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

Active:	No
Cancer Type:	Breast Cancer Unknown Primary	NCT ID:	NCT04345913
Trial Phases:	Phase I Phase II	Protocol IDs:	10382 (primary) 10382 NCI-2020-02319
Eligibility:	18 Years and older, Male and Female	Study Type:	Treatment
Study Sponsor:	Yale University Cancer Center LAO
NCI Full Details:	http://clinicaltrials.gov/show/NCT04345913

Summary

This phase I/II trial studies the side effects and best dose of copanlisib and how well it works when given together with eribulin in treating patients with triple negative breast cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib and eribulin may work better in treating advanced stage triple negative breast cancer compared to eribulin alone.

Objectives

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 versus (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. Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive eribulin intravenously (IV) over 2 to 5 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive copanlisib IV over 1 hour and eribulin IV over 2 to 5 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients in both groups also undergo a computed tomography (CT) scan and/or magnetic resonance imaging (MRI) at screening, cycle 3 day 1, and every 9 weeks thereafter. Patients also undergo a biopsy at baseline, cycle 2 day 1, and at time of disease progression and blood sample collection at baseline, cycle 2 day 1, every 9 weeks and at time of disease progression.

After completion of study treatment, patients are followed every 3 months for up to 36 months.

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