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 Maria Storniolo, Bryan Schneider, Dexiang Gao, John J. Tentler, Virginia F. Borges, Kathy Miller

Research output: Contribution to journalArticle

3 Citations (Scopus)

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

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Aurora Kinases
Triple Negative Breast Neoplasms
Phase II Clinical Trials
Angiogenesis Inhibitors
Microvessels
Nausea
Disease-Free Survival
Fatigue
Disease Progression
Diarrhea
Neoplasms
Therapeutics
Pharmacokinetics
Biomarkers
Cell Proliferation
ENMD 2076
Breast Neoplasms
Hypertension
Biopsy
Safety

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. / Diamond, Jennifer R.; Eckhardt, S. G.; Pitts, Todd M.; van Bokhoven, Adrie; Aisner, Dara; Gustafson, Daniel L.; Capasso, Anna; Sams, Sharon; Kabos, Peter; Zolman, Kathryn; Colvin, Tiffany; Elias, Anthony D.; Storniolo, Anna Maria; Schneider, Bryan; Gao, Dexiang; Tentler, John J.; Borges, Virginia F.; Miller, Kathy.

In: Breast Cancer Research, Vol. 20, No. 1, 82, 02.08.2018.

Research output: Contribution to journalArticle

Diamond, JR, Eckhardt, SG, Pitts, TM, van Bokhoven, A, Aisner, D, Gustafson, DL, Capasso, A, Sams, S, Kabos, P, Zolman, K, Colvin, T, Elias, AD, Storniolo, AM, Schneider, B, Gao, D, Tentler, JJ, Borges, VF & Miller, K 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, vol. 20, no. 1, 82. https://doi.org/10.1186/s13058-018-1014-y
Diamond, Jennifer R. ; Eckhardt, S. G. ; Pitts, Todd M. ; van Bokhoven, Adrie ; Aisner, Dara ; Gustafson, Daniel L. ; Capasso, Anna ; Sams, Sharon ; Kabos, Peter ; Zolman, Kathryn ; Colvin, Tiffany ; Elias, Anthony D. ; Storniolo, Anna Maria ; Schneider, Bryan ; Gao, Dexiang ; Tentler, John J. ; Borges, Virginia F. ; Miller, Kathy. / A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1.
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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 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.",
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T1 - A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer

AU - Diamond, Jennifer R.

AU - Eckhardt, S. G.

AU - Pitts, Todd M.

AU - van Bokhoven, Adrie

AU - Aisner, Dara

AU - Gustafson, Daniel L.

AU - Capasso, Anna

AU - Sams, Sharon

AU - Kabos, Peter

AU - Zolman, Kathryn

AU - Colvin, Tiffany

AU - Elias, Anthony D.

AU - Storniolo, Anna Maria

AU - Schneider, Bryan

AU - Gao, Dexiang

AU - Tentler, John J.

AU - Borges, Virginia F.

AU - Miller, Kathy

PY - 2018/8/2

Y1 - 2018/8/2

N2 - 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.

AB - 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.

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KW - Triple negative

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