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

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

Research output: Contribution to journalArticle

10 Scopus citations

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 250mg orally once daily with continuous dosing in 4-weekcycles 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 6.5cycles. 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 6months 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.

Original languageEnglish (US)
Article number82
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Aug 2 2018

Keywords

  • Aurora kinase inhibitor
  • Breast cancer
  • ENMD-2076
  • Triple negative

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Diamond, J. R., Eckhardt, S. G., Pitts, T. M., van Bokhoven, A., Aisner, D., Gustafson, D. L., Capasso, A., Sams, S., Kabos, P., Zolman, K., Colvin, T., Elias, A. D., Storniolo, A. M., Schneider, B. P., Gao, D., Tentler, J. J., Borges, V. F., & Miller, K. D. (2018). A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. Breast Cancer Research, 20(1), [82]. https://doi.org/10.1186/s13058-018-1014-y