Inclusion Criteria:

1. Men or women at least 18 years of age with histologically or cytologically confirmed
adenocarcinoma of the breast with unresectable or metastatic disease.

2. Most recent tumor biopsy or surgical resection specimen must be either ER positive,
PgR positive, or both, as defined by immunohistochemistry (IHC) 1% (as per the
ASCO-CAP guidelines).

3. HER2-negative breast cancer defined as a negative in situ hybridization test or an
IHC status of 0, 1+ or 2+. If IHC is 2+ (i.e. indeterminate), a negative in situ
hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. (as
per the ASCO-CAP guidelines).

4. Postmenopausal status or receiving ovarian ablation with a 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 FSH, 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 C1D1 of anti-estrogen therapy.

5. Have evidence of measurable or unmeasurable disease.

6. Eastern Cooperative Group (ECOG) performance status of 0 or 1.

7. Scenario 1: No prior cdk 4/6 inhibitor. 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 (anastrazole or exemestane, not supplied by study).
Ribociclib will be supplied by Novartis. If patient has previously received
letrozole, anastrazole, and exemestane, (s)he is not eligible. No prior fulvestrant
allowed.

8. Scenario 2: the patient must have received an aromatase inhibitor plus palbociclib as
standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib) as part
of a clinical trial, and demonstrated evidence of disease progression. If the patient
was enrolled in a randomized clinical trial involving ribociclib 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. Documentation of progression and duration of response on aromatase
inhibitor plus CDK 4/6 inhibitor should be provided whenever possible. No prior
fulvestrant allowed.

9. Adequate baseline laboratory studies (hematologic and chemistry), including the
following parameters:

- Absolute neutrophil count 1500 per microliter, Platelets 75,000 per
microliter, Hemoglobin level 8.0 gm/dL on screening complete blood count

- Potassium, sodium, total calcium (corrected for serum albumin), magnesium, and
phosphorus within normal limits of the central 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 absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) should be below 2.5 the upper limit of normal (ULN). If
the patient has liver metastases, ALT and AST should be < 5 ULN.

- Total bilirubin 1.5 x ULN. (In patients with well documented Gilbert's
Syndrome, total bilirubin 3 ULN with direct bilirubin within normal range.)

- INR 1.5

10. Subject must be capable of understanding and participating in the informed consent
process.

11. Must be able to swallow ribociclib and letrozole

Exclusion Criteria:

1. Prior fulvestrant use.

2. Patient has a known hypersensitivity to any of the excipients of ribociclib,
letrozole or fulvestrant

3. 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.

4. 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.

5. 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. To clarify, this prior line can be single agent or combination (example,
carboplatin/gemcitabine given concurrently). Patients do not need to have
demonstrated disease progression on chemotherapy to be eligible. Having received
prior targeted therapies for breast cancer (such as everolimus or experimental
agents) does not affect eligibility for this study, with the exception of patients
who have received the investigational CDK4/6 inhibitor abemaciclib (LY2835219). If
the patient has previously received abemaciclib, the patient is not eligible for this
study.

6. Completion of major surgery or radiation within 14 days prior to starting
investigational drug or has not recovered from major side effects.

7. Residual acute toxic effects of prior anti-cancer therapy that have not resolved to
CTCAE v.4 Grade 1 (except alopecia or other grade II or above toxicities not
considered a safety risk for the patient at investigator's discretion).

8. 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,

9. 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).

10. Patient has a known history of HIV infection (testing not mandatory)

11. 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:
i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia
or hypomagnesaemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia ii. 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) iii. Inability to determine
the QTc interval

- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g., bifascicular
block, Mobitz type II and third degree AV block)

12. Corrected QT interval (QTc) > 480 msec on screening electrocardiogram. If QTc
prolongation is felt to be related to electrolyte imbalance, an EKG can be repeated
after correction of electrolytes.

13. 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.

14. Currently receiving treatment with known strong inducers or inhibitors of cytochrome
p450 enzymes 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 at least one week prior to
receiving investigational drug. Anti-retrovirals, anti-microbials, and
anti-arrhythmics are the most common medications that interact with these enzymes.
Section 5: Pharmaceutical Information and Appendix B for more information and a list
of drugs that should not be used concurrently with ribociclib. In addition, this
includes grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.

15. 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.

16. Subject is pregnant or nursing. Serum or urine Beta-HCG must be checked in all pre-
and peri-menopausal patients. (Fulvestrant is pregnancy category D and CDK4/6
inhibitors have demonstrated teratogenicity/fetotoxicity in animal studies.)

17. The effects of ribocicilb on the developing human fetus are unknown. For this reason
and because the effects of chemotherapy are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of
study participation, and 3 weeks after completion of ribociclib administration.

Minimum Eligible Age: 18 Years

Maximum Eligible Age: N/A

Eligible Gender: Both