Study of Palbociclib and Trastuzumab With Endocrine Therapy in HER2-positive Metastatic Breast Cancer

Inclusion Criteria

• •For Cohorts A and B (Recruitment Closed)
• •1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.
• •2. Female patients
• •3. Age 18 years or older
• •4. ECOG performance status 0 or 1.
• •5. Invasive HER2 positive breast cancer, according to the local laboratory, defined according to ASCO/CAP criteria as:
• •1. 3+ overexpression on immunohistochemistry (\>10% of invasive tumor cells with intensive, circumferential membrane staining)
• •2. Positive in situ hybridization (FISH/CISH/SISH) in \>10% of invasive tumor cells, having counted at least 20 cells in the area and based on:
• •i. Single-probe HER2 gene copy number ≥ 6 signals/cell. ii. Dual-probe HER2/CEP17 ratio ≥ 2.0 with a mean HER2 gene copy number ≥ 4.0 signals/cell; HER2/CEP17 ratio ≥ 2.0 and \< 4.0 signals/cell; and HER2/CEP17 ratio \< 2.0 and ≥ 6.0 signals/cell.
• •6. Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.
• •7. Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced.
• •1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.
• •2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.
• •8. All patients must have received at least 2 (maximum 4) previous lines of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab. Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.
• •9. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor.
• •10. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria. (Appendix 5).
• •11. Adequate organ function, defined as:
• •1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
• •2. Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
• •3. Platelets \> 100,000/mm3.
• •4. Creatinine ≤ 1.5 x normal value
• •5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis).
• •6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.
• •7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).
• •12. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).
• •13. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study. ..14. Postmenopausal status defined as previous bilateral oophorectomy, age \>60 or \<60, and amenorrhoea for at least 12 months (in absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and FSH and estradiol in postmenopausal range, according to local laboratory.
• •For cohorts C:
• •1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.
• •2. Male or female patients. Premenopausal or postmenopausal women.
• •3. Age 18 years or older.
• •4. ECOG performance status 0 to 2.
• •5. Invasive HER2 positive breast cancer, according to the central laboratory, defined according to ASCO/CAP criteria.
• •6. Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.
• •7. Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B).
• •8. Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.
• •1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.
• •2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.
• •9. All patients must have received at least 1 previous line of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab and/or anti-HER2 Antibody-Drug conjugate). Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including but not limited to lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted. Also patients who recur during or within 12 months after completing adjuvant treatment with trastuzumab and/or antiHER2-ADCs (including but not limited to T-DM1) can be enrolled in the moment of the diagnosis of metastatic disease.
• •10. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumour.
• •11. Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria.
• •12. Adequate organ function, defined as:
• •1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
• •2. Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
• •3. Platelets \> 100,000/mm3
• •4. Creatinine ≤ 1.5 x normal value
• •5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)
• •6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.
• •7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).
• •13. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).
• •14. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study.
• •15. If female of childbearing potential, must have a negative result of serum pregnancy test performed within 7 days prior to the first dose of study treatment.
• •16. Participants with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
• •* Disease outside the CNS is present.
• •* No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
• •* No history of intracranial hemorrhage or spinal cord hemorrhage.
• •* Stable doses or no need of corticosteroids and anti-convulsants for symptomatic control
• •* Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of study treatment; and recovery from any significant (Grade ≥ 3) acute toxicity