Copanlisib, Letrozole, and Palbociclib in Treating Patients With Hormone Receptor Positive HER2 Negative Stage I-IV Breast Cancer

PRIMARY OBJECTIVES: I. Assess the safety, tolerability and to estimate the maximum tolerated dose (MTD) in a metastatic setting of the following combination: copanlisib + palbociclib + letrozole. (Phase Ib) II. Compare the biological activity of letrozole in combination with palbociclib, letrozole in combination with palbociclib and copanlisib, and letrozole in combination with copanlisib by assessing the percentage change from the baseline value in Ki67 expression after 2 weeks of therapy in non-metastatic breast cancer. (Phase II) SECONDARY OBJECTIVES: I. Evaluate the pathologic complete response (pCR) defined as absence of invasive cancer in the breast and sampled regional lymph nodes. II. Evaluate the clinical objective response Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. III. Assess safety and tolerability. IV. Evaluate the pharmacokinetics of copanlisib when given in combination with letrozole, and palbociclib. V. Measure the gene expression and/or biomarker changes that may be correlated with or predict biological, clinical, and pathologic response. OUTLINE: This is a dose-escalation study of copanlisib. PHASE Ib: Patients with metastatic breast cancer receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15, palbociclib orally (PO) once daily (QD) on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. PHASE II: After determination of MTD, subsequent non-metastatic breast cancer patients are randomized to 1 of 3 arms: ARM A: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression, or unacceptable toxicity. ARM B: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment with copanlisib and letrozole repeats every 28 days for up to 3.5 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 1 month.