Palbociclib With Everolimus + Exemestane In BC

Inclusion Criteria

• Participants must meet the following criteria on screening examination to be eligible to participate in the study. Laboratory tests required for eligibility must be completed within 14 days prior to the date of registration. Diagnostic tests, such as MRIs and CT scans, must be performed within 30 days of registration and baseline measurements must be documented within 14 days of the date of registration.
• Participants with histologically or cytologically confirmed hormone receptor (HR)-positive, Her2-negative metastatic breast cancer. Central confirmation of HR positivity is not required
• Postmenopausal women as defined as:
• Age >60 years

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• Age >45 with intact uterus and amenorrhea for ≥ 12 consecutive months or Follicle stimulating hormone (FSH) levels within postmenopausal range according to the ranges established by the testing facility

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• Premenopausal women who have been on a GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain on the GnRH agonist for the duration of protocol treatment

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• Status post bilateral oophorectomy, after adequate healing post surgery;
• Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.
• Participants must have measurable disease as per RECIST 1.1.
• Prior Treatment Specifics:
• Participants must have radiological or objective evidence of progression to a CDK4/6 inhibitor regimen in the metastatic setting AND relapse/progression on an NSAI (defined as either relapsed ≤ 12 months after completing adjuvant NSAI or progressed through an NSAI for metastatic or locally advanced breast cancer)
• Participants may have received any number of previous endocrine/hormonal lines of therapy in the metastatic setting, as long none of them were exemestane-based and the last dose is ≥ 14 days prior to registration;
• Participants may have received up to one prior chemotherapy line for advanced breast cancer as long as the last dose is ≥ 21 days prior to registration;
• Participants may have received prior biologic treatments or investigational drugs as long as the last dose is ≥ 21 days prior to registration;
• Participants may have received radiotherapy for palliative purposes but must not be experiencing > grade 1 treatment related toxicities and have completed treatment ≥ 14 days prior to registration
• Age ≥18 years. Age restriction applies given that no dosing or adverse event data are currently available on the use of palbociclib or exemestane in participants <18 years of age.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• For participants enrolling the phase IIa part of the study, accessible tumor lesion(s) for the purpose of research biopsy and willingness to undergo a research biopsy before treatment initiation and at the time of disease progression, as well as a single research blood sample before initiation of therapy. Participants who undergo an attempted on-treatment research biopsy and in whom inadequate tissue is obtained are still eligible to receive protocol therapy. They will not be required to undergo a repeat research biopsy attempt.
• For participants enrolling the phase IIa part of the study, willingness to provide archival tumor samples when available.
• Participants must have normal organ and marrow function, as defined below:
• absolute neutrophil count ≥1,5x109/L
• platelets ≥100 x109/L
• total hemoglobin ≥ 9 g/dL (which may be post transfusion)
• total bilirubin ≤1.5 x institutional upper limit of normal
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal or ≤5 × institutional upper limit of normal for participants with liver metastization
• creatinine ≤1.5 x above institutional normal or ≥ 60 ml/min/1.73m2 for subjects with creatinine levels above institutional normal.
• baseline QTc < 500 ms
• fasting plasma glucose <140 mg/dL / 7.8 mmol/L
• The effects of