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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research article

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer

Authors: Jennifer R. Diamond, S. G. Eckhardt, Todd M. Pitts, Adrie van Bokhoven, Dara Aisner, Daniel L. Gustafson, Anna Capasso, Sharon Sams, Peter Kabos, Kathryn Zolman, Tiffany Colvin, Anthony D. Elias, Anna M. Storniolo, Bryan P. Schneider, Dexiang Gao, John J. Tentler, Virginia F. Borges, Kathy D. Miller

Published in: Breast Cancer Research | Issue 1/2018

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Abstract

Background

Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC.

Methods

This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients.

Results

Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6–32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14–45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations.

Conclusions

Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies.

Trial registration

ClinicalTrials.gov, NCT01639248. Registered on July 12, 2012.
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Metadata
Title
A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer
Authors
Jennifer R. Diamond
S. G. Eckhardt
Todd M. Pitts
Adrie van Bokhoven
Dara Aisner
Daniel L. Gustafson
Anna Capasso
Sharon Sams
Peter Kabos
Kathryn Zolman
Tiffany Colvin
Anthony D. Elias
Anna M. Storniolo
Bryan P. Schneider
Dexiang Gao
John J. Tentler
Virginia F. Borges
Kathy D. Miller
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-1014-y

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