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Trial registered on ANZCTR


Registration number
ACTRN12616001265460
Ethics application status
Approved
Date submitted
14/07/2016
Date registered
8/09/2016
Date last updated
22/11/2022
Date data sharing statement initially provided
10/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Local HER-O: A study of local therapy for the treatment of brain metastases from Human Epidermal Growth Factor Receptor Type 2 (HER2) positive breast cancer.
Scientific title
A Phase II study of local therapy only (stereotactic radiosurgery and/or surgery) for treatment of up to 5 brain metastases from HER2 positive Breast Cancer
Secondary ID [1] 289300 0
NONE
Universal Trial Number (UTN)
U1111-1177-7526
Trial acronym
Local HER-O
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic HER2 positive breast cancer - brain metastases 298887 0
Condition category
Condition code
Cancer 298965 298965 0 0
Breast
Cancer 299511 299511 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For patients who have Human Epidermal Growth Factor Receptor Type 2 (HER2) positive breast cancer, which has metastasised to the brain, the main treatment options for these brain metastases are Whole Brain Radiotherapy (WBRT), Stereotactic Radiosurgery (SRS) and Neurosurgery (NS). Sometimes, if the metastases are small and are not causing any symptoms, they do not require any immediate treatment and will be observed.
The purpose of the study is to determine 1) How likely the tumour/s are controlled after treatment with local therapies Neurosurgery (NS) and/or Stereotactic Radiosurgery (SRS) and 2) How likely is it that other tumours develop at new sites in the brain when no Whole Brain Radiotherapy (WBRT) is given.

The local treatment offered will be determined by the patients doctor in consultation with the site multidisciplinary team and will be dependent on the size and location of the brain metastases. Each treatment will be performed by the specialist in that field, i.e. neurosurgeon and/or radiation oncologist.
Neurosurgery: The decision whether or not to recommend neurosurgery will be made independently of this research study. The surgery may be performed up to 6 weeks before participant being registered on the trial or up to 4 weeks after registration. The complexity and length of the surgery depends on the size and location of the tumour(s).
Sometimes stereotactic radiosurgery is required to be delivered to the cavity left after the metastasis has been removed (also known as a cavity boost). Timing of Cavity SRS is at the discretion of the treating team. SRS cavity boost must be given after registration and can be given up to 8 weeks after NS resection.
Stereotactic Radiosurgery: If the participant will be receiving stereotactic radiosurgery (either alone or in combination with neurosurgery), the Radiation Oncologist will organise for the participant to have a Radiotherapy planning. Treatment is to commence within 4 weeks of study registration.
The size, number and location of the brain metastasis will determine the dose and fractionation schedule of radiotherapy. Single metastasis, smaller than or equal to 2cm, may require 1 fraction. Alternately, multiple metastasis, metastasis in the brain stem, or those bigger than 2cm will required multiple fractions to treat. The dose range for the study is 20Gy/1 fraction to 24Gy/3 fractions. Each fraction is given on a separate day.
Intervention code [1] 294852 0
Treatment: Surgery
Intervention code [2] 295301 0
Treatment: Devices
Comparator / control treatment
No Control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298432 0
The percentage of patients treated with whole brain radiotherapy within 12 months after completion of local therapy. The rate of patients being treated with whole brain radiotherapy within 1 year of local treatment will be estimated together with its exact two-sided 95% confidence interval.
Assesed by: Review of follow up CRF
Timepoint [1] 298432 0
12 months after completion of local therapy
Secondary outcome [1] 324107 0
To describe distant brain failure incidence (overall and by number of treated metastases). Estimates at 12 months will be presented with 95% confidence intervals.
Time to distant brain failure will be measured from the time from registration to first date of documented distant brain failure.

Assesed by: Brain MRI, clincal assesment, MMSE
Timepoint [1] 324107 0
12 months after completion of local therapy
Secondary outcome [2] 324108 0
To describe distant extra-cranial failure incidence (development of new metastases at sites other than the brain). Estimates at 12 months will be presented with 95% confidence intervals.
Time to distant extra-cranial failure will be measured from the time from completion of local therapy to first date of documented distant extra-cranial failure.

Assesed by: Chest/Abdominal CT and Bone Scan
Timepoint [2] 324108 0
12 months after completion of local therapy
Secondary outcome [3] 324109 0
To describe the pattern of first failure using cumulative incidence curves assuming competing risks. Pattern of first failure is defined as cumulative incidence of first failure, considering each failure separately. Failures will be classified as local brain failure; distant brain failure; extra-cranial failure; and death.
Cumulative incidence of first failure will be measured from the date of registration to the date of first failure or death (without preceding failure) determined by MRI and/or clinical assessment.

Assesed by: Brain MRI, Chest/Abdominal CT, Bone Scan and clinical assesment
Timepoint [3] 324109 0
12 months after completion of local therapy
Secondary outcome [4] 324110 0
To describe overall survival using Kaplan-Meier methods. The number of neurological and non-neurological deaths will be provided.
Overall survival will be defined as the time from registration to the date of death from any cause.

Assesed by: Clinical assesment
Timepoint [4] 324110 0
12 months after completion of local therapy
Secondary outcome [5] 324111 0
To describe cause of death.

Assesed by: review of CRF
Timepoint [5] 324111 0
12 months after completion of local therapy
Secondary outcome [6] 324112 0
To describe Adverse Events (e.g. neurologic impairment, infection and wound problems from neurosurgery; and swelling and radiation necrosis from stereotactic radiosurgery) in tabular form as counts and percentages as determined by clinical assessment and collection using CTCAE v4.03.

Assesed by: Clincal examination
Timepoint [6] 324112 0
Baseline, and at 7-14 days, 3 months, 6 months, 9 months, and 12 months after completion of local therapy
Secondary outcome [7] 324113 0
To describe neurocognitive function using the mini-mental state examination assessed by linear mixed models (LMM).
Timepoint [7] 324113 0
Baseline, and at 3 months, 6 months, 9 months, and 12 months after completion of local therapy
Secondary outcome [8] 325847 0
To describe local brain failure incidence, at any site of neurosurgery or stereotactic radiosurgery. Estimates at 12 months will be presented with 95% confidence intervals.
Time to local brain failure will be measured from the time from completion of local therapy to first date of documented local brain failure determined by MRI.

Assesed by: Clincal examination and Brain MRI
Timepoint [8] 325847 0
12 months after completion of local therapy

Eligibility
Key inclusion criteria
- 18 years or older
- metastatic HER2 positive breast cancer
- 1-5 synchonous brain metastases (At least 1 lesion must require treatment with surgery or SRS, Maximum volume of any single PTV <10cm3 and Summated volume of all lesions to be treated with SRS is < 15cm3. If a lesion is too small for treatment and will be observed, then its volume is not included in this summation).
- ECOG 0-2
- Absent or stable extracranial disease or active extracranial disease that is likely to be controlled with further HER-2 targeted therapy.
- Receiving systemic HER2 targeted therapy, or planned to receive within 4 weeks of completion of brain metastasis treatment
- Able to undergo MRI scanning
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Previous treatment to the target brain metastases (excluding surgery within 6 weeks of registration)
- Previous whole brain radiotherapy (WBRT)
- Any brain metastasis that is greater than 40mm in size and unable to be resected
- Leptomeningeal disease
- Pregnant or breastfeeding

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
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size consideration:
The sample size of 50 patients is pragmatic, based on the number of patients expected to be recruited within 2 years. It is expected that up to 2 patients (4%) could be lost to follow-up prior to 1-year follow-up assessment resulting in 48 whole brain radiation therapy (WBRT) evaluable patients. Registered patients later found to be ineligible will be replaced. No other form of replacement is allowed.
If a 12 month WBRT rate above 50% is considered unacceptable, the current sample size of 48 WBRT evaluable patients will have 84% power for rejecting the null hypothesis that the true rate is 50% assuming the true underlying rate is 30% using a one-sided test for proportion with 5% alpha.

Statistical Analysis Plan:
All endpoints will be assessed after the last patient’s 12-month follow-up.
A one-sided test for proportions will be used to test whether the rate of WBRT at 12 months is less than 50%. The rate of patients being treated with WBRT within 1 year of local treatment will be estimated together with its exact two-sided 95% confidence interval.
Freedom from local, distant brain and distant extra cranial failure will be described as cumulative incidence curves assuming death as a competing risksevent for each endpoint assessed separatelly. Estimates at 12 months will be presented with 95% confidence intervals. Patients who are still on follow-up without any failure by the closeout date will be censored at the study closeout date. Distant prain failure incidence will also be assessed according to number of treated metastasis.
Pattern of first failure will be described using cumulative incidence curves assuming competing risks. Two separate pattern of first failure analysis will be provided. The first analysis will group the failures as local, distant brain, distant extra-cranial and death. The second analysis will group the failures as in-brain, distant extra-cranial and death.
An event chart will also be created showing the sequence of failures for each patient.
Overall survival will be described using Kaplan-Meier methods. The number of neurological and non-neurological deaths will be provided.
The maximum grade of each adverse event for each patient will be described in tabular form as counts and percentages. Use of corticosteroids will be reported as count and percentage.
A Llinear mixed models (LMM) will be used to assess MMSE. Time (as a factor) will be included as fixed effect while patient ID will be included as a random effect. No within-group correlation will be assumed and the model will be fitted by maximizing the restricted log-likelihood (REML). No imputation for missing values is intended. Means and 95% confidence intervals will be estimated from the LMM contrasts and presented in table format and graphically.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/11/2017
Actual
20/11/2017
Date of last participant enrolment
Anticipated
31/12/2019
Actual
22/12/2020
Date of last data collection
Anticipated
31/12/2020
Actual
21/07/2021
Sample size
Target
25
Accrual to date
Final
25
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 5850 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [2] 10087 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 23620 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 23621 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [5] 23622 0
The Canberra Hospital - Garran
Recruitment hospital [6] 23623 0
The Alfred - Melbourne
Recruitment hospital [7] 23624 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 21623 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 39039 0
5000 - Adelaide
Recruitment postcode(s) [3] 39040 0
6009 - Nedlands
Recruitment postcode(s) [4] 39041 0
2605 - Garran
Recruitment postcode(s) [5] 39042 0
3004 - Melbourne
Recruitment postcode(s) [6] 39043 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 293909 0
Other
Name [1] 293909 0
Trans Tasman Radiation Oncology Group (TROG) - CNS group
Country [1] 293909 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Trans Tasman Radiation Oncology Research Group (TROG)
Address
PO Box 88
Waratah, NSW 2298
Country
Australia
Secondary sponsor category [1] 292886 0
None
Name [1] 292886 0
N/A
Address [1] 292886 0
N/A
Country [1] 292886 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295327 0
Peter MacCullam Cancer Centre
Ethics committee address [1] 295327 0
Ethics committee country [1] 295327 0
Australia
Date submitted for ethics approval [1] 295327 0
08/08/2016
Approval date [1] 295327 0
13/02/2017
Ethics approval number [1] 295327 0

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

Contacts
Principal investigator
Name 66170 0
Dr Claire Phillips
Address 66170 0
Peter MacCallum Cancer Centre
305 Grattan St,
Melbourne VIC 3000
Country 66170 0
Australia
Phone 66170 0
+61 3 9656 1111
Fax 66170 0
Email 66170 0
[email protected]
Contact person for public queries
Name 66171 0
Kassandra Wagenfuehr
Address 66171 0
TROG Cancer Research
PO Box 88
Waratah, NSW 2298
Country 66171 0
Australia
Phone 66171 0
+61 02 401 43911
Fax 66171 0
Email 66171 0
[email protected]
Contact person for scientific queries
Name 66172 0
Claire Phillips
Address 66172 0
Peter MacCallum Cancer Centre
305 Grattan St,
Melbourne VIC 3000
Country 66172 0
Australia
Phone 66172 0
+61 3 9656 1111
Fax 66172 0
Email 66172 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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.