A Study of a New Drug Combination, Copanlisib and Fulvestrant, in Advanced Breast Cancer

PRIMARY OBJECTIVES: I. Establish safety of the combination of copanlisib and fulvestrant (FC). II. Evaluate the response rate (RR) of the combination of copanlisib and fulvestrant in patients with estrogen-receptor positive (ER+)/human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer that has previously progressed on aromatase inhibitor (AI)/cyclin dependent kinase (CDK) 4/6 inhibitor therapy. SECONDARY OBJECTIVES: I. Estimate progression-free survival (PFS) in patients treated with copanlisib and fulvestrant stratifying by actionable PIK3CA mutation, actionable PIK3CA or PTEN mutation, or wild type PIK3CA and PTEN. II. Estimate the RR in subjects with PTEN loss by immunohistochemistry (IHC) analysis performed retrospectively. III. Evaluate toxicity in patients treated with FC in Phase II. EXPLORATORY OBJECTIVES: I. Evaluate copanlisib pharmacokinetics (PK) when given in combination with fulvestrant. II. Explore association between intrinsic subtype and response to FC therapy. III. Assess baseline levels and treatment-induced proteomic changes and correlate with response to FC. IV. Evaluate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) mutations at baseline and over time for response predictors at baseline, clonal evolution associated with treatment, and resistance mechanisms at disease progression. V. Evaluate PFS in patients with baseline ctDNA PIK3CA actionable mutations versus (vs.) those with wild type PK3CA. VI. To evaluate genomic and gene expression changes in tumor cells and in associated tumor microenvironment before and after administration of copanlisib in combination with fulvestrant and at the time of progression. VII. Evaluate circulating markers of metabolism before and after PI3K inhibitor therapy which may predict treatment response and resistance mechanisms. OUTLINE: Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15 and fulvestrant intramuscularly (IM) over 1-2 minutes on days 1 and 15 of cycle 1 and on day 1 beginning cycle 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.