CDK 4/6 Inhibitor, LEE011 (Ribociclib), in Combination With Adjuvant Endocrine Therapy at Varying Duration for ER-positive Breast Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.

This research study is a Pilot Study of two different doses, which is the first time
investigators are examining this study drug at the different dosage, for early breast cancer.
There is no placebo in this study.

The FDA (the U.S. Food and Drug Administration) has approved ribociclib in combination with
aromatase inhibitors as a treatment option for advanced/metastatic (stage IV) breast cancer.

In this research study, The investigators are comparing the safety and efficacy of ribociclib
given at two different doses given on different schedules during a period of 28 days.

Ribociclib is a drug designed to block certain proteins called cyclin-dependent protein
kinases 4 and 6 (CDK4/6). These proteins are needed for cells to divide and may also control
the ability of certain cancers to grow. The investigators believe that ribociclib may stop
the participant cancer cells from growing and dividing by blocking these CDK4/6 proteins.

Inclusion Criteria:

- Participants must have biopsy proven localized ER+ (≥ 10%), HER2 negative, invasive
breast cancer, with pathological stage (including post-neoadjuvant therapy) T1c-T4c,
any N, M0, by AJCC 7th edition staging. Invasive breast cancer must be ER+ in ≥10% of
the cells and HER2 negative (IHC 0 or 1+ and/or FISH negative with a ratio <2) by
ASCO/CAP guidelines. For IHC 2+, the tumor must be FISH negative with a ratio <2. PR
status must be performed. ER, PR and HER2 measurements should be performed according
to institutional (local) guidelines, in a CLIA-approved setting. Evaluation for
metastatic disease is not required in the absence of symptoms. Patients must have
completed definitive surgery for breast cancer.

- No prior history of other malignancies within past 5 year (besides breast cancer as
per 3.1.1). Individuals with the following cancers are eligible if diagnosed and
treated within the past 5 years: ductal carcinoma in situ of the breast, cervical
cancer in situ, and basal cell or squamous cell carcinoma of the skin. No concurrent
malignancy or other serious medical condition as deemed by the investigator.

- Participants may or may not have received (neo)adjuvant chemotherapy, but must be at
least 30 days after last dose of chemotherapy and/or biological therapy, with no more
than grade 1 residual toxicity at the time of screening.

- Participants may or may not have received adjuvant radiotherapy, but must be at least
30 days after last dose radiotherapy, with no more than grade 1 residual toxicity at
the time of screening.

- Pre- and postmenopausal women are eligible. Premenopausal women must have a negative
serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female
patients who are: age ≥ 60 years; or age < 60 with intact uterus and amenorrhea for 12
consecutive months or more AND estrogen (estradiol) levels within postmenopausal
range; or status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal
ligation.

- QTc (Fredericia's formula) < 470ms.

- Must be ≥ 18 years of age.

- No history of prior CDK 4/6 inhibitor use.

- ECOG performance status 0-1 (Karnofsky ≥70%, see Appendix A)

- Patients may enroll within 10 years of breast cancer diagnosis, as long as there is a
plan for at least 1 more year of adjuvant endocrine therapy.

- Ability to understand and the willingness to sign a written informed consent document.
Patient must sign the Informed Consent (ICF) prior to any screening procedures being
performed and is able to comply with protocol requirements.

- Participants must have been on adjuvant endocrine therapy, either tamoxifen or
aromatase inhibitor (AI), for at least 6 months without any significant adverse events
leading to drug interruption for more than 1 month, and must not have had any change
in endocrine therapy in the past 6 months (till date of trial consent). Prior use of
any AI, including letrozole, anastrozole or exemestane, or tamoxifen is allowed.

- Patient has adequate bone marrow and organ function as defined by the following
laboratory values at screening:

- Absolute neutrophil count ≥1.5 × 109/L

- Platelets ≥100 × 109/L

- Hemoglobin ≥9.0 g/dL

- Potassium, total calcium (corrected for serum albumin), magnesium, sodium and
phosphorus within normal limits for the institution or corrected to within normal
limits with supplements before first dose of study medication

- Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN.

- Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x
ULN in patients with well-documented Gilbert's Syndrome.

- Fasting plasma glucose <140 mg/dL / 7.7 mmol/L..

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Participants who are receiving any other investigational agents. History of prior
PI3K, mTOR or CDK 4/6 inhibitor use for breast cancer.

- Participants with known brain metastases, or any other metastases from cancer.

- Participants receiving any medications or substances that are inhibitors or inducers
of CYP3A4 are ineligible. Because the lists of these agents are constantly changing,
it is important to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.

- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. 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).

- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality including any of the following:

- History of angina pectoris, symptomatic pericarditis, coronary artery bypass
graft (CABG) or myocardial infarction within 6 months prior to study entry.

- Documented cardiomyopathy.

- Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated
acquisition (MUGA) scan or echocardiogram (ECHO) detected during screening.

- History of cardiac failure, significant/symptomatic bradycardia, Long QT
syndrome, family history of idiopathic sudden death or congenital long QT
syndrome or any of the following:

- Known risk to prolong the QT interval or induce Torsade's de Pointes.

- Uncorrected hypomagnesemia or hypokalemia.

- Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.

- Bradycardia (heart rate <50 at rest), by ECG or pulse.

- On screening, inability to determine the QTcF interval on the ECG (i.e.:
unreadable or not interpretable) or QTcF >450 screening ECG (based on a mean of 3
ECGs).

- History of hypersensitivity to ribociclib or any of its components.

- HIV-positive participants on combination antiretroviral therapy are ineligible. These
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

- Pregnant women are excluded from this study because the safety of ribociclib is not
established in pregnant women. For this reason and because CDK4/6 agents as well as
other therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential (WOCBP) and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of treatment, and for at least 3 months after the completion of
treatment. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she must inform her treating physician immediately. Prior
to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy
during trial participation and the potential risk factors for an unintentional
pregnancy. In addition, men enrolled on this study should understand the risks to any
sexual partner of childbearing potential. All WOCBP must have a negative pregnancy
test within 72 hours prior to receiving the first dose of the investigational
agent(s). Registration may occur prior to this pregnancy test. If the pregnancy test
is positive, the patient must not receive protocol treatment and must not be enrolled
in the study. WOCBP is defined as follows: Any female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or a bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea
> 12 consecutive months, or women on hormone replacement therapy (HRT) with documented
plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml). Even women who are using
oral, implanted, or injectable contraceptive hormones or mechanical products
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or
where partner is sterile (e.g. vasectomy), should be considered to be a WOCBP.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 8 weeks after study drug discontinuation. Women are
considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential. Highly effective contraception methods include:

- Total abstinence when this is in line with the preferred and usual lifestyle of
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception.

- In case of use of oral contraception, women should have been stable on the same
pill for a minimum of 3 months before taking study treatment. Note: While oral
contraceptives are allowed, they should be used in conjunction with a barrier
method of contraception due to unknown effect of drug-drug interaction