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

CAREGIVER is a prospective, randomized, multicenter, open, five-arm study with unequal allocation ratios of 1:1:2:1:2 (palbociclib : paclitaxel : palbociclib + paclitaxel : carboplatin : carboplatin + paclitaxel). Study will be performed in untreated patients with triple-negative breast cancer (TNBC). Potential candidates without previously established diagnosis of TNBC will be included in a Pre-screening Phase, when a biopsy of breast tumor will be taken to confirm the diagnosis of cancer, select patients with TNBC and collect tissue for translational research.


Eligibility Criteria:
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.