A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer
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 d...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-08-01
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| Series: | Breast Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13058-018-1014-y |
| _version_ | 1818728557126352896 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jennifer R. Diamond |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T22:31:53Z |
| format | Article |
| id | doaj.art-b8114fdcf25045a88513879cfaf4520b |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-17T22:31:53Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-b8114fdcf25045a88513879cfaf4520b2022-12-21T21:30:10ZengBMCBreast Cancer Research1465-542X2018-08-0120111010.1186/s13058-018-1014-yA phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancerJennifer R. Diamond0S. G. Eckhardt1Todd M. Pitts2Adrie van Bokhoven3Dara Aisner4Daniel L. Gustafson5Anna Capasso6Sharon Sams7Peter Kabos8Kathryn Zolman9Tiffany Colvin10Anthony D. Elias11Anna M. Storniolo12Bryan P. Schneider13Dexiang Gao14John J. Tentler15Virginia F. Borges16Kathy D. Miller17University of Colorado Cancer CenterDepartment of Oncology, University of Texas at Austin, Dell Medical SchoolUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterDepartment of Oncology, University of Texas at Austin, Dell Medical SchoolUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterIndiana University Melvin and Bren Simon Cancer CenterIndiana University Melvin and Bren Simon Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterUniversity of Colorado Cancer CenterIndiana University Melvin and Bren Simon Cancer CenterAbstract 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.http://link.springer.com/article/10.1186/s13058-018-1014-yBreast cancerENMD-2076Aurora kinase inhibitorTriple negative |
| spellingShingle | 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 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 Breast cancer ENMD-2076 Aurora kinase inhibitor Triple negative |
| 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 |
| title_full | A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer |
| title_fullStr | A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer |
| title_full_unstemmed | A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer |
| title_short | A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer |
| title_sort | phase ii clinical trial of the aurora and angiogenic kinase inhibitor enmd 2076 for previously treated advanced or metastatic triple negative breast cancer |
| topic | Breast cancer ENMD-2076 Aurora kinase inhibitor Triple negative |
| url | http://link.springer.com/article/10.1186/s13058-018-1014-y |
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