Testing the Addition of Copanlisib to Eribulin for the Treatment of Advanced-Stage Triple Negative Breast Cancer

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PRIMARY OBJECTIVES: I. To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib hydrochloride (copanlisib) in combination with eribulin mesylate (eribulin) in metastatic triple negative breast cancer (TNBC...

PRIMARY OBJECTIVES: I. To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib hydrochloride (copanlisib) in combination with eribulin mesylate (eribulin) in metastatic triple negative breast cancer (TNBC). (Phase I) II. To compare progression free survival (PFS) between eribulin and eribulin plus copanlisib arms in patients with metastatic TNBC treated with prior taxane and anthracycline. (Phase II) SECONDARY OBJECTIVES: I. To determine the objective response rate (ORR) and clinical benefit rate (CBR) of the combination. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To compare the ORR, CBR (complete response [CR]+partial response [PR]+stable disease [SD] >= 24 weeks) and safety of eribulin and eribulin plus copanlisib arms. (Phase II) IV. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring mutations in PIK3CA/ PTEN or with loss of PTEN expression by immunohistochemistry (IHC) on baseline tumor biopsy. (Phase II) V. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors lacking PIK3CA/ PTEN pathway alterations. (Phase II) VI. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring loss of PTEN expression by IHC in pre-treatment metastatic site (in patients with available tissue from metastatic site). (Phase II) VII. To compare PTEN IHC results between paired archival primary tumor vs. baseline tumor biopsies. (Phase II) VIII. To assess targeted inhibition by copanlisib and eribulin by measuring treatment induced changes in phosphorylated (phospho)-AKT (T308), phospho-AKT (S473), phospho-histone H3, and inhibition of apoptosis (cleaved caspase 3) between post-treatment tumor (C2D1-2) versus baseline. (Phase II) IX. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring mutations in PIK3CA/PTEN by circulating tumor-derived deoxyribonucleic acid (ctDNA) at baseline, and potential changes over time. (Phase II) EXPLORATORY OBJECTIVES: I. To compare PTEN IHC results between paired baseline tumor biopsy versus at time of disease progression. II. Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to correlate treatment response. III. Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment biopsies for gene expression and proteomic changes. IV. Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in mutation profile and variant allele frequencies (VAFs) on cycle 2 day 1 (C2D1) and at disease progression compared to baseline to correlate with treatment response. V. Assess circulating biomarkers predictive of treatment response. VI. Assess plasma and serum proteomics and metabolomics predictive of treatment response. OUTLINE: This is a phase I dose-escalation study of copanlisib and eribulin followed by a phase II study. PHASE I: Patients receive copanlisib intravenously (IV) over 60 minutes and eribulin IV over 2-5 minutes on days 1 and 15 or days 1 and 8. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. PHASE II. Patients are randomized to 1 of 2 groups. GROUP I: Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive copanlisib IV over 60 minutes on days 1 and 8 and eribulin IV over 2-5 minutes on days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years.

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