HR+/HER2- Advanced Breast Cancer and Endocrine Resistance

Exclusion Criteria

• •1. Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or capecitabine. Short-term (\<28 days) exposure to mTOR or PI3K inhibitor in the (neo)adjuvant setting is allowed.
• •2. More than one prior chemotherapy lines for metastatic breast cancer. Previous (neo)adjuvant chemotherapy or for radically treated local or regional relapse is allowed in addition to one prior chemotherapy line for metastatic breast cancer Note: A chemotherapy line in advanced disease is an anticancer regimen that contains at least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression and the decision for its discontinuation was taken within 21 days after starting it, then this regimen does not count as a "prior line of chemotherapy". Chemotherapy regimens composed of more than one drug are considered as one line of therapy.
• •3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash, sclerotic bone etc).
• •4. CNS metastases unless asymptomatic and adequately controlled with surgery or radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that have been definitively treated and the patient is clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
• •5. Leptomeningeal carcinomatosis
• •6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening complications in the short term.
• •7. Concurrent malignancy of any site, except adequately controlled limited basal cell carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in situ of the cervix.
• •8. Active cardiac disease or a history of cardiac dysfunction including any of the following:
• •1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry
• •2. History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• •3. Documented cardiomyopathy
• •4. QTc \> 480 msec as measured by Bazett's formula, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
• •5. Uncontrolled hypertension.
• •9. Patients being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) continuously for at least 7 days during any time period in the last 2 weeks prior to randomization.
• •10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous severe reactions to a fluoropyrimidine.
• •11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment with anticoagulants that preclude intramuscular administration of drugs.
• •12. Ongoing pregnancy or lactation.
• •13. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• •14. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor and progesterone receptor (i.e. \<1% for both), or positive for HER2 status (amplified ERBB2).