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

Study Overview
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Brief Summary
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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.

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

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This 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)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CDK4/6 inhibitor alone: Palbociclib (IMP)<br>Palbociclib alone (125 mg orally (PO) per day, days 1-14) | Drug: Palbociclib<br>* CDK4/6 inhibitor<br>* Other names: Ibrance;|
| Active Comparator: Chemotherapy alone: Paclitaxel<br>Paclitaxel alone (80 mg/m^2 intravenously (IV), day 1, 8, 15 and 22) | Drug: Paclitaxel<br>* Chemotherapy<br>|
| Experimental: CDK4/6 inhibitor + chemotherapy: Paclitaxel + Palbociclib<br>Paclitaxel (80 mg/m^2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21) | Drug: Palbociclib<br>* CDK4/6 inhibitor<br>* Other names: Ibrance;Drug: Paclitaxel<br>* Chemotherapy<br>|
| Active Comparator: Chemotherapy alone: Carboplatin<br>Carboplatin alone (area under the curve (AUC) 2 IV, day 1, 8, 15 and 22) | Drug: Carboplatin<br>* Chemotherapy<br>|
| Experimental: CDK4/6 inhibitor + chemotherapy: Carboplatin + Palbociclib<br>Carboplatin (AUC 2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21) | Drug: Palbociclib<br>* CDK4/6 inhibitor<br>* Other names: Ibrance;Drug: Carboplatin<br>* Chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early metabolic response | Difference in early (i.e., after three weeks of therapy, 1 cycle) metabolic response to treatment in chemotherapy-containing arms (chemotherapy ± palbociclib), as assessed by Blinded Central Review comparison of decrease in SUVmax between baseline and Day 27 (± 3 days) 18-fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography - computed tomography (PET-CT). Primary analysis will include comparison between chemotherapy + palbociclib vs chemotherapy alone arms. | Day 27 (± 3 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SUVmax change | Difference in proportion of patients with SUVmax change above the predefined cut-off of 30% between chemotherapy + palbociclib vs chemotherapy alone arms. | Day 27 (± 3 days) | 
| Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) | Difference in Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)-based peak standardized uptake value corrected for lean body mass in a spherical 1 cm3 volume of interest (SULpeak) decrease in PET-CT between chemotherapy + palbociclib vs chemotherapy alone arms. | Day 27 (± 3 days) | 
| Metabolic tumor volume (MTV) difference | Difference in metabolic tumor volume (MTV) regression between chemotherapy + palbociclib vs chemotherapy alone arms. | Day 27 (± 3 days) | 
| Tumor diameter change | Maximum tumor diameter change in largest continuous tumor mass based on MR imaging. | Day 27 (± 3 days) | 
| Change in tumor characteristic | Change in tumor characteristic in Day 27 biopsy (presence of viable cancer cells). | Day 27 (± 3 days) | 
| Treatment toxicity | Treatment toxicity (with special attention to myeloid toxicity to explore potential myeloprotective activity): number and severity of adverse events (AEs); toxicity will be described according to ICD-10 codes and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). | Day 27 (± 3 days) |