| Eligibility |
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) not
amenable to curative treatment by surgery or radiotherapy.
2. ER positive tumour: Histological or cytological confirmation of estrogen and/or
progesterone-receptor positive, as determined by routine IHC. Positivity is defined as
=1% positive stained cells. The receptor status determined by utilizing an assay
consistent 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 these
relatively young women, owing to the potential effect of prior chemotherapy and /or
endocrinal therapy particularly OFS) defined either by:
i. Any age below 40 years , irrespective to E2 level or menstrual history ii. If the
woman had a menstrual period any time within the last 12 months iii. If the woman has
amenorrhea of more than 12 months (in the absence of chemotherapy or ovarian function
suppression) that is associated with serum hormone levels that are NOT in the
postmenopausal range (either estradiol (E2) < 30 pg/mL and follicle-stimulating
hormone (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 disease
i. Secondary hormonal resistance is defined as recurrence after 24 months from the
start of adjuvant tamoxifen treatment or within 12 months from the end of the 5 years
of 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 irradiated
lesions are deemed measurable only if progression is documented at the site after
completion of radiation.
i. Patients must either have at least one lesion that can be accurately measured; OR
ii. Patients have bone lesions: lytic or mixed (lytic + sclerotic) in the absence of
measurable disease as defined above.
7. ECOG Performance Status 0, 1, & 2.
8. Resolution of all acute toxic effects of prior therapy or surgical procedures to
National Cancer Institute (NCI) CTCAE Grade 1 (except alopecia or other toxicities not
considered 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) and
alanine 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 Gilberts
Syndrome) vii. Serum creatinine < 1.5 x ULN viii. QTc< 470 msec (based on the mean
value of the triplicate ECGs).
10. Written informed consent obtained before any trial related activity and according to
local guidelines.
Exclusion Criteria:
1. Postmenopausal women. Postmenopausal status is defined by age>40years with amenorrhea
of more than 12 months, associated with serum hormonal levels of the postmenopausal
range (either estradiol (E2) < 30 pg/mL and follicle-stimulating hormone (FSH) < 20
mU/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 months
from the start of adjuvant tamoxifen treatment.
3. Symptomatic and/or life threatening visceral metastases i. Diffuse lymphangitic
carcinomatosis. 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 adequately
treated in-situ carcinoma of the cervix, uterus, basal or squamous cell carcinoma or
non-melanomatous skin cancer.
8. Uncontrolled (clinically or radiologically progressive) CNS metastases, carcinomatous
meningitis, or leptomeningeal disease.
9. Major surgery within 3 weeks of first study treatment.
10. Chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks before
randomization. Patients who previously received radiotherapy to 25% of bone marrow are
not eligible independent of when it was received.
11. Current treatment with any anti-cancer therapies for advanced disease; any
experimental treatment of another clinical trial; therapeutic doses of anticoagulant.
N.B. Low dose anticoagulants for deep vein thrombosis prophylaxis are allowed. Low
molecular weight heparin is allowed. Aspirin is permitted.
12. Active bleeding diathesis.
13. History of non-compliance to medical regimens. Patients unwilling to or unable to
comply with the protocol.
14. Pregnant or breast feeding women or those who are not using effective birth control
methods. Adequate contraceptives must be used throughout the trial and for 8 weeks
after the last study drug administration. Patients must have a negative serum
pregnancy 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 be
potent 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, myocardial
infarction < 6months prior to enrollment, serious uncontrolled cardiac arrhythmia ii.
Uncontrolled diabetes as defined by fasting serum glucose > 3 x ULN iii. Acute and
chronic active infectious disorders (except for Hepatitis B and Hepatitis C positive
patients) and non-malignant medical illnesses that are uncontrolled or whose control
may be jeopardized by the complications of this study therapy iv. Known human
immunodeficiency virus infection v. Impairment of gastrointestinal function or
gastrointestinal disease that may significantly alter the absorption of study drugs
(e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption
syndrome)
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