1. Pre/peri- or post-menopausal women 18 years and older (or local legal age, whichever is
higher) 2. Primary tumor greater than 2 cm in diameter 3. Histologically proven invasive
breast cancer 4. Positive hormone receptor (ER and/or PgR ≥ Allred 3) 5. Negative HER-2
receptor 6. Ki67 index equal to or greater than 14% (Ki67 ≥ 14%) by central assessment 7.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1 or Karnofsky
performance status ≥ 70% 8. No previous history of radiotherapy or systemic therapy
including chemotherapy and hormone therapy for breast cancer 9. Laboratory values must be
as follows: Absolute neutrophil count: ≥ 1,500/mm3 Platelets: ≥ 100,000/mm3 Hemoglobin: ≥ 9
g/dL Bilirubin: ≤ 1.5 × upper limits of normal (ULN) Serum Creatinine: ≤ 1.5 × ULN Alkaline
phosphatase: ≤ 2 × ULN AST and ALT: ≤ 2 × ULN Cardiac function: Normal finding of
Electrocardiogram (ECG) QTc ≤ 480 msec (based on the mean value of the triplicate ECGs).
10. Able to give written informed consent form 11. Willingness and ability to comply with
scheduled visits, treatment plan, laboratory tests, and other study procedures
2. Locally advanced breast cancer (T3N1 or Any T4 or Any N2, N3), or distant me-tastasis
3. Multifocal or multicentric breast cancer
4. Prior treatment with chemotherapy, radiotherapy and/or endocrine therapy
5. Previous use of SERMs such as raloxifene.
6. Prior therapy with any CDK4/6 inhibitor or with everolimus, or any agent whose
mechanism of action is to inhibit the PI3K-mTOR pathway.
7. Prior history of other malignancy within 5 years of study entry, aside from basal cell
carcinoma of the skin or carcinoma-in-situ of the uterine cervix
8. Major surgery within 3 weeks of first study treatment
9. Patients treated within the last 7 days prior to randomization with:
- Food or drugs that are known strong and moderate CYP3A4 inhibitors (e.g.,
amprenavir, aprepitant, atazanavir, boceprevir, casopitant, cimetidine,
ciprof-loxacin, clarithromycin, conivaptan, cobicistat, crizotinib, cyclosporine,
da-runavir, diltiazem, dronedarone, elvitegravir, erythromycin, fluconazole,
fosamprenavir, imatinib, indinavir, isavuconazole, istradefylline,
itraconazole,ketoconazole, letermovir, lopinavir, mibefradil, miconazole,
nefazodone, nelfinavir, nilotinib, posaconazole, ritonavir, saquinavir,
schisandra sphenan-thera extract, telaprevir, telithromycin, tofisopam,
verapamil, voriconazole, and grapefruit, grapefruit juice or any product
- Drugs that are known strong and moderate CYP3A4 inducers (e.g., bosentan,
carbamazepine, efavirenz, etravirine, modafinil, phenobarbital, phenytoin,
ri-fampin, rifapentin, and St. John's wort);
10. Any of the following in the previous 6 months of randomization: myocardial
in-farction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version
4.03 grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident in-cluding
transient ischemic attack, or symptomatic pulmonary embolism
11. Family or personal history of long or short QT syndrome, Brugada syndrome or known
history of QTc prolongation, or Torsade de Pointes (TdP).
12. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomag-nesemia)
that can compound the effects of a QTc-prolonging drug.
13. Active inflammatory bowel disease or chronic diarrhea. Short bowel syndrome. Upper
gastrointestinal surgery including gastric resection.
14. Prior hematopoietic stem cell or bone marrow transplantation.
15. Known abnormalities in coagulation such as bleeding diathesis, or treatment with
anticoagulants precluding subcutaneous injections of leuprorelin or goserelin.
16. Hepatitis B and/or hepatitis C carriers (unless with normal hepatic function)
17. Known human immunodeficiency virus (HIV) infection
18. Known hypersensitivity to anti-aromatase drugs, tamoxifen or any cell cycle
19. Patients who are pregnant or lactating. Patients of childbearing potential and/or her
partner who are unwilling or unable to use a method of highly effective non-hormonal
contraception throughout the study and continue for at least 21 days in patients and
90 days in her partner after the last dose of investigational drug.
20. Other severe acute or chronic medical or psychiatric condition, or laboratory
ab-normality that would impart, in the judgment of the investigator, excess risk
as-sociated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
21. Patients who are investigational site staff members or relatives of those site staff
OOTR-N016/KBCRN-B-003/HT-PAB Protocol (version 1.2 dated Oct 11, 2018) 24 members or
patients who are the sponsor employees directly involved in the con-duct of the trial.
22. Participation in other studies involving investigational drug (s) (Phases 1-4)
within 2 weeks before randomization and/or during participation in the active
treatment phase of the trial.