Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib

For inclusion in the study subjects should fulfill the following criteria:

• Signed informed consent
• Patients must have histologically or cytologically confirmed invasive breast cancer that is ER+ (>1% staining) with radiographical or clinical evidence of metastatic disease

a. Measurable and/or non-measurable disease

• Prior therapies:
• Patients must have previously received an aromatase inhibitor in the adjuvant, neo-adjuvant or metastatic setting.
• Patients must have previously received palbociclib in the adjuvant, neo- adjuvant or metastatic setting. If patient is currently taking palbociclib at time of screening for the trial they may continue taking palbociclib.
• The minimum duration of AI in the adjuvant setting is 2 years.
• There is no minimum duration of AI in the metastatic setting or neoadjuvant setting.
• Patients may have been previously treated with an mTOR inhibitor or other investigational agent in addition to an aromatase inhibitor.
• Prior treatment with tamoxifen is allowed in the adjuvant setting provided that it was followed by a minimum of 2 years of an AI.
• Brain metastasis is allowed if previously treated, stable and off steroids for a minimum of 56 days
• Age > 18 years
• Male or female breast cancer is allowed
• Patients may be pre- or post-menopausal; pre-menopausal patients must be on ovarian suppression and must be adequately suppressed on LHRH agonists with estradiol levels in the post-menopausal range

a. Premenopausal patients cannot be pregnant and must agree to adequate birth control in addition to ovarian suppression. Agreement by the patient and/or partner to use highly effective, nonhormonal form of contraception or two effective forms of non-hormonal contraception. Contraception use should continue during the duration of study treatment and for at least 6 months after the last dose of study treatment.

• ECOG performance status 0-2
• Adequate bone marrow function as indicated by the following, within 14 days of enrollment:
• ANC ≥ 1500 cells/mm3
• Platelets ≥ 100,000 cells/ mm3
• Hemoglobin ≥ 9 g/dL
• Adequate liver function, as indicated by the following, within 14 days of enrollment.
• Total bilirubin 1.5 upper limit of normal (ULN)
• AST 1.5 ULN
• ALT ≤ 2.5 ULN
• Alkaline phosphatase ≤ 2.5 ULN with the following exception; ALP ≤ 5× ULN in patients with bone metastases.
• Adequate hemostatic function as determined by PT, INR and aPTT < 1.5× ULN (unless on therapeutic coagulation, in which case the adequate level of anticoagulation will be determined by the investigator).
• Adequate renal function, as indicated by creatinine ≤ 1.5 ULN.

Subjects should not enter the study if any of the following exclusion criteria are fulfilled

• Prior therapy exclusions:
• Prior therapy with fulvestrant
• Prior therapy with tamoxifen in the metastatic setting
• More than 3 prior lines of endocrine therapy in the metastatic setting
• More than one prior line of chemotherapy in the metastatic setting
• Washout of 2 weeks is required for aromatase inhibitors; washout of 4 weeks is required for, everolimus or other biological agents with the exception of Palbociclib.
• Patients must not be receiving any other investigational agent.
• Patients with symptomatic, untreated CNS metastases are not eligible.
• Patients may not have significant concurrent illness, infection, pregnancy or lactation
• Patients must not have a different active malignancy, except for skin basal cell carcinoma, skin squamous cell carcinoma and cervical intraepithelial neoplasia.