Three Pillars Study

Overview

Three 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.

Objectives

Primary:

To assess the pathological complete response rate after 24 weeks of Palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib.

Secondary:

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 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 ERpositive, HER2-positive and PgR-positive early breast cancer in postmenopausal women.

Inclusion criteria

Patients eligible for the trial must comply with all of the following at registration:

1. 18 years or greater
2. Newly diagnosed (no previous history of invasive breast cancer)
   histologically confirmed breast cancer
3. Tumour measuring ≥15mm in longest diameter by ultrasound (US) or
   mammogram or MRI or any size with axillary lymph node involvement
   (must be performed ideally within 56 days prior to study registration)*
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
5. Postmenopausal as defined by one of the following criteria:

• Prior bilateral oophorectomy
• 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
• Age < 55 years with an intact uterus, amenorrhoeic for >12
  month AND Follicle-Stimulating Hormone (FSH) and
  oestradiol levels within the post-menopausal range
• 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 or H score of ≥67 *
7. PgR positive defined as a Quick Allred Score of ≥6 or H score of ≥67 *
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:

• Haemoglobin (Hb) ≥10 g/dl
• White cell count ≥3.0x109
• Absolute Neutrophil Count (ANC) >1.5 x109/L
• Platelets ≥100 x109/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 all of the following:

• Total bilirubin ≤ 1.5 ULN (except for patients with clearly
  documented Gilbert’s syndrome)
• Alanine transaminase (ALT) or aspartate transaminase (AST)
  ≤1.5 ULN
• 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 (diagnostic core biopsy of the breast should
    have been performed ideally within 60 days prior to study registration)
15. Able to swallow capsules
16. Provided written informed consent

*Where there are multiple tumours at least one has to measure greater than 15mm, but all must meet entry criteria in terms of receptors expression.

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. Any concomitant use of Hormone Replacement Therapy (HRT) or any other oestrogen-containing medication or supplementation within 1 week of starting study treatment
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:

• History of documented congestive cardiac failure
• Angina pectoris requiring anti-anginal medication
• Evidence of transmural infarction on ECG
• Poorly controlled hypertension or uncontrolled asymptomatic hypertension as determined by the investigator
• Clinically significant valvular heart disease
• Ventricular significant arrhythmia requiring therapy
• 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 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
22. Any acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration and, in the judgment of the investigator, would make the patient inappropriate for study entry
23. Participation in a Clinical Trial of an Investigational Medicinal Product 

(CTIMP) within 4 weeks prior to registration