Comprehensive Analysis of Spatial, Temporal and Molecular Patterns of Ribociclib Efficacy and Resistance in Advanced Breast Cancer Patients

This is a prospective, multicenter, phase IV, one-arm, open-label clinical trial investigating patients treated with ribociclib and standard of care endocrine therapy for hormone receptor positive (HR+) / human epidermal growth factor receptor negative (HER2-) advanced breast cancer in the first therapy line. Patients eligible for this trial will receive on-label ribociclib according to Summary of Product Characteristics (SmPC) and as well as the specified inclusion/exclusion criteria.

The survival rates for progression-free survival (PFS) and overall survival (OS) at month 12 are the co-primary objectives. Quality of life and toxicity are secondary objectives. Additionally, there is a comprehensive biomarker discovery and validation program included into the study.

A total of 1000 patients are planned to be enrolled into this trial in 75 trial sites in Germany.

Biomarkers will be evaluated before, during and after treatment or at progression. A comprehensive biospecimens sampling will be done to enable translational research projects and evaluation of potential biomarkers within circulation tumor desoxyribonucleic acid (ctDNA), circulating tumor ribonucleic acid (ctRNA), formaldehyde-fixed paraffin-embedded tissue (FFPE) tissue, Serum, Plasma and circulating immune cells

Inclusion criteria

• Indication for treatment with ribociclib in combination with endocrine therapy in the locally advanced or 1st line metastatic therapy setting according to SmPC. (Previous treatment with cycline dependent kinase 4/6 (CDK4/6) inhibitors is allowed in the adjuvant setting)
• Written informed consent prior to beginning of trial specific procedures
• Subject must be female and aged ≥ 18 years on the day of signing informed consent
• Locally advanced or metastatic breast cancer not amenable to curative treatment
• Patient has HER2-negative breast cancer confirmed by local laboratory defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory
• Histologically confirmed estrogen receptor (ER) positive and/ or progesterone receptor (PgR) positive breast cancer determined by core biopsy according to local in-house standard.
• corrected QT (QTcF) interval < 450 ms
• Adequate organ function amenable for treatment with ribociclib as assessed by local laboratory
• Women of childbearing potential must have a negative urine or serum pregnancy test within 72 h prior to study entry and be willing to use highly effective method of contraception for course of the trial through 21 days after the last dose of trial treatment.
• Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.

Exclusion criteria

• Concurrent participation in a study with an investigational agent/device or within 14 days of study entry or 5 half-lives of the respective investigational agent/device, whichever is longer
• Patients who are not treated for advanced HR+, HER2- breast cancer in the first line therapy setting.
• Patient not eligible for treatment with ribociclib according to SmPC or investigator's discretion
• Patients who are pregnant or lactating.
• Patients with existing or patients who are at significant risk of developing corrected QT interval (QTc) prolongation. This includes

• patients with long QT syndrome
• uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmia
• electrolyte abnormalities
• Patients with known hypersensitivity to the active substance of ribociclib, soya, peanut or any other of the excipients of ribociclib.
• Patients with active systemic infections (for example, bacterial infection requiring intravenous antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection requiring systemic therapy) or viral load (such as known human immunodeficiency virus positivity or with known active hepatitis B or C, for example, hepatitis B surface antigen positive).
• Patients with serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (such as severe renal impairment, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in clinically significant diarrhea).
• Patient who do not agree to collection of biospecimens samples (blood, stool, tissue)