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

Prior treatment

• Treatment with any investigational anticancer drug within 14 days of the start of study treatment.
• Patient has received more than 4 previous lines of treatment (anti-HER2 drug +/- chemotherapy) for metastatic breast cancer or locally advanced disease. Exclusively hormonal treatments will not be taken into account.
• Previous treatment with a cyclin-dependent kinase inhibitor.
• Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to \> 30% of the bone marrow.
• Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Biphosphonates will be permitted for the prevention of bone events.
• Major surgery in the 28 days prior to randomisation or foreseeable during study treatment period.
• Treatment with any investigational anticancer drug within 14 days of the start of study treatment.
• Previous treatment with a cyclin-dependent kinase inhibitor.
• Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to \> 30% of the bone marrow.
• Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Bisphosphonates or RANKL inhibitors will be permitted for the prevention of bone events.
• Major surgery in the 28 days prior to randomization or foreseeable during study treatment period.

Other illness

• History of other malignant tumours in the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumours with an expected curative outcome.
• History of exposure to cumulative anthracycline doses greater than follows:
  • Adriamycin \> 400 mg/m2
  • Epirubicin \> 720 mg/m2
  • Mitoxantrone \> 120 mg/m2
  • Idarubicin \> 90 mg/m2
  • If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.
• Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or haematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).
• Infection with HIV or active Hepatitis B and/or Hepatitis C.
• History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.
• Known hypersensitivity to any of the study drugs, including inactive ingredients.
• History of other malignant tumors in the past 3 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumors with an expected curative outcome.
• History of exposure to cumulative anthracycline doses greater than follows:
  • Adriamycin \> 400 mg/m2
  • Epirubicin \> 720 mg/m2
  • Mitoxantrone \> 120 mg/m2
  • Idarubicin \> 90 mg/m2
  • If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.
• Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or hematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).
• Infection with HIV or active Hepatitis B and/or Hepatitis C.
• History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.
• Known hypersensitivity to any of the study drugs, including inactive ingredients.
• Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.
  • In cohort C, patients that are initially allocated in the control arm (physician's treatment choice) and have a documented disease progression can be re-randomized to receive the experimental or control treatment (if they meet the inclusion criteria after progression).

Lab values

• Cardiopulmonary dysfunction, defined as:
  • Uncontrolled hypertension (systolic \> 150 mmHg and/or diastolic \> 100 mmHg) despite optimum medical treatment.
  • Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.
  • History of congestive heart failure NCI CTCAE version 4.0 grade ≥ 3 NYHA class ≥ 2.
  • History of LVEF decrease to \< 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.
  • Myocardial infarction within 6 months before randomisation.
  • Resting dyspnoea due to complications of the malignant disease, requiring continuous oxygen therapy.
• Cardiopulmonary dysfunction, defined as:
  • Uncontrolled hypertension (systolic \> 150 mmHg and/or diastolic \> 100 mmHg) despite optimum medical treatment.
  • Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.
  • History of congestive heart failure NCI CTCAE version 5.0 grade ≥ 3 NYHA class ≥ 2.
  • History of LVEF decrease to \< 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.
  • Myocardial infarction within 6 months before randomization.
  • Resting dyspnea due to complications of the malignant disease, requiring continuous oxygen therapy.

Other

• For cohorts A, B (Recruitment Closed)
• Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.

• For Cohorts A and B (Recruitment Closed)
• Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.
• Female patients
• Age 18 years or older
• ECOG performance status 0 or 1.
• Invasive HER2 positive breast cancer, according to the local laboratory, defined according to ASCO/CAP criteria as:
  • 3+ overexpression on immunohistochemistry (\>10% of invasive tumor cells with intensive, circumferential membrane staining)
  • 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:
  • 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.
• Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.
• Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced.
  • 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.
  • In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.
• 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.
• Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor.
• Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria. (Appendix 5).
• Adequate organ function, defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
  • Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
  • Platelets \> 100,000/mm3.
  • Creatinine ≤ 1.5 x normal value
  • AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis).
  • 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.
  • Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).
• Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).
• 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:
• Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.
• Male or female patients. Premenopausal or postmenopausal women.
• Age 18 years or older.
• ECOG performance status 0 to 2.
• Invasive HER2 positive breast cancer, according to the central laboratory, defined according to ASCO/CAP criteria.
• Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.
• Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B).
• Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.
  • 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.
  • In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.
• 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.
• Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumour.
• Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria.
• Adequate organ function, defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
  • Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
  • Platelets \> 100,000/mm3
  • Creatinine ≤ 1.5 x normal value
  • AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)
  • 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.
  • Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).
• Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).
• 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.
• 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.
• 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