Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer

Inclusion criteria

• Pre/peri- or post-menopausal women 18 years and older (or local legal age, whichever is higher)
• Primary tumor greater than 15 mm in diameter
• Histologically proven invasive breast cancer
• Positive hormone receptor (ER and/or PgR ≥1% in proportion of positive staining score)
• Negative HER-2 receptor (based on 2018 ASCO/CAP Guideline)
• Ki67 index equal to or greater than 14% (Ki67 ≥ 14%) by central assessment using actual or virtual slides
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1
• No previous history of radiotherapy or systemic therapy including chemotherapy and hormone therapy for breast cancer
• 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).

• Able to give written informed consent form
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion criteria

• Male
• Locally advanced breast cancer ( Any T4 or Any N2, N3), or distant metastasis
• Multicentric breast cancer (Note: Multifocal breast cancer,located in one quadrant/are is eligible)
• Prior treatment with chemotherapy, radiotherapy and/or endocrine therapy
• Previous use of SERMs such as raloxifene.
• Prior therapy with any CDK4/6 inhibitor or with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.
• 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
• Major surgery within 3 weeks of first study treatment
• 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 containing grapefruit);
• 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);
• 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
• Family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
• Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomag-nesemia) that can compound the effects of a QTc-prolonging drug.
• Active inflammatory bowel disease or chronic diarrhea. Short bowel syndrome. Upper gastrointestinal surgery including gastric resection.
• Prior hematopoietic stem cell or bone marrow transplantation.
• Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding subcutaneous injections of leuprorelin or goserelin.
• Hepatitis B and/or hepatitis C carriers (Patients with HBsAg+ or HBV-DNA+ who need antiviral treatment during any anti-cancer therapy based on guidelines are excluded even if the patient's hepatic function is normal. Patients with HCVAb+, whose HCV-RNA is positive (+) are excluded.)
• Known human immunodeficiency virus (HIV) infection
• Known hypersensitivity to anti-aromatase drugs, tamoxifen or any cell cycle in-hibitor.
• 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 after the last dose of investigational drug.
• 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 study
• 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.
• Participation in other studies involving investigational drug (s) (Phases 1-4) within 2 weeks before randomization and/or until a visit at 4 weeks (+7 days) after operation.