Combination treatment for early hormone-positive HER-positive breast cancer
| ISRCTN | ISRCTN37422164 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN37422164 |
| EudraCT/CTIS number | 2021-006077-34 |
| IRAS number | 1004806 |
| Secondary identifying numbers | UoL001650, IRAS 1004806, CPMS 58079 |
- Submission date
- 06/04/2023
- Registration date
- 20/11/2023
- Last edited
- 05/02/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
Background and study aims
This is a study where patients with early breast cancer will be given a combination of medications before they have their operation to remove the breast cancer. We want to look at whether this combination of drugs may be successful as a treatment for early breast cancer. We will be looking at post-menopausal women with early breast cancer that is ER-positive, PgR-positive and HER2-positive, and who are eligible for surgery. Breast cancer that has a significant number of receptors for either oestrogen (ER+) or progesterone (PgR+) is considered hormone-receptor positive and can be treated with either hormone therapy alone or chemotherapy followed by hormone therapy. ER+ breast cancers are routinely treated with hormone therapy that blocks the oestrogen receptor, this type of therapy is more effective when combined with another drug which blocks a molecule called CDK4/6. About 15% of all breast tumours have higher levels of a protein known as HER2, called HER2-positive (HER2+) breast cancers. These cancers tend to grow and spread faster than breast cancers that are HER2-negative, but are much more likely to respond to routine treatment with drugs that target the HER2 protein. 50% of HER2+ breast cancers are also ER+. Research has shown that the combination of HER2 therapy with hormone therapy is more active than hormone therapy alone.
Who can participate?
Patients aged 18 years and over with early breast cancer that is ER+, PgR+ and HER2+
What does the study involve?
Participants receive a combination of treatments: letrozole to block oestrogen receptor (ER), plus trastuzumab and tucatinib to block HER2 and palbociclib to block CDK4/6.
What are the possible benefits and risks of participating?
The study enables the avoidance of chemotherapy and all its potential side effects and issues while allowing access to a neoadjuvant regimen with agents which have previously shown evidence of clinical activity. The treatment may benefit the patient by reducing the size of their tumour and hence reducing the extent of surgery including breast preservation. The information we get from this study may help us to improve the future treatment of patients with ER+, PgR+ and HER2+ breast cancer. The results from this study will be used to help us improve treatments for postmenopausal women with ER+, PgR+ and HER2+ early breast cancer who require neoadjuvant therapy. Participants will attend additional visits, whether for screening or for treatment that falls outside of standard care. There may be associated costs of travel and availability of time for patients (e.g. taking annual leave). Additional tests and procedures will be required as part of the trial including taking blood at five additional timepoints, two additional research breast biopsies and two additional breast scans. This will be explained in the patient information sheet including the risks of these procedures. Patients may experience adverse events that may be painful, life-threatening or cause death. All possible mitigations have been put in place to protect patients including stringent inclusion and exclusion criteria and patient monitoring. Patients will be informed of possible adverse events and directed to where to find more information in the patient information sheet.
Where is the study run from?
The University of Liverpool (UK)
When is the study starting and how long is it expected to run for?
April 2023 to January 2026
Who is funding the study?
1. Seagen (USA)
2. Pfizer (USA; Donation of palbociclib)
Who is the main contact?
3-pillars@liverpool.ac.uk, Liverpool Clinical Trials Centre (UK)
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-palbociclib-letrozole-trastuzumab-and-tucatinib-before-surgery-for-breast-cancer
Contact information
Principal Investigator
University of Liverpool
Department of Molecular and Clinical Cancer Medicine
Biosciences Building
Crown Street
Liverpool
L69 7BE
United Kingdom
 ORCID ID |
0000-0001-9496-2718 |
|---|---|
| Phone | +44 (0)151 7949813 |
| C.Palmieri@liverpool.ac.uk |
Scientific
University of Liverpool
Department of Molecular and Clinical Cancer Medicine
Biosciences Building
Crown Street
Liverpool
L69 7BE
United Kingdom
| Phone | +44 (0)151 7949813 |
|---|---|
| C.Palmieri@liverpool.ac.uk |
Public
Waterhouse Building Bloc C
1-5 Brownlow Street
Liverpool
L69 3GL
United Kingdom
| Phone | None provided |
|---|---|
| 3-pillars@liverpool.ac.uk |
Study information
| Study design | Single-arm open-label non-randomized study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 43448 _PIS_v1.0_21November2022.pdf |
| Scientific title | 3-Pillars Study: a phase II open label study of the cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole, trastuzumab plus tucatinib as neoadjuvant treatment for ER-positive, PgR-positive and HER2-positive early breast cancer in post-menopausal women |
| Study acronym | 3-Pillars Study |
| Study hypothesis | Primary objective: To assess the pathological complete response rate after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib Secondary objectives: 1. To assess change in Ki67 proliferation index after 2 weeks and 23 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 2. To assess the radiological response rate as measured by ultrasound/MRI/mammogram after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 3. To assess objective clinical response rate after 24 weeks of Palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 4. To assess the proportion of tumours with a Preoperative Endocrine Prognostic Index (PEPI) score of 0 or 1 after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 5. To assess the safety and tolerability of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib as neoadjuvant treatment for ER-positive, HER2-positive early breast cancer |
| Ethics approval(s) |
Approved 14/09/2023, Seasonal REC (Health Research Authority) (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 800; seasonal.rec@hra.nhs.uk), ref: 23/LO/0388 |
| Condition | ER-positive, PgR-positive and HER2-positive early breast cancer |
| Intervention | 3-Pillars is a single-arm trial so participants will not be randomised. All participants taking part in the 3-Pillars trial will receive the same treatment as follows: 1. Tucatinib (300mg tablet taken orally twice daily for 24 weeks or until surgery) 2. Palbociclib (75mg/day on a 28 day schedule of 21 days on and 7 days off for a total of 24 weeks) 3. Letrozole (2.5mg tablet taken orally once daily for 24 weeks or until surgery) 4. Trastuzumab (600mg subcutaneous injection every 3 weeks for 24 weeks or until surgery) Dose reductions are permissible for tucatinib as follows: 1. Tucatinib – 300mg starting dose, 250mg first dose reduction, 200mg second dose reduction, 150mg third dose reduction 2. Palbociclib – no dose reduction 3. Letrozole – no dose reduction 4. Trastuzumab – no dose reduction No dose reductions are permissible for palbociclib, letrozole and trastuzumab. Participants will receive a 4-week post-surgery follow-up for a translational blood sample and adverse event recording. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Tucatinib, palbociclib, letrozole, trastuzumab |
| Primary outcome measure | The pathological complete response (PCR) rate after completion of study treatment as defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery irrespective of in situ carcinoma in the breast (ypT0/ypTis, ypN0). Measured after 24 weeks of treatment. |
| Secondary outcome measures | 1. The difference in the proliferation marker Ki67 (% positive tumour cells) as tested by IHC from baseline to 2 weeks of treatment and from baseline to after 23 weeks of treatment. 2. The objective radiological response rate as defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1, as per Investigator’s assessments by breast USS, mammogram or MRI after completion of study treatment. Measured after 24 weeks of treatment. 3. The objective clinical response rate after 24 weeks of treatment as per tumour overall objective response rate (ORR), defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1 as per Investigator’s assessments by breast USS, mammogram or MRI after completion of study treatment. Measured after 24 weeks of treatment. 4. The proportion of tumours with a Preoperative Endocrine Prognostic Index (PEPI) score of 0 or 1 after completion of study treatment. Measured after 24 weeks of treatment. 5. Safety and tolerability in terms of: 5.1. Defined Grade 1 and 2 toxicities as classified by NCI-CTCAE v5.0 recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.2. Grade 3+ toxicity as classified by NCI-CTCAE v5.0 recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.3. Serious Adverse Events (SAEs) recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.4. Withdrawal from trial treatment due to toxicity recorded at End of Treatment 5.5. Delays to scheduled surgery (due to treatment related toxicities as determined by the investigator) recorded at the Surgery visit |
| Overall study start date | 04/04/2023 |
| Overall study end date | 31/01/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Sex | Female |
| Target number of participants | 90 |
| Participant inclusion criteria | Patients eligible for the trial must comply with all of the following at registration: 1. 18 years old and greater 2. Newly diagnosed (no previous history of invasive breast cancer) histologically confirmed breast cancer 3. Tumour measuring ≥15 mm in longest diameter by ultrasound (US), mammogram or MRI or any size with axillary lymph node involvement 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 5. Postmenopausal as defined by one of the following criteria: 5.1. Prior bilateral oophorectomy 5.2. Age ≥55 years with an intact uterus and EITHER amenorrhoeic for >12 month OR have recorded Follicle-Stimulating Hormone (FSH) and oestradiol levels within the post-menopausal range within the last 12 months 5.3. Age <55 years with an intact uterus, amenorrhoeic for >12 month AND Follicle-Stimulating Hormone (FSH) and oestradiol levels within the post-menopausal range within the last 12 months 5.4. Women who have had a hysterectomy with intact ovaries with FSH and estradiol levels in the postmenopausal range (as per local reference ranges) 6. ER-positive defined as a Quick Allred Score of ≥6 7. PgR-positive defined as a Quick Allred Score of ≥6 8. HER2-positive defined by immunohistochemistry - 3+ by Herceptest/similar assay or gene amplification as determined by FISH/CISH/D-DISH and the ratio of HER2 to CEP17 probes >2.0 9. Adequate bone marrow function defined by all of the following: 9.1. Haemoglobin (Hb) ≥10 g/dl 9.2. White cell count ≥3.0x10^9 9.3. Absolute Neutrophil Count (ANC) >1.5 x10^9/L 9.4. Platelets ≥100 x10^9/L 10. Adequate renal function defined by a serum creatinine ≤1.5 x Upper Limit of Normal (ULN) (according to local reference ranges) 11. Adequate liver function defined by: 11.1. Total bilirubin ≤1.5 ULN (except for patients with clearly documented Gilbert’s syndrome) 11.2. Alanine transaminase (ALT) or aspartate transaminase (AST) ≤1.5 ULN 11.3. Alkaline phosphatase ≤1.5 ULN 12. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤1.5 X ULN, unless on medication known to alter INR and PTT/aPTT (values within acceptable ranges as per local protocol) 13. Left ventricular ejection fraction (LVEF) of 50% or higher (determined by echocardiography or multiple-gated acquisition scanning) 14. Available paraffin-embedded tumour block taken at diagnostic biopsy for central assessment of Ki67 15. Able to swallow capsules 16. Provided written informed consent |
| Participant exclusion criteria | Any patient meeting any of the criteria listed below will be excluded from study participation: 1. Inflammatory or inoperable breast cancer 2. Evidence of bilateral invasive breast cancer 3. Clinically or radiological evidence of metastatic disease (staging to be done in accordance with local guideline) 4. Concomitant use (defined as use within 12 weeks prior to entry) of Hormone Replacement Therapy (HRT) or any other oestrogen-containing medication or supplementation 5. Any prior treatment with any CDK 4/6 inhibitor 6. Use of a strong CYP3A4 or CYP2C8 inhibitor, or food or drugs that are known CYP3A4 inhibitors, within 2 weeks of starting study treatment and during study (See Appendix 3) 7. Use of a strong CYP3A4 or CYP2C8 inducer, or drugs known to be CYP3A4 inducers, within 5 days of starting study treatment and during study (See Appendix 2 and Appendix 3) 8. No plan to commence treatment with CYP3A substrates within 2 weeks of starting study treatment and during study (See Appendix 1) 9. Any prior treatment with HER2-directed therapy 10. Previous investigational medicinal products for any condition within 4 weeks of registration date 11. Any prior history of invasive malignancy within 5 years of starting treatment where there is a medium or high risk of reoccurrence (other than treated basal cell carcinoma or squamous cell carcinoma of the skin and cervical carcinoma in situ or cancers treated with surgery alone). 12. QTc >480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP) 13. Significant cardiovascular disease including but not limited to: 13.1. History of documented congestive cardiac failure 13.2. Angina pectoris requiring anti-anginal medication 13.3. Evidence of transmural infarction on ECG 13.4. Poorly controlled hypertension or uncontrolled asymptomatic hypertension as determined by the investigator 13.5. Clinically significant valvular heart disease 13.6. Ventricular significant arrhythmia requiring therapy 13.7. High-risk uncontrolled arrhythmias or sudden cardiac arrest 14. Has significant gastro-intestinal disease including but not limited to active inflammatory bowel disease, chronic diarrhoea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection which would preclude the adequate oral absorption of medications. 15. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia) 16. Evidence of bleeding diathesis 17. Active bacterial infection (as defined by the use of oral or IV antibiotics at the time of study registration or systemic fungal infection 18. Known human immunodeficiency virus (HIV) positivity (screening HIV is not required for study enrolment) 19. Known active or inactive hepatitis carrier, for example, hepatitis B surface antigen (HBsAg) positive (screening hepatitis B or C is not required for study enrolment) 20. Recent vaccination with a live virus defined as within 28 days of study registration 21. Known hypersensitivity to letrozole, palbociclib, trastuzumab or tucatinib, or to any of the excipients. |
| Recruitment start date | 29/08/2024 |
| Recruitment end date | 01/03/2026 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Liverpool
L7 8YA
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
University Hospitals Bristol and Weston NHS Foundation Trust
Horfield Road
Bristol
BS2 8ED
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Anlaby Road
Hull
HU3 2JZ
United Kingdom
Sponsor information
University/education
Clinical Directorate
Liverpool
L69 3BX
England
United Kingdom
| Phone | +44 (0)151 795 1048 |
|---|---|
| sponsor@liverpool.ac.uk | |
| Website | http://www.liv.ac.uk/ |
"ROR" |
https://ror.org/04xs57h96 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Pfizer Inc., Pfizer Consumer Healthcare, Davis, Charles Pfizer & Company, Warner-Lambert, King Pharmaceuticals, Wyeth Pharmaceuticals, Seagen
- Location
- United States of America
Results and Publications
| Intention to publish date | 31/01/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Conference presentation 3. Publication on a website 4. Other publication 5. Submission to regulatory authorities 6. Access to raw data and right to publish freely by all investigators in the study or by the Independent Steering Committee on behalf of all investigators |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Liverpool Clinical Trials Centre, LCTC@liverpool.ac.uk. At the end of the trial, after the primary results have been published, the anonymised individual participant data (IPD) and associated documentation (e.g. protocol, statistical analysis plan, annotated blank CRF) will be prepared in order to be shared with external researchers. Patient identifiable data will only be shared with external researchers if the participants have consented to this onward disclosure in accordance with the Common Law Duty of Confidentiality, or if the external researchers obtain approval to waive this Common Law requirement (i.e. Section 251 Approval via the Confidentiality Advisory Group (CAG) / approval from the Public Benefit & Privacy Panel for Health & Social Care (PBPP)) or if the IPD has been fully anonymised prior to sharing. All requests for access to the IPD will be assessed by the Sponsor and must be agreed upon by all Data Controller organisations. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 1.0 | 21/11/2022 | 26/04/2023 | No | Yes |
| Participant information sheet | Adult PISC version 1.0 |
06/02/2023 | 26/04/2023 | No | Yes |
| Participant information sheet | version 3.0 | 28/03/2024 | 05/02/2025 | No | Yes |
Additional files
Editorial Notes
05/02/2025: The following changes were made to the trial record:
1. The recruitment start date was changed from 31/01/2024 to 29/08/2024.
2. The recruitment end date was changed from 01/06/2025 to 01/03/2026.
3. The study participating centres Nottingham University Hospitals NHS Trust, University Hospitals Bristol and Weston NHS Foundation Trust, Leeds Teaching Hospitals NHS Trust, Hull University Teaching Hospitals NHS Trust were added.
4. The participant information sheet for adults v3.0 was uploaded as an additional file.
5. The funder was changed from Seagen to Pfizer.
07/01/2025: Cancer Research UK plain English summary link added to plain English summary field.
01/12/2023: Internal review.
15/09/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 15/09/2023
06/04/2023: Trial's existence confirmed by the HRA.
