Palbociclib Plus Fulvestrant in Women With Hormone Receptor Positive and Human Epidermal Growth Factor Receptor Type 2 Negative Locally Advanced or Metastatic Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination With Hormonal Therapy

Exclusion Criteria

• •1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive).
• •2. Patients who received \> 1 line of chemotherapy as treatment for MBC.
• •3. Patients who received \> 1 line of a CDK4/6 inhibitor in combination with hormonal treatment for LABC or MBC or who have relapsed at less than 12 months from the end of adjuvant treatment with a CDK4/6 inhibitor. For metastatic disease, patients with a progressive disease within the first 6 months of treatment while on first line therapy with a CDK4/6 inhibitor, will be excluded.
• •4. Patients receiving chemotherapy or any type of hormonal therapy after treatment with a CDK4/6 inhibitor for metastatic disease.
• •5. Patients interrupting the previous treatment with CDK4/6 inhibitor for cardiac and/or hepatic toxicity and not for disease progression.
• •6. Pregnant, lactating women.
• •7. Known hypersensitivity to CDK4/6 inhibitors, fulvestrant, or to any of the excipients.
• •8. Radiotherapy within four weeks prior to enrollment (baseline/treatment start) except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment (baseline/treatment start). Patients must have recovered from radiotherapy toxicities prior to enrollment.
• •9. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
• •10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:
• •1. short duration (\<2 weeks) of systemic corticosteroids is allowed (e.g., chronic obstructive pulmonary disease, anti-emetic);
• •2. low doses of corticosteroids for brain metastasis treatment is allowed.
• •11. Patients with symptomatic visceral disease in need of urgent disease control (e.g., significant dyspnea related to pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful symptomatic liver metastasis at the judgement of treating investigator).
• •12. Symptomatic brain metastases.
• •13. Patients with a known history of HIV seropositivity.
• •14. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, low-molecular-weight heparin (LMWH) and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0).
• •15. Any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia.
• •16. Acute and chronic, active infectious disorders.
• •17. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatments (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
• •18. Inability to swallow oral medications.
• •19. Significant symptomatic deterioration of lung function.
• •20. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to enrollment.
• •21. History of non-compliance to medical regimens.
• •22. Patients refusing to perform liquid biopsy at study entry and disease progression.
• •23. Patients unwilling to or unable to comply with the protocol.