Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer

Inclusion Criteria

• Women >18 years-old.
• Diagnostic of metastatic or locally advanced non-resectable TNBC.
• Patient that have received at least one and up to two previous lines of therapy for metastatic TNBC and failed to last treatment. Previous treatments can be of any nature (chemotherapy, immunotherapy, antiangiogenics, experimental therapy, etc.).

Women with known BRCA1/BRCA2 germline mutations must have received a platinum based treatment or treatment with a PARP inhibitor.

• Patient must have experienced disease progression to the previous treatment line according to the RECIST 1.1 or iRECIST criteria.
• Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study inclusion, preferably obtained after last treatment or the most recent sample as possible (from metastatic site or first diagnosis according to sample availability). If the patient has not a tumor sample available prior to study inclusion, the patient will not be allowed to participate in the study.
• Ability to understand and signing of the written patient information/informed consent form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be performed centrally at CNIO.
• Ability to understand and signing the written PIS/ICF for study treatment eligibility. Signed informed consent form must be available before any studyspecific procedure for the respective study parts may begin.
• Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-quartile according to published definitions [1].
• ECOG performance status of 0-1.
• Evaluable disease according to RECIST 1.1 criteria.
• Life expectancy >24 weeks.
• Adequate bone marrow, liver and renal function as assessed by laboratory requirements conducted within 7 days before first study drug administration:
• Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte colony-stimulating factor support within 2 weeks before the first study drug administration)
• Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks before the first study drug administration)
• Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the first study drug administration)
• Total bilirubin ≤ 2 X the upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 X ULN (≤ 5 times ULN for patients with liver metastases)
• Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the modification of diet in renal disease (MDRD) abbreviated formula.
• Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, and alopecia).
• Patients must be able to take oral medications.
• Patients must have adequate cardiac function, defined as:
• Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram or multigated acquisition scan (MUGA).
• QTc 160 mmHg despite medical management
• myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting 3 years before the first study drug administration
• Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator.
• Pregnant women or breast-feeding.
• Known HIV-positive individuals on combination antiretroviral therapy.
• Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C infection requiring treatment.
• Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible if HBV DNA is negative.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Any condition that in the opinion of the investigat