CDK 4/6 Inhibitor, Ribociclib, With Adjuvant Endocrine Therapy for ER-positive Breast Cancer

Inclusion Criteria:

• Participants must have biopsy proven localized ER+ (≥ 10%), HER2 negative, invasivebreast 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) byASCO/CAP guidelines. For IHC 2+, the tumor must be FISH negative with a ratio <2. PRstatus must be performed. ER, PR and HER2 measurements should be performed accordingto institutional (local) guidelines, in a CLIA-approved setting. Evaluation formetastatic disease is not required in the absence of symptoms. Patients must havecompleted definitive surgery for breast cancer.

• Detectable ctDNA

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

• Participants may or may not have received (neo)adjuvant chemotherapy, but must be atleast 4 weeks after last dose of chemotherapy and/or biological therapy at the timeof screening, with no more than grade 1 residual toxicity (except ≤ grade 2neuropathy or ≤ grade 2 alopecia).

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

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

• QTc (Fredericia's formula) < 470ms.

• Must be ≥ 18 years of age.

• Prior CDK 4/6 inhibitor is permitted provided it was more than 12 months ago (fromconsent date).

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

• Patients may enroll within 20 years of breast cancer diagnosis, as long as there isa plan for at least 1 more year of adjuvant endocrine therapy.

• Ability to understand and the willingness to sign a written informed consentdocument. Patient must sign the Informed Consent (ICF) prior to any screeningprocedures being performed and is able to comply with protocol requirements.

• Currently on adjuvant endocrine therapy (tamoxifen and/or aromatase inhibitor (AI)),i.e prior use of any AI, including letrozole, anastrozole or exemestane, ortamoxifen is allowed. However, tamoxifen use is not allowed during the study withribociclib. Patients on tamoxifen interested in this trial could be switched to AIon C1D1 or before/during screening. Concurrent GNRH agonist is allowed, and isrecommended with AI in pre/peri-menopausal patients.

• Patient has adequate bone marrow and organ function as defined by the followinglaboratory 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 andphosphorus within normal limits for the institution or corrected to withinnormal 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 xULN 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 fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events due to agents administered more than 4 weeks earlier.

• Participants who are receiving any other investigational agents.

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

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

• Uncontrolled inter-current illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements. Patient has impairment of gastrointestinal (GI) function orGI disease that may significantly alter the absorption of the study drugs (e.g.,ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorptionsyndrome, or small bowel resection).

• Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormality including any of the following:

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

• Documented cardiomyopathy.

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

• History of cardiac failure, significant/symptomatic bradycardia, Long QTsyndrome, family history of idiopathic sudden death or congenital long QTsyndrome 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 withmarrow-suppressive therapy. Appropriate studies will be undertaken in participantsreceiving combination antiretroviral therapy when indicated.

• Pregnant women are excluded from this study because the safety of ribociclib is notestablished in pregnant women. For this reason and because CDK4/6 agents as well asother therapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of treatment, and for at least 3 months after the completion oftreatment. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she must inform her treating physician immediately.Prior to study enrollment, WOCBP must be advised of the importance of avoidingpregnancy during trial participation and the potential risk factors for anunintentional pregnancy. In addition, men enrolled on this study should understandthe risks to any sexual partner of childbearing potential. All WOCBP must have anegative pregnancy test within 72 hours prior to receiving the first dose of theinvestigational agent(s). Registration may occur prior to this pregnancy test. Ifthe pregnancy test is positive, the patient must not receive protocol treatment andmust not be enrolled in the study. WOCBP is defined as follows: Any female who hasexperienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a bilateral oophorectomy) or is notpostmenopausal (defined as amenorrhea > 12 consecutive months, or women on hormonereplacement therapy (HRT) with documented plasma follicle-stimulating hormone (FSH)level > 35 mIU/ml). Even women who are using oral, implanted, or injectablecontraceptive hormones or mechanical products (diaphragm, condoms, spermicides) toprevent 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 ofbecoming pregnant, unless they are using highly effective methods of contraceptionthroughout the study and for 8 weeks after study drug discontinuation. Women areconsidered post-menopausal and not of child bearing potential if they have had 12months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateraloophorectomy (with or without hysterectomy) or tubal ligation at least six weeksago. In the case of oophorectomy alone, only when the reproductive status of thewoman has been confirmed by follow up hormone level assessment is she considered notof child bearing potential. Highly effective contraception methods include:

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

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception.

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