ER-positive, PgR-positive and HER2-positive early breast cancer Cancer
Conditions
Interventions
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
Sponsors
University of Liverpool
Eligibility
Sex/Gender
Female
Inclusion criteria
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 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
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, United Kingdom
Contacts
Public ContactLiverpool Clinical Trials Centre
Outcome results
None listed