PalbocIclib in PreMenopausal Women With ER Positive/HER-2 Negative MetAstatic Breast Cancer

Inclusion Criteria:

1. Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer (histologically or cytologically proven diagnosis of adenocarcinoma of the breast) notamenable to curative treatment by surgery or radiotherapy.
2. ER positive tumour: Histological or cytological confirmation of estrogen and/orprogesterone-receptor positive, as determined by routine IHC. Positivity is defined as ≥1% positive stained cells. The receptor status determined by utilizing an assayconsistent with local laboratory standards.
3. HER2 negative breast cancer as confirmed by IHC, SISH or FISH.
4. Premenopausal women : (definition of a real menopause is not a simple task in theserelatively young women, owing to the potential effect of prior chemotherapy and /orendocrinal therapy particularly OFS) defined either by: i. Any age below 40 years , irrespective to E2 level or menstrual history ii. If thewoman had a menstrual period any time within the last 12 months iii. If the woman hasamenorrhea of more than 12 months (in the absence of chemotherapy or ovarian functionsuppression) that is associated with serum hormone levels that are NOT in thepostmenopausal range (either estradiol (E2) < 30 pg/mL and follicle-stimulatinghormone (FSH) < 20 mU/mL OR E2 ≥ 30 pg/mL and FSH ≥ 20 mU/mL) [30].
5. Secondary hormonal resistance to tamoxifen or endocrinal sensitive metastatic diseasei. Secondary hormonal resistance is defined as recurrence after 24 months from thestart of adjuvant tamoxifen treatment or within 12 months from the end of the 5 yearsof adjuvant Tamoxifen ii. Endocrinal sensitive disease is defined as recurrence after 12 months from the end of adjuvant tamoxifen treatment or de novo metastatic disease
6. Measurable disease according to RECIST or bone-only metastases. Previously irradiatedlesions are deemed measurable only if progression is documented at the site aftercompletion of radiation. i. Patients must either have at least one lesion that can be accurately measured; ORii. Patients have bone lesions: lytic or mixed (lytic + sclerotic) in the absence ofmeasurable disease as defined above.
7. ECOG Performance Status 0, 1, & 2.
8. Resolution of all acute toxic effects of prior therapy or surgical procedures toNational Cancer Institute (NCI) CTCAE Grade 1 (except alopecia or other toxicities notconsidered a safety risk for the patient).
9. Adequate organ function as defined by the following criteria: i. Absolute neutrophil count (ANC) ≥ 1.5 10˄9/L ii. Platelets > 100 x10˄9/L iii.Hemoglobin (Hgb) > 9.0g/dL iv. INR < 2 v. Serum aspartate aminotransferase (AST) andalanine aminotransferase (ALT) < 2.5x ULN (or <5 if hepatic metastases are present)vi. Total serum bilirubin < 1.5 x ULN (<3 x ULN for patients known to have GilbertsSyndrome) vii. Serum creatinine < 1.5 x ULN viii. QTc< 470 msec (based on the meanvalue of the triplicate ECGs).
10. Written informed consent obtained before any trial related activity and according tolocal guidelines.

Exclusion Criteria:

1. Postmenopausal women. Postmenopausal status is defined by age>40years with amenorrheaof more than 12 months, associated with serum hormonal levels of the postmenopausalrange (either estradiol (E2) < 30 pg/mL and follicle-stimulating hormone (FSH) < 20mU/mL or E2 ≥ 30 pg/mL and FSH ≥ 20 mU/mL) [30], in the absence of chemotherapy,tamoxifen, or OFS.
2. Patients with primary endocrinal resistance, defined as recurrence within 24 monthsfrom the start of adjuvant tamoxifen treatment.
3. Symptomatic and/or life threatening visceral metastases i. Diffuse lymphangiticcarcinomatosis. ii. Bulky liver or pulmonary metastases
4. Patients with only non-measurable lesions other than bone metastasis as defined above (e.g., pleural effusion, ascites, etc.).
5. Patients who have received hormonal treatment other than neo/adjuvant tamoxifen ± LHRH agonist for their early breast cancer.
6. Patients who received prior chemotherapy for metastatic or recurrent breast cancer.
7. Another malignancy within 5 years prior to enrolment with the exception of adequatelytreated in-situ carcinoma of the cervix, uterus, basal or squamous cell carcinoma ornon-melanomatous skin cancer.
8. Uncontrolled (clinically or radiologically progressive) CNS metastases, carcinomatousmeningitis, or leptomeningeal disease.
9. Major surgery within 3 weeks of first study treatment.
10. Chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks beforerandomization. Patients who previously received radiotherapy to 25% of bone marrow arenot eligible independent of when it was received.
11. Current treatment with any anti-cancer therapies for advanced disease; anyexperimental treatment of another clinical trial; therapeutic doses of anticoagulant. N.B. Low dose anticoagulants for deep vein thrombosis prophylaxis are allowed. Lowmolecular weight heparin is allowed. Aspirin is permitted.
12. Active bleeding diathesis.
13. History of non-compliance to medical regimens. Patients unwilling to or unable tocomply with the protocol.
14. Pregnant or breast feeding women or those who are not using effective birth controlmethods. Adequate contraceptives must be used throughout the trial and for 8 weeksafter the last study drug administration. Patients must have a negative serumpregnancy test within 7 days prior to first administration of study drug.
15. Prior hematopoietic stem cell or bone marrow transplantation.
16. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to bepotent CYP3A4 inducers, and drugs that are known to prolong the QT interval.
17. Known or possible hypersensitivity to goserelin during the adjuvant setting.
18. Any severe and/or uncontrolled medical conditions such as: i. Unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction < 6months prior to enrollment, serious uncontrolled cardiac arrhythmia ii.Uncontrolled diabetes as defined by fasting serum glucose > 3 x ULN iii. Acute andchronic active infectious disorders (except for Hepatitis B and Hepatitis C positivepatients) and non-malignant medical illnesses that are uncontrolled or whose controlmay be jeopardized by the complications of this study therapy iv. Known humanimmunodeficiency virus infection v. Impairment of gastrointestinal function orgastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorptionsyndrome)