This is an international (4 countries) randomized phase III study with 2 cohorts, patients
will be randomized 1:1 to endocrine therapy (cohort 1: exemestane 25 mg daily, cohort 2:
fulvestrant 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus palbociclib (125
mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3
weeks). Postmenopausal patients with HR+/HER2 MBC are eligible if resistant to previous
nonsteroidal aromatase inhibitors (NSAI) (letrozole or anastrozole) in cohort 1 or previous
aromatase inhibitors (AI) (letrozole, anastrozole or exemestane) in cohort 2 defined as:
recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or
progression while on or within 1 month after the end of treatment with NSAI/AI for MBC.
Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line
for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic
or mixed, in the absence of measurable disease.
1. The patient has signed the informed consent document.
2. a) Patients in cohort 1: Females with histologically confirmed MBC whose disease is
resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole) b)
Patients in cohort 2: Females with histologically confirmed MBC whose disease was
resistant to previous aromatase inhibitors (exemestane, letrozole or anastrozole).
Resistance is defined as: Recurrence while on or within 12 months after the end of
adjuvant treatment with NSAI/AI or Progression while on or within 1 month after the
end of treatment with NSAI/AI for advanced disease.
3. Previous chemotherapy is permitted either in the (neo) adjuvant setting and/or first
line therapy for MBC (chemotherapy administered as "second adjuvant therapy" for
locoregional recurrence should be considered as first line chemotherapy for MBC).
4. It is not mandatory to have exemestane, letrozole or anastrozole as the most recent
treatment before randomization but recurrence or progression of breast cancer while
receiving (or immediately after the enf of) the most recent systemic therapy has to be
documented before randomization.
5. Hormonal receptor positive (HR+) breast cancer based on local laboratory
determination. HR+ defined as major or equal to 1 percent positive cells by
Immunohistochemistry (IHC) for ER and/or Progesterone Receptor (PgR).
6. Documented HER2 negative breast cancer based on local laboratory determination on most
recent tumor biopsy. HER2 negative tumor is determined as IHC score 0 or 1+ or
negative by ISH (FISH/Chromogenic In Situ Hybridization (CISH)/SISH) defined as a
HER2/CEP17 ratio minor to 2 or for single probe assessment a HER2 copy number minor to
7. Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which
has not been previously irradiated and is assessable by CT/MRI in the absence of
measurable disease according to RECIST 1.1 criteria.
8. Patient is at least 18 years of age.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status minor or equal to 1.
10. Life expectancy major or equal to 12 weeks.
11. Adequate organ and bone marrow function.
12. Postmenopausal women defined as women with:
Prior bilateral surgical oophorectomy, or Age > 60 years, or Age < 60 years and
medically confirmed post-menopausal status defined as spontaneous cessation of regular
menses for at least 12 consecutive months with no alternative pathological or
physiological cause or follicle-stimulating hormone (FSH) and estradiol blood levels
in their respective postmenopausal ranges
13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical
procedures to NCI CTCAE version 4.0 Grade minor or equal to 1 (except alopecia or
other toxicities not considered a safety risk for the patient at investigator´s
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests and other study procedures.
1. Have received more than 1 prior chemotherapy regimen for MBC. (NOTE: Chemotherapy
administered as "second adjuvant therapy" for locoregional recurrence should be
considered one prior chemotherapy for MBC).Other previous anticancer endocrine
treatments for advanced disease are allowed.
2. Patients with advanced, symptomatic, visceral spread that are at risk of
life-threatening complications in the short term (including patients with massive
uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis and
over 50% liver involvement).
3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,
carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms,
cerebral edema, and/or progressive growth. Patients with a history of CNS metastases
or cord compression are eligible if they have been definitively treated with local
therapy (eg, radiotherapy,) and are clinically stable off anticonvulsants and steroids
for at least 4 weeks before randomization.
4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor (any agent whose mechanism of
action is to inhibit the PI3 kinase-mTOR pathway) or capecitabine.
5. a) Patients included in cohort 1: Prior treatment with exemestane in the metastatic
setting. If the patient has received exemestane in the adjuvant setting and developed
MBC, she will be eligible for the study provided:
- She has received letrozole/anastrozole as first-line MBC and progressed.
- At least 1 year has elapsed since the end of adjuvant exemestane treatment. b)
Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic
setting. If the patient has received fulvestrant in the adjuvant setting and
developed MBC, she will be eligible for the study provided:
- She has received letrozole/anastrozole as first-line MBC and progressed.
- At least 1 year has elapsed since the end of adjuvant fulvestrant treatment.
6. Patients treated within the last 7 days prior to randomization with:
- Food or drugs that are known to be CYP3A4 inhibitors
- Drugs that are known to be CYP3A4 inducers
- Drugs that are known to prolong the QT interval
7. Patients who received before randomization:
- Any investigational agent within 4 weeks
- Chemotherapy within a period of time that is minor than the cycle length used for
that treatment (e.g. less 3 weeks for fluorouracil, doxorubicine, epirubicin or
less than 1 week for weekly chemotherapy)
- Previous endocrine therapy is permitted without any window
- Radiotherapy within 2 weeks (all acute toxic effects must be resolved to NCI
CTCAE version 4.0 grade minor 1, except toxicities not considered a safety risk
for the patient at investigator´s discretion) but patients who received prior
radiotherapy to less than 25 per cent of bone marrow are not eligible independent
of when it was received
- Major surgery or other anti-cancer therapy not previously specified within 4
weeks, (all acute toxic effects must be resolved to NCI CTCAE version 4.0 grade
minor 1, except toxicities not considered a safety risk for the patient at
8. Diagnosis of any other malignancy within 3 years prior to randomization, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
9. QTc major 480msec, family or personal history of long or short QT syndrome, Brugada
syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
11. Any of the following within 6 months of randomization: myocardial infarction,
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade
major or equal to 2, atrial fibrillation of any grade, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular accident including
transient ischemic attack, or symptomatic pulmonary embolism.
12. Difficulties to swallow tablets, malabsorption syndrome disease significantly
affecting gastrointestinal function, resection of the stomach or small bowel, or
active inflammatory bowel disease or chronic diarrhea.
13. Known hypersensitivity to exemestane, palbociclib, capecitabine, fulvestrant or any of
14. Any of the following contraindications for chemotherapy with capecitabine:
- Known deficiency or family history of deficiency of dihydropyrimidine
- Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or
chemically related analogues, such as brivudine.
15. Only for patients in Cohort 2 any of the following contraindications for treatment
- Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting
factor deficiency) or long-term anticoagulant therapy (other than antiplatelet therapy
and low dose warfarin) provided that the International Normalised Ratio (INR) is less
16. Known human immunodeficiency virus infection.
17. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
18. Recent or active suicidal ideation or behavior