A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104).
Breast cancer research and treatment
Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease.
- 1Fox Chase Cancer Center, Philadelphia, PA, USA. email@example.com.
- 2Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, MA, USA.
- 3Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, MA, USA.
- 4Fox Chase Cancer Center, Philadelphia, PA, USA.
- 5West Chester Medical Center, Valhalla, NY, USA.
- 6Fox Chase Cancer Center, Philadelphia, PA, USA.
- 7MD Anderson Cancer Center, Houston, TX, USA.
- 8West Chester Medical Center, Valhalla, NY, USA.
- 9Fox Chase Cancer Center, Philadelphia, PA, USA.
- 10University of Alabama, Birmingham, AL, England, UK.
- 11Beth Israel Medical Center, New York, USA.
- 12Stanford University, Stanford, CA, USA.
In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated.
The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment.
In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.
This article is
licensed under the
the National Library of Medicine License. It uses material from the PubMed
National Library of Medicine Data.
||Last Modified: 2016-03-27