Fulvestrant or Exemestane with or without Ribociclib in Patients with Recurrent, Unresectable, or Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

Inclusion Criteria

• Men or women at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease.
• Most recent tumor biopsy or surgical resection specimen must be either estrogen receptor (ER) positive, progesterone receptor (PgR) positive, or both, as defined by immunohistochemistry (IHC) >= 1% (as per the American Society of Clinical Oncology-College of American Pathologists [ASCO-CAP] guidelines)
• Human epidermal growth factor receptor 2 (HER2)-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 1+; if IHC is 2+ (i.e. indeterminate), a negative in situ hybridization (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver in situ hybridization [SISH]) test is required by local laboratory testing; (as per the ASCO-CAP guidelines)
• Postmenopausal status or receiving ovarian ablation with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin * Postmenopausal status is defined by any one of the following criteria: ** Prior bilateral oophorectomy ** Age >= 60 years ** Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range per local normal * If the patient does not meet criteria for postmenopausal status but is receiving ovarian ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin, the patient is eligible for this study, provided that the GnRH agonist is started at least 2 weeks prior to cycle 1 day 1 (C1D1) of anti-estrogen therapy
• Have evidence of measurable or unmeasurable disease
• Eastern Cooperative Group (ECOG) performance status of 0 or 1
• Scenario 1: No prior cdk 4/6 inhibitor (Closed to Accrual); if patient has not previously received letrozole, letrozole will be supplied by Novartis; if previously progressed on letrozole, another aromatase inhibitor that the patient has not previously received is allowed, per standard of care (anastrozole or exemestane, not supplied by study); ribociclib will be supplied by Novartis; if patient has previously received letrozole, anastrozole, and exemestane, (s)he is not eligible; for scenario 1, patients are allowed to have started the aromatase inhibitor within 4 consecutive weeks prior to protocol registration; for instance, it is acceptable for patient who will be treated with letrozole in scenario #1, to have started letrozole within 4 consecutive weeks prior to protocol registration; no prior fulvestrant allowed
• Scenario 2: the patient must have received an aromatase inhibitor (letrozole, arimidex, exemestane) or tamoxifen or fulvestrant plus palbociclib as standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib or abemaciclib), and demonstrated evidence of disease progression; if the patient was enrolled in a randomized clinical trial involving ribociclib or abemaciclib or palbociclib (such as the MONALEESA or PALOMA series of trials), then it must be known after study discontinuation and unblinding that the patient received the investigational drug and not placebo; ribociclib or abemaciclib or palbociclib can also be given as standard of care; documentation of progression and duration of response on aromatase inhibitor or tamoxifen plus CDK 4/6 inhibitor should be provided whenever possible; if patient received prior fulvestrant, exemestane must be the hormone therapy backbone in the randomization; if patient received prior exemestane, fulvestrant must be the hormone therapy backbone in the randomization; if neither has been administered, selection of fulvestrant or exemestane in the randomization will be per investigator discretion
• Absolute neutrophil count >= 1500 per microliter
• Platelets >= 75,000 per microliter
• Hemoglobin level >= 8.0 gm/dL on screening complete blood count
• Potassium and total calcium (corrected only in the case of hypoalbuminemia) within normal limits of the local laboratory (screening values can be rechecked after electrolyte repletion and before the first dose of study medication, if necessary)
• Serum creatinine level =< 1.5 mg/dL or estimated glomerular filtration rate >= 50 mL/min
• In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 x the upper limit of normal (ULN); if the patient has liver metastases, ALT and AST should be < 5 x ULN
• Total bilirubin =< 1.5 x ULN; (in patients with well documented Gilbert’s syndrome, total bilirubin =< 3 x ULN with direct bilirubin within normal range)
• International normalized ratio (INR) =< 1.5
• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization obtained from the subject/legal representative prior to performing any protocol-related procedures
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Must be able to swallow ribociclib and oral aromatase inhibitor, such as letrozole or exemestane

Exclusion Criteria

• Patient has a known hypersensitivity to any of the excipients of ribociclib, aromatase inhibitors (such as letrozole) or fulvestrant
• Active central nervous system (CNS) disease; history of CNS metastases or cord compression is allowable if the patient has been clinically stable for at least 4 weeks since completion of definitive treatment and is off systemic steroids; in the case of brain metastases, the patient must have stable or improved imaging at least 4 weeks after completion of definitive treatment; if there is evidence of active leptomeningeal disease, the patient is ineligible
• Identified as having visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis; visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease
• Received more than 1 prior systemic chemotherapy in the unresectable or metastatic setting; if the patient received 1 prior systemic chemotherapy, the patient is eligible; having received prior therapies for breast cancer (such as everolimus or experimental agents) does not affect eligibility for this study
• Completion of major surgery, chemotherapy, targeted therapy (such as everolimus or experimental agents or radiation within 14 days prior to starting investigational drug or has not recovered from major side effects; there is no required washout period from completion of prior anti-estrogen therapy (either scenario) or prior CDK 4/6 inhibitor (if scenario 2) to initiation of ribociclib/placebo and anti-estrogen on trial
• Residual acute toxic effects of prior anti-cancer therapy that have not resolved to Common Terminology Criteria for Adverse Events version 4 (CTCAE v.4) grade =< 1; exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator’s discretion, are allowed to enter the study
• Presence of a concurrent malignancy or malignancy diagnosed within 5 years of randomization, with the exception of basal or squamous cell carcinoma, non-melanomatous skin cancer, curatively resected cervical cancer, localized prostate cancer treated with curative intent, and stage I colorectal cancer treated with curative resection
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: * History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry * Documented cardiomyopathy * Patient has a known left ventricular fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) * Long QT syndrome or family history of long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: ** Risk factors for torsades de pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesaemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ** Concomitant medications(s) with a known risk to prolong the QT interval and/or known to cause torsades de pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug) ** Inability to determine the corrected QT (QTc) interval * Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) * Systolic blood pressure (SPB) > 160 or < 90 mmHg
• Corrected QT interval (QTcF) > 450 msec (QT interval using Fridericia’s correction) on screening electrocardiogram; if QTc prolongation is felt to be related to electrolyte imbalance, an electrocardiogram (EKG) can be repeated after correction of electrolytes; mean resting heart rate 50-100 beats per minute (bpm) (determined from ECG)
• The presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator or treating physician’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol; this includes uncontrolled infections that could potentially be exacerbated by anti-neoplastic treatment, active untreated or uncontrolled fungal bacterial or viral infections, etc
• Currently receiving treatment, including medications and herbal preparations with known strong inducers or inhibitors of cytochrome p450 enzymes cytochrome P450 family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) medications that have a narrow therapeutic window and are predominately metabolized through CYP3A4/5 or herbal preparations/medications, dietary supplements, which cannot be discontinued prior to receiving investigational drug; anti-retrovirals, anti-microbials, and anti-arrhythmics are the most common medications that interact with these enzymes
• Patients who are receiving any other investigational agents concurrently or have received investigational agents within 14 days or 5 half-lives of the compound or active metabolites, whichever is longer before the first dose of the study treatment
• Patient is concurrently using hormone replacement therapy
• Subject is pregnant or nursing; serum or urine beta-human chorionic gonadotropin (HCG) must be checked in all non-postmenopausal patients or patients of childbearing potential; (fulvestrant is pregnancy category D and CDK4/6 inhibitors have demonstrated teratogenicity/fetotoxicity in animal studies.)