Fulvestrant (F)+Placebo vs F+Palbociclib First Line for Postmenopausal Hormone Receptor+ Advanced Breast Cancer
Fulvestrant (F)+Placebo vs F+Palbociclib First Line for Postmenopausal Hormone Receptor+ Advanced Breast Cancer
This is an international, multicentre, double-blind, controlled, randomized phase II study
 comparing the efficacy and safety of fulvestrant in combination with palbociclib versus
 fulvestrant plus placebo in postmenopausal women with HR-positive/HER2-negative metastatic
 breast cancer who have received ≥5 years of endocrine therapy in the adjuvant setting as
 treatment for early disease and remained disease free for > 12 months following its
 completion or have "de novo" metastatic disease.
Patients must have at least one lesion (measurable and/or non-measurable) that can be
 accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan
 x-ray. Patients with bone-only disease must have a lytic or mixed (lytic + blastic) lesion,
 which has not been previously irradiated and can be accurately assessed by CT/MRI or x-ray.
 Approximately 190 patients will be randomized 1:1 between the experimental arm (approximately
 95 patients treated with fulvestrant plus palbociclib) and the control arm (approximately 95
 patients treated with fulvestrant plus placebo).

 Primary Objective:

 • To compare the efficacy of fulvestrant in combination with palbociclib versus fulvestrant
 plus placebo in terms of the rate of Progression-Free Survival (PFS) at 1 year in
 postmenopausal women with HR-positive/HER2-negative metastatic breast cancer previously
 treated with endocrine therapy for at least 5 years and remaining disease free for more than
 12 months following its completion or have "de novo" metastatic disease
Inclusion Criteria:

 1. The patient has signed and dated the informed consent document and it has been
 obtained before conducting any procedure specifically for the study.

 2. Availability of a tumor tissue sample, archival (primary tumour) or from the
 metastatic lesions (preferable) for the central ER, PgR and HER2 testing.

 3. Histological/cytological confirmation of breast cancer with evidence of metastatic
 disease (loco-regional or distant), not amenable to resection or radiation therapy
 with curative intent.

 4. Documented positive hormone receptor status (> or = 1% of tumour cells with oestrogen
 receptor [ER] and/or progesterone receptor [PgR] expression) based on central testing
 on the most recent tumour biopsy.

 5. Documented HER2-negative tumour based on central testing on the most recent tumour
 biopsy. HER2-negative tumour is determined as immunohistochemistry score 0/1+ or
 negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio <2 or
 for single probe assessment a HER2 copy number <4.

 6. Patients must have received at least 5 years of endocrine therapy in the adjuvant
 setting as treatment for early disease and remained disease free for more than 12
 months following its completion or have "de novo" metastatic disease. Patients that
 have been scheduled 5 years with adjuvant endocrine therapy and stopped treatment, by
 patient's own decision, after completing at least 3 years of treatment, can be also be
 included as long as they have remained free of disease 3 years after discontinuing the
 endocrine therapy.

 7. Patients must have at least one lesion (measurable and/or non-measurable) that can be
 accurately assessed at baseline and is suitable for repeated assessment by CT, MRI,
 plan x-ray or physical examination. Clinical lesions will only be considered
 measurable when they are superficial and ≥10mm diameter as assessed using callipers
 (e.g. skin nodules). Patients with bone-only disease must have a lytic or mixed (lytic
 + blastic) lesion, which has not been previously irradiated and can be accurately
 assessed by CT/MRI according to RECIST version 1.1.

 8. Postmenopausal patient, defined as a woman fulfilling any one of the following
 criteria (based on the NCCN definition of menopause [National Comprehensive Cancer
 Network 2008]):

 -  Prior bilateral oophorectomy.

 -  Age > 60 years.

 -  Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of
 chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle
 stimulating hormone and estradiol in the postmenopausal range.

 9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.

 10. At least 18 years of age.

 11. Life expectancy ≥ 12 weeks.

 12. Adequate organ and bone marrow function:

 -  ANC ≥ 1,500/mm3 (1.5x109/L);

 -  Platelets ≥ 100,000/mm3 (100x109/L);

 -  Haemoglobin (Hgb) ≥ 9g/dL (90g/L);

 -  Serum creatinine ≤ 1.5xUpper Limit of Normal (ULN) or estimated creatinine
 clearance ≥ 60ml/min as calculated using the method standard for the institution;

 -  Total serum bilirubin ≤ 1.5xULN (<3xULN if Gilbert´s disease);

 -  AST and/or ALT ≤ 3xULN (≤5xULN if liver metastases present);

 -  Alkaline Phosphatase (AP) ≤ 2.5xULN (≤5xULN if bone or liver metastases present).

 13. Patients consent to biological sample provision for biomarker exploratory analysis.

 14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
 tests and other study procedures.

 Exclusion Criteria:

 1. Prior systemic therapy for metastatic disease. Note: patients with a local recurrent
 disease treated with surgery (R0) and receiving a "second hormonal adjuvant therapy
 for five years" will be allowed, provided they have remained disease free for more
 than 12 months following its completion.

 2. Have "de novo" locally advanced disease.

 3. 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.

 4. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic
 involvement, or any degree of brain or leptomeningeal involvement (past or present),
 or symptomatic pulmonary lymphangitis spread, or any known bone marrow infiltration
 due to breast cancer. Patients with discrete pulmonary parenchymal metastases are
 eligible, provided their respiratory function is not significantly compromised as a
 result of disease.

 5. Treatment with a non-approved or experimental drug within 4 weeks before
 randomization.

 6. Prior treatment with any CDK4/6 inhibitor or fulvestrant.

 7. Current or prior malignancy within previous 5 years (other than breast cancer or
 adequately treated basal cell or squamous cell carcinoma of the skin or in-situ
 carcinoma of the cervix).

 8. History of:

 -  Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting
 factor deficiency) or long-term (>6 months) anticoagulant therapy (other than
 antiplatelet therapy and low dose coumarin derivatives provided that the
 International Normalised Ratio (INR) is less than 1.6). Hypersensitivity to
 active or inactive excipients of fulvestrant, palbociclib/placebo or castor oil.

 -  Any severe concomitant condition which makes it undesirable for the patient to
 participate in the trial or which would jeopardize compliance with the trial
 protocol, e.g. uncontrolled cardiac disease or uncontrolled diabetes mellitus.

 9. QTc interval > 480msec, family or personal history of long or short QT syndrome,
 Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.

 10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging
 drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia).

 11. Impairment of gastro-intestinal (GI) function or GI disease that may significantly
 alter the absorption of palbociclib, such as history of GI surgery which may result in
 intestinal blind loops and patients with clinically significant gastro-paresis, short
 bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or
 diarrhoea of CTCAE grade > 1.

 12. Prior hematopoietic stem cell or bone marrow transplantation.

 13. Known human immunodeficiency virus infection.

 14. 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.