Cyclin dEpendent Kinase in tRiple nEGatIVe brEast canceR - a "Window of Opportunity" Study

Inclusion criteria

• females or males >18 years old at the time of informed consent signature;
• diagnosis of potentially resectable or de novo metastatic (stage II-IV) invasive carcinoma of the breast;
• eligible for standard neoadjuvant or palliative paclitaxel and/or carboplatin-based chemotherapy as determined by Investigator;
• triple negative tumor defined as:

• hormone receptor-negative (<1% ER/PgR expression);
• HER2-negative (Immunohistochemistry (IHC) score ≤1 or IHC score =2 and negative for the amplification by in situ hybridization);
• multicentric/multifocal disease is allowed, provided that all lesions have been biopsied and their phenotype has been confirmed pathologically as TNBC;
• no previous anticancer therapy for this malignancy;
• clinically or radiographically measurable disease (discrete lesion only, enhancement is not included) within the breast, that can be biopsied, defined as longest diameter >2 cm;
• multicentric or multifocal disease is allowed if at least 1 lesion is >2 cm;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
• adequate bone marrow and organ function as defined by the following local laboratory values:
• hemoglobin ≥9 g/dL;
• absolute neutrophil count (ANC) ≥1500/μL;
• platelets ≥100,000/μL;
• total bilirubin ≤ institutional upper limit of normal (ULN), unless diagnosis of Gilbert syndrome;
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN;
• creatinine ≤ ULN OR creatinine clearance ≥50 mL/min per Cockcroft-Gault equation for patients with creatinine levels greater than ULN.
• blood glucose level <120 mg/dL after at least 6 hours of fasting;
• standard 12-lead electrocardiogram (ECG) without clinically significant abnormalities;
• ability to undergo contrast-enhanced MRI;
• ability to swallow and retain oral medication;
• all study participants of child-bearing potential must agree to use adequate contraceptive methods prior to study entry, during the study and for the following 3 weeks (females) or 14 weeks (males);
• prior chemotherapy, other targeted anticancer therapies, or prior radiation therapy (outside of treated breast) for other malignancy treated with radical intent is allowed, provided the treatment was completed ≥1 year before informed consent signature;
• prior bisphosphonate therapy is allowed;
• willing and able to undergo all the procedures required by the study protocol;
• provision of written informed consent form prior to receiving any study related procedure.

Exclusion criteria

• inflammatory breast cancer;
• prior systemic treatment for this malignancy;
• prior treatment with CDK4/6 inhibitor;
• known hypersensitivity to study medications or any of their excipients;
• major surgery or radiotherapy (apart from limited field radiotherapy for symptom control) within 14 days prior to randomization;
• concurrent invasive malignancy;
• known HIV, active HBV or HCV infection;
• active autoimmune disease requiring ongoing immunosuppressive therapy;
• history of allotransplantation;
• concurrent treatment with systemic immunosuppressive agents, including steroids, within 3 weeks of enrolment;
• presence of implants or devices not compatible with MRI;
• pregnant or nursing female participants;
• receiving strong inhibitors or inducers of CYP3A4/5 or medications with narrow therapeutic window that are predominantly metabolized through CYP3A4/5;
• impairment of GI function that may significantly alter the absorption of the oral trial treatments;
• unwilling or unable to follow protocol requirements, including obligatory biopsies;
• any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drugs;
• any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.