cyclin dependent kinase in triple negative breast cancer - a "window of opportunity" study

Conditions: Triple Negative Breast Neoplasms

Summary: 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.