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. firstname.lastname@example.org.
- 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.
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||Last Modified: 2016-03-27