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 Res. 2018 Aug 2;20(1):82. doi: 10.1186/s13058-018-1014-y.


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.

Keywords: Aurora kinase inhibitor; Breast cancer; ENMD-2076; Triple negative.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / metabolism
  • Biopsy
  • Breast / pathology
  • Breast Neoplasms, Male / blood
  • Breast Neoplasms, Male / drug therapy*
  • Breast Neoplasms, Male / pathology
  • Diarrhea / chemically induced
  • Diarrhea / epidemiology
  • Disease Progression
  • Fatigue / chemically induced
  • Fatigue / epidemiology
  • Female
  • Humans
  • Hypertension / chemically induced
  • Hypertension / epidemiology
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Nausea / epidemiology
  • Progression-Free Survival
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Triple Negative Breast Neoplasms / blood
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology


  • Antineoplastic Agents
  • ENMD 2076
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • AURKA protein, human
  • Aurora Kinase A

Associated data

  • ClinicalTrials.gov/NCT01639248