented using the mean, standard deviation, median, minimum, maximum and number of subjects. In general, minima and maxima will be quoted to the number of decimal places as recorded in the CRFs; means and standard deviations will be quoted to one further decimal place. Percentages will be rounded to one decimal place.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
28/09/2021
Actual
2/09/2021
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
50
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20580 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 20581 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [3] 24075 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 35367 0
3168 - Clayton
Recruitment postcode(s) [2] 35368 0
3144 - Malvern
Recruitment postcode(s) [3] 39584 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304807 0
Commercial sector/Industry
Name [1] 304807 0
Senz Oncology Pty Ltd
Country [1] 304807 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Senz Oncology Pty Ltd
Address
714 Main Street,
Eltham
VIC 3095.
Country
Australia
Secondary sponsor category [1] 305133 0
None
Name [1] 305133 0
Address [1] 305133 0
Country [1] 305133 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309513 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 309513 0
Ethics committee country [1] 309513 0
Australia
Date submitted for ethics approval [1] 309513 0
17/02/2021
Approval date [1] 309513 0
01/06/2021
Ethics approval number [1] 309513 0

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

Contacts
Principal investigator
Name 99666 0
Dr Sophia Frentzas
Address 99666 0
Monash Medical Centre, 7th Floor MHTP Building,
246 Clayton Road, Clayton, VIC 3168,
Country 99666 0
Australia
Phone 99666 0
+61 3 85722392
Fax 99666 0
Email 99666 0
[email protected]
Contact person for public queries
Name 99667 0
Sophia Frentzas
Address 99667 0
Monash Medical Centre, 7th Floor MHTP Building,
246 Clayton Road, Clayton, VIC 3168,
Country 99667 0
Australia
Phone 99667 0
+61 3 85722392
Fax 99667 0
Email 99667 0
[email protected]
Contact person for scientific queries
Name 99668 0
Sophia Frentzas
Address 99668 0
Monash Medical Centre, 7th Floor MHTP Building,
246 Clayton Road, Clayton, VIC 3168,
Country 99668 0
Australia
Phone 99668 0
+61 3 85722392
Fax 99668 0
Email 99668 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
Individual participant data will not be shared. All data will be analysed and presented as an aggregate or de-identified.


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.