This is a 2-stage master protocol with multiple substudies testing investigational drugs/drug combinations in patients with CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer. First line endocrine therapy (1LET, aromatase inhibitors; AI) improve clinical outcomes, but are not curative, and acquired resistance develops (median ~2 years). CDK4/6i-resistant MBC is a clinical unmet need, and is marked by numerous potential resistance alterations / mechanisms. Currently, most patients receive second line (2L) ET (e.g., fulvestrant) which has a median progression-free survival (PFS) of ~2 months in this setting. Circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) are detectable in peripheral blood in >90% of patients with MBC.~Patients who wish to participate but progression has not yet occurred may be enrolled in the monitoring substudy and followed until progression. This monitoring component of IND.241 aims to characterize the molecular and clinical features of CDK4/6i resistance as it occurs after first line CDK4/6i + AI. Besides addressing the principal objectives described above (ctDNA genotyping and evaluation of dynamic changes in ctDNA and CTC levels), banked samples will create a biorepository for interrogation of emerging assays (e.g., DNA methylation, CTC protein or single cell analyses) that may have prognostic or predictive application. These data will inform future efforts that may consider intervention prior to clinical treatment failure.
This study is being done to answer the following question: Can testing breast cancer for DNA abnormalities or biomarkers help predict which patients are most likely to be helped by certain treatments? The pre-study screening is being done to test a sample of blood (or tumour tissue) for biomarkers to see if patients can participate in the study