Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000148572p
Ethics application status
Not yet submitted
Date submitted
18/01/2024
Date registered
16/02/2024
Date last updated
16/02/2024
Date data sharing statement initially provided
16/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Frequency of Cardiac Monitoring in Patients Treated with HER2-Directed Therapies for Breast Cancer
Scientific title
The Effects of 3 monthly versus 6 monthly Cardiac Monitoring on Left Ventricular Ejection Fraction in Patients Treated with HER2-Directed Therapies for Breast Cancer
Secondary ID [1] 311354 0
None
Universal Trial Number (UTN)
Trial acronym
MONITOR-HER2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer 332615 0
Condition category
Condition code
Cancer 329318 329318 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be a single-centre prospective, randomised, open-label, non-inferiority 2 by 2 factorial design trial investigating the safety of six-monthly cardiac monitoring versus standard of care three-monthly cardiac monitoring and abbreviated versus full transthoracic echocardiography (TTE) protocols in participants with HER2-positive breast cancer treated with HER2-directed therapies. There are optional extension arm and cardiac magnetic resonance imaging sub-studies available for interested participants. The duration of the primary study is 12 months.

Participants will be randomised to the following arms through the course of the study:
• Three-monthly surveillance TTE and full TTE protocol (control)
• Three-monthly surveillance TTE and abbreviated TTE protocol
• Six-monthly surveillance TTE and full TTE protocol
• Six-monthly surveillance TTE and abbreviated TTE protocol

The abbreviated TTE protocol used will only assess left ventricular ejection fraction which is the parameter of interest with HER2-directed therapies, whilst the full TTE protocol in the study assesses left ventricular ejection fraction, cardiac chamber size, valvular function, cardiac chamber pressures, and the pericardium. The abbreviated TTE protocol will take approximately 15 minutes to complete whilst the full TTE protocol will take approximately 45 minutes to complete. All TTE scans will be performed by qualified cardiac sonographers and images will be reported by a cardiologist. A study coordinator will coordinate and organise all TTE scans as allocated by randomisation and monitor adherence to the randomisation. Participants will be allowed to have additional TTE scans at any timepoint during the study if deemed clinically necessary by their treating clinician (either full or abbreviated protocol at the clinician's discretion). In addition to the surveillance TTEs organised as part of the randomised arms, participants will also attend a final follow up study appointment in clinic at the end of the primary study at 12 months to record adverse events and to complete a medication log. This final study appointment is estimated to take 1 hour.

Participants with metastatic breast cancer who are planned to have longer than 12 months treatment with HER2-directed therapies can provide additional optional consent to participate in the optional extension arm of the study. Following the primary 12 month study period, participants who consent to the optional extension arm will continue to have either three-monthly or six-monthly surveillance TTE as originally randomised for as long as they continue to be treated with HER2-directed therapies. However, only full TTE protocols will be utilised in the extension arm of the study (ie patients will continue to have either three-monthly surveillance TTE with full TTE protocol or six-monthly surveillance TTE with full protocol). The anticipated time for each TTE scan is 45 minutes. Participants will be allowed to have additional TTE scans at any timepoint during the extension arm of the study if deemed clinically necessary by their treating clinician (full TTE protocol will be utilised). Participants will be required to attend annual study appointments in clinic during the extension arm of the study to record adverse events and to complete a medication log. This is estimated to take 1 hour.

Interested participants can also consent to participate in an optional cardiac magnetic resonance imaging sub-study. Consenting participants will undergo two cardiac magnetic resonance imaging scans during the study: the first will be at time of enrolment into the study and the second at 12 months at the end of the primary study period. Cardiac magnetic resonance imaging scans will be performed by a trained radiographer and the images will be co-reported by qualified radiologists and cardiologists. Each cardiac magnetic resonance imaging scan will take approximately 15 minutes. Participants will be allowed to have additional cardiac magnetic resonance imaging scans at any timepoint during the study if deemed clinically necessary by their treating clinician. Participants who consent to the optional cardiac magnetic resonance imaging sub-study will not need to attend any additional study appointments in clinic for the sub-study.
Intervention code [1] 327797 0
Early detection / Screening
Comparator / control treatment
The control arm of the study will undergo three-monthly transthoracic echocardiography surveillance using a full echocardiography protocol. This is the standard of care for cardiac monitoring for patients with breast cancer receiving HER2-directed therapies.

The full TTE protocol in the study assesses left ventricular ejection fraction, cardiac chamber size, valvular function, cardiac chamber pressures, and the pericardium. The full TTE protocol will take approximately 45 minutes to complete. All TTE scans will be performed by qualified cardiac sonographers and images will be reported by a cardiologist.
Control group
Active

Outcomes
Primary outcome [1] 337134 0
Left ventricular ejection fraction
Timepoint [1] 337134 0
Baseline and 12 months post-randomisation
Secondary outcome [1] 430826 0
HER2-directed therapy interruption
Timepoint [1] 430826 0
During the 12 month timeframe of the study and assessed once at the end of the study at 12 months during final study follow up in clinic.
Secondary outcome [2] 430827 0
Asymptomatic left ventricular dysfunction
Timepoint [2] 430827 0
Baseline, 3 months, 6 months, 9 months, and 12 months post-randomisation for patients randomised to the 3-monthly surveillance arms
Baseline, 6 months, and 12 months post-randomisation for patients randomised to the 6-monthly surveillance arms
Secondary outcome [3] 430828 0
Troponin levels
Timepoint [3] 430828 0
Baseline and 12 months post-randomisation
Secondary outcome [4] 430829 0
Incidental cardiac findings
Timepoint [4] 430829 0
Baseline and 12 months post-randomisation
Secondary outcome [5] 430830 0
Cost-effectiveness analysis
Timepoint [5] 430830 0
12 months post-randomisation
Secondary outcome [6] 430831 0
Left ventricular ejection fraction
Timepoint [6] 430831 0
Baseline and 12 months post-randomisation
Secondary outcome [7] 430832 0
Volumetric and myocardial measurements
Timepoint [7] 430832 0
Baseline and 12 months post-randomisation
Secondary outcome [8] 431350 0
Brain natrieutic peptide levels
Timepoint [8] 431350 0
Baseline and 12 months post-randomisation
Secondary outcome [9] 431351 0
Lipid profile levels
Timepoint [9] 431351 0
Baseline and 12 months post-randomisation
Secondary outcome [10] 431352 0
Glycosylated haemoglobin A1c levels
Timepoint [10] 431352 0
Baseline and 12 months post-randomisation
Secondary outcome [11] 431353 0
High sensitivity C-reactive protein levels
Timepoint [11] 431353 0
Baseline and 12 months post-randomisation

Eligibility
Key inclusion criteria
• Capable of providing written informed consent and willing to adhere to all protocol requirements
• Histologically confirmed HER2-positive breast cancer, as confirmed on immunohistochemistry (IHC) or fluorescence in situ hybridisation; Participants with IHC 1+ or 2+ results, also known as HER2-low cancer, are allowed to participate if they are planned for treatment with HER2-directed therapies
• Planned for or commenced treatment with HER2-directed therapy for less than 3 months, which include monotherapy or combination therapy with any of the following agents - Trastuzumab, Pertuzumab, Trastuzumab emtansine, Trastuzumab deruxtecan, Neratinib, Lapatinib
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Unable to provide written informed consent
• Unable or unwilling to adhere to all protocol requirements
• Commenced current treatment with HER2-directed therapy for 3 months or longer
• History of left ventricular dysfunction or heart failure with reduced ejection fraction, defined as left ventricular ejection fraction of <50% (this includes patients with left ventricular dysfunction identified on baseline screening echocardiogram or previous left ventricular dysfunction that recovered with cardioprotective medications)
• History of left ventricular dysfunction during previous treatment with HER2-directed therapies
• History of severe valvular heart disease
• Poor imaging quality on baseline screening echocardiogram limiting interpretation of baseline and potentially future echocardiogram results
• Severe uncontrolled tachyarrhythmia
• History of ventricular tachycardia or ventricular fibrillation
• History of permanent pacemaker or implantable cardiac defibrillator implantation
• Prognostic factors associated with an expected survival less than 12 months as per treating clinician discretion.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed by using central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software will be conducted. Randomisation will be stratified according to HER2-directed therapy treatment intent (curative versus palliative) and prior anthracycline exposure.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Baseline characteristics will be summarised for the randomised groups and imbalances between groups identified by differences of 0.5 standard deviation (continuous measures, log transformed if necessary) or odds ratios of 1.5 or greater (categorical measures). Average change in left ventricular ejection fraction at an individual patient-level will be compared between groups using analysis of covariance with baseline levels as a covariate. Cox proportional hazards regression models will be generated to estimate the hazard ratio and 95% confidence intervals for number of treatment interruptions, frequency of asymptomatic left ventricular ejection fraction decline, and changes in biomarkers. All analyses will be intention to treat. Sensitivity analysis using multiple imputation will also be performed to accommodate patients who dropped out of the study due to progression of breast cancer limiting survival. Subgroup analyses will be performed to compare results according to age, treatment intent, baseline cardiotoxicity risk, and previous left chest radiation.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/05/2024
Actual
Date of last participant enrolment
Anticipated
29/05/2026
Actual
Date of last data collection
Anticipated
30/06/2027
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26043 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [2] 26045 0
Victorian Heart Hospital - Clayton
Recruitment postcode(s) [1] 41890 0
3165 - East Bentleigh
Recruitment postcode(s) [2] 41891 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 315610 0
Hospital
Name [1] 315610 0
Monash Health Department of Oncology
Country [1] 315610 0
Australia
Primary sponsor type
Hospital
Name
Monash Health Department of Oncology
Address
823-865 Centre Road, Bentleigh, Victoria 3165
Country
Australia
Secondary sponsor category [1] 317707 0
None
Name [1] 317707 0
Address [1] 317707 0
Country [1] 317707 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 314498 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 314498 0
Ethics committee country [1] 314498 0
Australia
Date submitted for ethics approval [1] 314498 0
21/02/2024
Approval date [1] 314498 0
Ethics approval number [1] 314498 0

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

Contacts
Principal investigator
Name 131798 0
Dr Sean Tan
Address 131798 0
Victorian Heart Hospital, 631 Blackburn Road, Clayton, Victoria 3168
Country 131798 0
Australia
Phone 131798 0
+613 7511 1264
Fax 131798 0
Email 131798 0
sean.tan@monashhealth.org
Contact person for public queries
Name 131799 0
Sean Tan
Address 131799 0
Victorian Heart Hospital, 631 Blackburn Road, Clayton, Victoria 3168
Country 131799 0
Australia
Phone 131799 0
+613 7511 1264
Fax 131799 0
Email 131799 0
sean.tan@monashhealth.org
Contact person for scientific queries
Name 131800 0
Sean Tan
Address 131800 0
Victorian Heart Hospital, 631 Blackburn Road, Clayton, Victoria 3168
Country 131800 0
Australia
Phone 131800 0
+613 7511 1264
Fax 131800 0
Email 131800 0
sean.tan@monashhealth.org

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.