Pre- and post-menopausal women age ≥ 18 years with HR-positive and HER2-negative with ABC
that had previously received first-line endocrine therapy in combination with palbociclib and
had achieved clinical benefit during palbociclib-based treatment. Patients relapsing on a
palbociclib-based regimen in the adjuvant setting are also eligible. Patients are not
eligible if they are candidates for a local treatment with a curative intention. Evidence of
either measurable and biopsable metastatic disease (as for Response Evaluation Criteria In
Solid Tumors (RECIST v.1.1)) or non-measurable disease with bone lesion is required.
Pre-menopausal women must be under treatment with luteinizing hormone-releasing hormone
1. Female patients over 18 years of age.
2. Pre-menopausal women provided they are being treated with a LHRH analogue for at least
28 days (if shorter, post-menopausal levels of serum estradiol/Follicle-stimulating
hormone (FSH) must be confirmed analytically) prior to study entry or post- menopausal
women as defined by any of the following criteria:
1. Age ≥60 years;
2. Age <60 years and cessation of regular menses for at least 12 consecutive months
with no alternative pathological or physiological cause; and serum estradiol
and/or FSH level within the laboratory's reference range for postmenopausal
3. Documented bilateral oophorectomy.
3. Eastern Cooperative Oncology Group (ECOG) performance status lower or equal to 1.
4. Life expectancy greater or equal to 12 weeks.
5. Histologically proven diagnosed of ABC not amenable to curative treatment.
6. Documented recurrent ER-positive and/or progesterone receptor (PgR)-positive (with ≥1%
positive stained cells (according to NCCN and ASCO guidelines) and HER2-negative (0-1+
by immunohistochemistry (IHC) or 2+ and negative by in situ hybridization (ISH) test)
breast cancer in the advanced setting.
7. Radiological or clinical evidence of disease progression on first- line combination of
palbociclib plus endocrine therapy (aromatase inhibitor (AI) or fulvestrant). Patients
previously treated with the combination of palbociclib and tamoxifen will be excluded.
8. Patients have achieved clinical benefit criteria to a first-line palbociclib-based
endocrine regimen (defined as at least stable disease ≥ 24 weeks or partial or
complete response confirmed or unconfirmed).
9. Patients must have been treated with a stable minimum dose of 100 mg palbociclib
during the last 2 cycles of the prior palbociclib-based regimen.
10. Last dose of palbociclib administered not later than 8 weeks and not earlier than 7
days from study entry, with the exception of patients relapsing on a palbociclib-based
regimen in the adjuvant setting.
11. Patients should not have been treated in the advanced setting with at least one of
these endocrine therapy options: either fulvestrant or AI.
12. Patients must have measurable disease or evaluable disease according to RECIST
criteria v.1.1. Patients with only bone lesions are eligible.
13. Willingness and ability to provide tumor biopsy (if feasible) both at the time of the
inclusion and after disease progression in order to perform exploratory studies. If
not feasible, patient eligibility should be evaluated by a Sponsor's qualified
14. Patients agree to collection of blood samples (liquid biopsy) at the time of
inclusion, after 2 weeks of treatment, and upon progression or study termination.
15. Adequate organ function: (Hematological, hepatic and renal)
16. Patients who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
17. Patients have been informed about the nature of study, and have agreed to participate
in the study, and signed the informed consent form prior to participation in any
18. Resolution of all acute toxic effects of prior anti-cancer therapy to grade 1
1. HR or HER2 unknown disease.
2. HER2-positive disease based on local laboratory results (performed by IHC / ISH test).
3. Locally ABC candidate for curative treatment.
4. Formal contraindication to endocrine therapy defined as visceral crisis and rapidly or
symptomatic progressive visceral disease.
5. Prior therapy with any other CDK4/6 inhibitor different from palbociclib.
6. 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 and are
clinically stable off anticonvulsants and steroids for at least 4 weeks before
7. Patients are currently receiving food or drugs known to be strong inducers or
inhibitors of CYP3A4.
8. Current or prior malignancy which could affect compliance with the protocol or
interpretation of results. Patients with curatively- treated non-melanoma skin cancer,
non-muscle-invasive bladder cancer, or carcinoma in situ, among others, are generally
9. No other systemic therapy for metastatic disease including chemotherapy,
immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine
therapy excluding first-line palbociclib-based regimen.
10. Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 2 weeks of start of study drug, or patients who have not recovered from
the side effects of any major surgery, or patients who may require major surgery
during the study.
11. Radiotherapy or limited-field palliative radiotherapy within 7 days prior to study
enrolment, or patients who have not recovered from radiotherapy-related toxicities to
baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously
12. Use of concurrent investigational agents or other concomitant anticancer therapies.
13. Active bleeding diathesis, previous history of bleeding diathesis, or chronic
anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon
as it is used as prophylaxis intention).
14. Serious concomitant systemic disorder (e.g., active infection including HIV, or
cardiac disease) incompatible with the study (at the discretion of investigator).
15. Unable to swallow capsules or tablets.
16. History of malabsorption syndrome or other condition that would interfere with enteral
17. Any of the following within 6 months of randomization:
myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of
NCI-CTCAE v.5.0 grade ≥2, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident including transient ischemic
attack, or symptomatic pulmonary embolism.
18. Uncontrolled electrolyte disorders of NCI-CTCAE v.5.0 grade ≥ 2.
19. Known hypersensitivity to palbociclib or any of its excipients.