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Goldstein LJ, Zhao F, Wang M, Swaby RF, Sparano JA, Meropol NJ, Bhalla KN, Pellegrino CM, Katherine Alpaugh R, Falkson CI, Klein P, Sledge GW
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 Res Treat (2017) 165:375-382.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Publication Date: 2017-09-01.
PMCID: PMC5682621
Last updated on Saturday, August 22, 2020