Tailoring treatment for HER2-positive early breast cancer
| ISRCTN | ISRCTN81408940 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN81408940 |
| EudraCT/CTIS number | 2021-001240-10 |
| IRAS number | 292122 |
| Secondary identifying numbers | CPMS 50425, IRAS 292122 |
- Submission date
- 05/10/2021
- Registration date
- 11/10/2021
- Last edited
- 21/12/2023
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-personalised-treatment-for-early-her2-positive-breast-cancer-her2-radical
Background and study aims
Patients with the “HER2-positive” type of early breast cancer (HER2+ EBC) usually receive a course of drug treatment as well as surgery. This drug treatment improves chances of cure by destroying any breast cancer cells that might have already begun to spread. The aim is to reduce the burden of treatment and the risk of serious long-term side effects for some patients with HER2+ EBC. The researchers want to find out if they can adjust the amount of drug treatment given to patients after surgery according to the way the cancer initially responds to drug treatment before surgery.
Who can participate?
Patients aged 16 years and over with HER2+ EBC treated with neoadjuvant chemotherapy, pertuzumab and trastuzumab, who have a pathological complete response (pCR) at surgery.
What does the study involve?
Before entry into the study, a review of medical history and a pregnancy test (for all women who are able to get pregnant) will be conducted to determine if a patient is eligible to enter. Following study entry patients will continue to receive trastuzumab until a total of 9 cycles (about 6 months) of treatment have been given. This number of cycles includes the trastuzumab treatment received before entering the study. For patients who do not take part in the study it is likely that 17 or 18 cycles (about 1 year in total) of trastuzumab would be given. For some patients, the possibility of receiving pertuzumab and/or chemotherapy after surgery may have been discussed by their doctor, however, patients who have entered HER2-RADiCAL will not receive pertuzumab or any further chemotherapy after surgery. Patients will continue to receive trastuzumab in the same way that they would receive it if they were not taking part in the study. This may be as an injection under the skin or through a drip in the arm. During trastuzumab treatment the following assessments will be conducted. Before each cycle of trastuzumab the patient will have a discussion with their study doctor or nurse to document if there have been changes in their health since the last visit. Patients will continue to have their heart function measured with an echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan in the same way that would have happened if they were not taking part in the study. In many hospitals this will be done around 4 and 8 months after starting trastuzumab. Patients may receive other preventative treatments like hormone treatment, radiotherapy and bisphosphonates, just as they would if they were not taking part in this study. The study research team will request a sample of tumour tissue collected at the time of initial diagnosis and a copy of the pathology report. They will also ask for tissue samples (or images of tissue samples) collected at the time of surgery from about 100 study participants. These samples and images will be analysed by the research team to ensure that they agree with the diagnosis of pCR made by the hospital pathologist. About 30 days after the last cycle of trastuzumab, patients will have a discussion with their study doctor to document if there have been any changes in their health since the last visit. After treatment has finished, patients will have a mammogram and a follow up once a year for at least 5 years. The study research team also plan to collect routine information about the health of study participants, such as hospital admissions, information relating to their cancer, any treatments they might go on to receive and continued information about their overall health and wellbeing, from NHS databases.
What are the possible benefits and risks of participating?
By receiving a shorter duration of antibody treatment (trastuzumab and pertuzumab) and by not receiving adjuvant chemotherapy (if this had been discussed), patients may benefit from having fewer visits for treatment as well as a lower risk of short- and long-term side effects. Patients who take part in this study will be less likely to have some of these side effects because treatment is given for a shorter time.
By receiving less treatment patients may have a slightly increased risk of their cancer coming back. It is well known that patients who are suitable for this study have a high chance of remaining cancer-free with current treatment: about 96 in every 100 patients (96%) will remain free of cancer 3 years after diagnosis and about 94 in every 100 (94%) will remain cancer-free at 5 years from diagnosis. Based on previous research the study team think it is likely that carefully reducing treatment, as planned in this study, may not increase the risk of the cancer returning or may only increase the risk by a very small amount that could be balanced by the benefits of fewer side effects. However, this is not known for certain and this is why this research is being done. An independent group of scientists and doctors will closely monitor the progress and early results of the study to ensure that the continuation of the study remains safe and in the best interest of those patients volunteering to take part.
Where is the study run from?
The Institute of Cancer Research (ICR) (UK)
When is the study starting and how long is it expected to run for?
December 2019 to November 2029
Who is funding the study?
National Institute for Health Research – Health Technology Assessment (HTA) Programme (UK)
Who is the main contact?
Katie Goddard
her2radical-icrctsu@icr.ac.uk
Contact information
Scientific
Senior Trial Manager
ICR - Clinical Trials & Statistics Unit (ICR-CTSU)
The Institute of Cancer Research
15 Cotswold Road
Sutton
SM2 5NG
United Kingdom
| Phone | +44 (0)20 8722 4185 |
|---|---|
| her2radical-icrctsu@icr.ac.uk |
Study information
| Study design | Interventional non-randomized study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | The HER2-RADiCAL study (Response ADaptive CAre pLan) – tailoring treatment for HER2 positive early breast cancer |
| Study acronym | HER2-RADiCAL |
| Study hypothesis | HER2-RADiCAL seeks to test the hypothesis that a pathological complete response (pCR) to preoperative chemotherapy and anti-HER2 drug therapy can be used as a functional response biomarker to select patients who can safely receive less intensive personalised therapy, with minimal or no loss of efficacy in the population. |
| Ethics approval(s) | Approved 20/08/2021, London - South East Research Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8085; londonsoutheast.rec@hra.nhs.uk), REC ref: 21/LO/0529 |
| Condition | HER2-positive early breast cancer |
| Intervention | Current interventions as of 21/12/2023: Patients taking part in the study will continue treatment with trastuzumab until 9 cycles have been completed (rather than 18 cycles), including those cycles administered prior to study entry. No more pertuzumab will be given after study registration, and patients will not receive chemotherapy after surgery. Some patients may not receive a type of chemotherapy called an anthracycline if this was being deferred to after surgery. Any other treatment that might have been recommended (like hormone therapy or radiotherapy) will be given as normal. Trastuzumab (original or biosimilar) should be given every 3 weeks to complete a total of 9 cycles including those cycles administered prior to study entry; the number of cycles given within the HER2-RADiCAL study is altered according to the number of cycles received prior to study entry. Trastuzumab may be administered via IV or subcutaneous routes in accordance with the standard practice at the site and will be administered as per the SmPC and local guidelines. Subcutaneous trastuzumab is administered at a dose of 600 mg every 3 weeks. Intravenous trastuzumab is administered at a dose of 6 mg/kg body weight every 3 weeks (with a loading dose of 8 mg/kg if required). No dose reductions are permitted. Previous interventions: Patients taking part in the study will continue treatment with trastuzumab until 9 cycles have been completed (rather than 18 cycles), including those cycles administered prior to study entry. No more pertuzumab will be given after study registration, and patients will not receive a type of chemotherapy called an anthracycline, or any other type of chemotherapy, after surgery. Any other treatment that might have been recommended (like hormone therapy or radiotherapy) will be given as normal. Trastuzumab (original or biosimilar) should be given every 3 weeks to complete a total of 9 cycles including those cycles administered prior to study entry; the number of cycles given within the HER2-RADiCAL study is reduced according to the number of cycles received prior to study entry. Trastuzumab may be administered via IV or subcutaneous routes in accordance with the standard practice at the site and will be administered as per the SmPC and local guidelines. Subcutaneous trastuzumab is administered at a dose of 600 mg every 3 weeks. Intravenous trastuzumab is administered at a dose of 6 mg/kg body weight every 3 weeks (with a loading dose of 8 mg/kg if required). No dose reductions are permitted. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Trastuzumab |
| Primary outcome measure | Relapse-free-interval (RFI), defined as time from registration to invasive local or distant relapse or death from breast cancer in the absence of a previously identified relapse (intercurrent deaths and second primary cancers censored). The primary timepoint of interest will be 3 years. |
| Secondary outcome measures | Efficacy: 1. Relapse-free-survival (RFS) defined as time from registration to invasive local or distant relapse or death from any cause (second primary cancers censored) 2. Invasive breast cancer-free survival (iBCFS) defined as time from registration to invasive local or distant relapse or ipsilateral or contralateral invasive second primary breast cancer (non-breast second primary cancers censored) or death from any cause 3. Invasive disease-free survival (iDFS) defined as time from registration to invasive local or distant recurrence, new invasive second cancer or death from any cause 4. Distant recurrence-free interval (DRFI) defined as time from registration to distant recurrence or death from any cause (second primary cancers and intercurrent deaths censored) 5. Breast cancer-free interval (BCFI) defined as time from registration to invasive local or distant relapse, or ipsilateral or contralateral invasive second primary breast cancer or DCIS or death from breast cancer in the absence of a previously identified relapse (intercurrent deaths and second primary cancers censored) 6. Overall survival defined as time from registration to death from any cause Other: 1. Treatment pathway adherence: non-adherence is defined as the proportion of patients who receive >9 cycles of trastuzumab or who receive further adjuvant systemic anti-HER2 treatment (e.g. pertuzumab) or chemotherapy prior to recurrence or second primary 2. Cost-effectiveness: quality-adjusted life-years derived from a health economic model developed using clinical trial and real-world data at 3 and 5 years after study entry |
| Overall study start date | 09/12/2019 |
| Overall study end date | 30/11/2029 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 720; UK Sample Size: 720 |
| Participant inclusion criteria | Current inclusion criteria as of 21/12/2023: 1. Female or male, age ≥16 years 2. Histologically confirmed invasive breast cancer that is HER2-positive (IHC3+, and/or ISH positive/amplified) as determined by the local laboratory in accordance with national guidelines 3. Has received neoSACT chemotherapy with concomitant trastuzumab and pertuzumab 4. pCR (ypT0/is ypN0) in breast and sampled regional lymph nodes as per local pathology reporting 5. Imaging of breast and axilla prior to initiation of neoSACT and either: 5.1. Breast primary radiological measurement ≤20 mm prior to neoSACT and limited nodal involvement (cN1) confirmed by axillary core biopsy or FNA (cT1N1) OR 5.2. Breast primary radiological measurement >20 mm but ≤50 mm and node-negative (cT2N0) or limited nodal involvement (cT2N1) 6. Multiple ipsilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 7. Bilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 8. Pre-treatment diagnostic breast tumour biopsy sample available 9. Patient must be fit to continue treatment with trastuzumab and have no concomitant medical, psychiatric or social problems that might interfere with informed consent, adherence to the reduced treatment pathway or follow-up 10. Provision of written informed consent to participate in HER2-RADiCAL Previous inclusion criteria: 1. Female or male, age ≥16 years 2. Histologically confirmed invasive breast cancer that is HER2-positive (IHC3+, and/or ISH positive/amplified) as determined by the local laboratory in accordance with national guidelines 3. Has received neoSACT with a non-anthracycline chemotherapy regimen with at least 3 cycles of concomitant trastuzumab and pertuzumab 4. pCR (ypT0/is ypN0) in breast and sampled regional lymph nodes as per local pathology reporting 5. Imaging of breast and axilla prior to initiation of neoSACT and either: 5.1. Breast primary radiological measurement ≤20 mm prior to neoSACT and limited nodal involvement (cN1) confirmed by axillary core biopsy or FNA (cT1N1) OR 5.2. Breast primary radiological measurement >20 mm but ≤50 mm and node-negative (cT2N0) or limited nodal involvement (cT2N1) 6. Multiple ipsilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 7. Bilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 8. Pre-treatment diagnostic breast tumour biopsy sample available 9. Study consent ≤6 weeks after completing breast cancer surgery 10. Patient must be fit to continue treatment with trastuzumab and have no concomitant medical, psychiatric or social problems that might interfere with informed consent, adherence to the reduced treatment pathway or follow-up 11. Provision of written informed consent to participate in HER2-RADiCAL |
| Participant exclusion criteria | Current exclusion criteria as of 21/12/2023: 1. Evidence of metastatic disease at any time since diagnosis 2. Any residual invasive disease following neoSACT. This includes isolated tumour cells in axillary nodes or tissue or evidence of lymphovascular invasion in the breast. Persistent ductal or lobular non-invasive disease (DCIS or LCIS) is permitted. Resection margins must be deemed clear of any residual DCIS according to local MDT protocol 3. Breast-conserving primary surgery where it is known that breast irradiation will not be administered (e.g. due to contraindication or patient preference) 4. Intraoperative assessment of post-neoSACT axillary SLN using one-stop nucleic acid amplification (OSNA) 5. Any planned further resectional surgery for breast cancer (including re-excision, mastectomy, or axillary surgery) 6. HER2-negative invasive breast carcinoma 7. Breast cancer with clinical stage of T≥3 at diagnosis 8. Evidence of scarring (or other pathological features consistent with previous malignant involvement) in >4 axillary nodes or clinical nodal stage N≥2 at any time9. Positive SLNB pre-neoadjuvant systemic therapy as this precludes determination of pCR 10. Pregnant and/or lactating women 11. Female patient of child-bearing potential, unwilling to use an effective form of contraception during trastuzumab treatment and for 7 months after their last dose of trastuzumab 12. Previous diagnosis of invasive breast carcinoma 13. Previous diagnosis of any other (non-breast) malignancy unless disease-free for at least 5 years and considered to be at low risk of recurrence or treated basal cell or localised squamous cell carcinoma of the skin or cervical intraepithelial neoplasia 14. Chemotherapy administered following surgery (NB. Pertuzumab and/or trastuzumab may have been continued after surgery as per local practice prior to study entry) 15. Has received >9 cycles trastuzumab. In the event a patient has received 9 cycles prior to study entry then consent must occur within 3 weeks of the last dose of trastuzumab. 16. Clinically significant cardiac disease within 12 months of starting trastuzumab, including unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident, or cardiac arrhythmia associated with haemodynamic instability 17. Left ventricular ejection fraction (LVEF) less than 50% on most recent cardiac imaging 18. History of interstitial lung disease 19. Any medical or other contra-indication to continuing trastuzumab Previous exclusion criteria: 1. Evidence of metastatic disease at any time since diagnosis 2. Any residual invasive disease following neoSACT. This includes isolated tumour cells in axillary nodes or tissue or evidence of lymphovascular invasion in the breast. Persistent ductal or lobular non-invasive disease (DCIS or LCIS) is permitted. Resection margins must be deemed clear of any residual DCIS according to local MDT protocol 3. Any planned further resectional surgery for breast cancer (including re-excision, mastectomy, or axillary surgery) 4. HER2-negative invasive breast carcinoma 5. Breast cancer with clinical stage of T≥3 at diagnosis 6. Evidence of scarring (or other pathological features consistent with previous malignant involvement) in >4 axillary nodes or clinical nodal stage N≥2 at any time 7. Positive SLNB pre-neoadjuvant systemic therapy as this precludes determination of pCR 8. Pregnant and/or lactating women 9. Female patient of child-bearing potential, unwilling to use an effective form of contraception during trastuzumab treatment and for 7 months after their last dose of trastuzumab 10. Previous diagnosis of invasive breast carcinoma 11. Previous diagnosis of any other (non-breast) malignancy unless disease-free for at least 5 years and considered to be at low risk of recurrence or treated basal cell or localised squamous cell carcinoma of the skin or cervical intraepithelial neoplasia 12. Chemotherapy administered following surgery (NB. Pertuzumab and/or trastuzumab may have been continued after surgery as per local practice prior to study entry) 13. Has received >9 cycles trastuzumab 14. Any medical or other contra-indication to continuing trastuzumab |
| Recruitment start date | 03/12/2021 |
| Recruitment end date | 31/07/2025 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Glasgow
G12 0XH
United Kingdom
2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom
Belfast
BT9 7AB
United Kingdom
Brighton
BN2 5BE
United Kingdom
Maidstone
ME16 9QQ
United Kingdom
London
NW3 2QG
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Yeovil
BA21 4AT
United Kingdom
Colchester
CO4 5JL
United Kingdom
Bangor
LL57 2PW
United Kingdom
Stirling
FK8 1DX
United Kingdom
Truro
TR1 3LJ
United Kingdom
Poole
BH15 2JB
United Kingdom
Canterbury
CT1 3NG
United Kingdom
London
SE1 7EH
United Kingdom
Withington
Manchester
M20 4BX
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Melrose
TD6 9DB
United Kingdom
King's Lynn
PE30 4ET
United Kingdom
London
W2 1BL
United Kingdom
Worcester
WR5 1DD
United Kingdom
Sheffield
S5 7AU
United Kingdom
Glasgow
G12 0YN
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Willesborough
Ashford
TN24 0LZ
United Kingdom
Margate
CT9 4AN
United Kingdom
Nottingham
NG5 1PB
United Kingdom
London
W6 8RF
United Kingdom
Bristol
BS2 8ED
United Kingdom
Bretton Gate
Bretton
Peterborough
PE3 9GZ
United Kingdom
Dumfries
Dumfries and Galloway
DG2 8RX
United Kingdom
Lancaster
LA1 4RP
United Kingdom
Kendal
LA9 7RG
United Kingdom
Barrow-in-furness
LA14 4LF
United Kingdom
Liverpool
L7 8YA
United Kingdom
Parkhurst Road
Newport
PO30 5TG
United Kingdom
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom
Wrexham Technology Park
Wrexham
LL13 7TD
United Kingdom
Broomhall
Sheffield
S10 2SJ
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Isleworth
TW7 6AF
United Kingdom
Uphill
Weston-super-mare
BS23 4TQ
United Kingdom
London
NW1 2PQ
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom
Northampton
NN1 5BD
United Kingdom
Sponsor information
Research organisation
15 Cotswold Road
London
SM2 5NG
England
United Kingdom
| Phone | +44 (0)20872253604161 |
|---|---|
| Barbara.Pittam@icr.ac.uk | |
"ROR" |
https://ror.org/043jzw605 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/11/2030 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. The study protocol is available online at https://fundingawards.nihr.ac.uk/award/NIHR131362 2. The main study results will be published in a peer-reviewed journal, on behalf of all collaborators. The manuscript will be prepared by a writing group, consisting of members of the Trial Management Group. Participating clinicians may be selected to join the writing group on the basis of intellectual and time input. All participating clinicians will be acknowledged in the publication. Additional documents are not available at this time. |
| IPD sharing plan | The datasets generated and/or analysed during the current study will be available on request from the HER2-RADiCAL trial team via her2radical-icrctsu@icr.ac.uk via completion of a data access request form after such time that the primary analysis publication and any other key analyses have been completed. Optional advanced consent/authorisation for the possible future sharing of information collected about patients will be obtained at study entry. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 2.0 | 11/10/2021 | 16/05/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 4.0 | 24/02/2023 | 21/12/2023 | No | No |
Additional files
Editorial Notes
21/12/2023: The following changes were made to the study record:
1. Protocol uploaded.
2. Study website added.
3. The interventions, inclusion and exclusion criteria were updated.
4. The recruitment end date was changed from 30/08/2024 to 31/07/2025.
5. The following study participating centres were added: Dumfries and Galloway Royal Infirmary, Royal Lancaster Infirmary, Westmorland General Hospital, Furness General Hospital, Clatterbridge Cancer Centre, St Mary’s Hospital Isle of Wight, Glan Clwyd Hospital, Wrexham Maelor Hospital, Weston Park Hospital, Aberdeen Royal Infirmary, West Middlesex University Hospital, Weston General Hospital, University College Hospital, Royal Devon and Exeter Hospital, Maidstone Hospital, Northampton General Hospital.
20/01/2023: John Radcliffe Hospital was removed as a trial participating centre.
23/09/2022: The following trial participating centres were added: Beatson West of Scotland Cancer Centre, Bournemouth Hospital, William Harvey Hospital, Queen Elizabeth the Queen Mother Hospital, Nottingham City Hospital, Charing Cross Hospital, Bristol Haematology and Oncology Center, Peterborough City Hospital.
16/05/2022: The following changes have been made:
1. The recruitment start date has been changed from 01/11/2021 to 03/12/2021.
2. The protocol (not peer reviewed) has been uploaded as an additional file.
22/04/2022: The Cancer Research UK plain English summary has been added.
05/10/2021: Trial's existence confirmed by the NIHR.
