Palbociclib and Fulvestrant in Treating Patients with Hormone Receptor-Positive, HER2-Negative Metastatic or Locally Advanced Breast Cancer

Inclusion Criteria

• Women may be premenopausal or postmenopausal; however, premenopausal women and men must be treated with concurrent luteinizing hormone-releasing hormone (LHRH) agonist (goserelin preferred) initiated at least 4 weeks prior to enrollment; NOTE: Postmenopausal status is defined by at least one of the following criteria: * Age >= 60 years * Age < 60 and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females * Documented bilateral oophorectomy; or, * Medically confirmed ovarian failure
• Histologically or cytologically confirmed adenocarcinoma of the breast with evidence of metastatic disease (stage IV) or locally advanced disease, not amenable to surgery or radiation with curative intent
• Documentation of the following receptors based on local testing from most recent assessment: * ER-positive and/or PR-positive tumor (>= 1% positive stained cells) * HER2-negative tumor; NOTE: HER2-negative is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio < 2, for single probe assessment a HER2 copy number < 6 or per current American Society Clinical Oncologists (ASCO)-College of American Pathologists (CAP) or National Comprehensive Cancer Network (NCCN) guidelines
• Patients must satisfy the following criteria for prior therapy: * Progressed on and following at least 6 months of combined treatment with palbociclib and AI therapy for advanced/metastatic breast cancer, and be able and willing to receive additional palbociclib treatment; palbociclib and AI must be the most recently received treatment prior to enrollment; up to one (1) prior line of chemotherapy for advanced/metastatic disease is allowed in addition to any number of prior lines of endocrine therapy * No prior treatment with fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway in the metastatic setting; use of these agents in the neoadjuvant and/or adjuvant settings is permitted * Patients receiving bisphosphonate therapy prior to registration may continue at the same intervals used prior to study registration
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Evaluable or measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); NOTE: Enrollment of patients with bone-only disease may be limited if we find we are not able to get adequate tissue for research correlates from bone biopsies
• Patients must have disease that is amenable to biopsy and be willing to provide the same; NOTE: Patients in whom a baseline biopsy is attempted, but is not successful, will still be considered eligible for the study; in addition, if the primary oncologist has a concern regarding the feasibility of a biopsy, it may be omitted after consulting with the protocol chair
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated creatinine clearance >= 60 ml/min per modified Cockcroft-Gault formula
• Total bilirubin =< 1.5 x upper limit of normal (< 3 x ULN if Gilbert’s disease)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (=< 5 x ULN if lever metastases present)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x upper limit of normal (=< 5 x ULN if liver metastases present)
• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN if bone or liver metastases present)
• Patients with a history of central nervous system metastasis are allowed provided they have been treated (i.e., surgery, radiation, and/or radiosurgery) at least 4 weeks prior to registration and have stable neurologic function, including no requirement for medication(s) to control symptoms for at least 2 weeks; patients with known leptomeningeal disease are not eligible; NOTE: Stable low dose dexamethasone allowed at discretion of protocol chair
• Patients who have received prior radiation therapy must have recovered from toxicity of the prior radiation therapy prior to registration, and must have disease evaluable for response outside of the radiation fields or have evidence of post-radiation progression of previously irradiated sites of disease
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Women who are pregnant or breast-feeding; NOTE: Premenopausal women on ovarian suppression therapy are still considered of childbearing potential; women of childbearing potential and men must be strongly advised to use an accepted and effective method of non-hormonal contraception; acceptable contraception includes barrier methods (e.g., condoms or diaphragm) or intrauterine devices (IUDs) (these may include low-dose hormones at the discretion of the study chair)
• Concurrent use of any of the following medications during study participation: * Inhibitors or inducers of CYP3A4 that may affect serum concentrations of palbociclib * Medications which prolong the QTc interval and may predispose to torsades de pointes
• Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks before registration; patients who received prior radiotherapy to >= 25% of bone marrow are not eligible independent of when it was received * NOTE: Patients taking Palbociclib must hold treatment for a minimum of 1 week prior to initiating study treatment. Patients are not required to hold treatment for aromatase inhibitors prior to initiating study treatment
• Any other malignancy within 3 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
• Any of the following within 6 months of registration: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism; no QTc interval > 480 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or torsade de pointes
• Prior hematopoietic stem cell or bone marrow transplantation
• Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or goserelin (if applicable)
• Known or possible hypersensitivity to palbociclib, fulvestrant, goserelin (if applicable) or to any of their excipients
• Known human immunodeficiency virus infection
• Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study