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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)

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Abstract

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.

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Acknowledgements

This study was supported by Grant CA-23318, awarded by the National Cancer Institute, DHHS. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180794, CA180820, CA189859, CA189851, CA180853, CA180855, CA180816, CA180795, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Funding

The project described was supported by Award Number P30 CA006927 (Richard Fisher, MD) and U10 CA027525 (Lori J. Goldstein, MD) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Author information

Author notes

  1. Ramona F. Swaby

    Present address: Merck Pharmaceuticals, North Wales, PA, USA

  2. Joseph A. Sparano

    Present address: West Chester Medical Center, Valhalla, NY, USA

  3. Neal J. Meropol

    Present address: University Hospitals Case Medical Center, Cleveland, OH, USA

  4. Kapil N. Bhalla

    Present address: MD Anderson Cancer Center, Houston, TX, USA

  5. Paula Klein

    Present address: Beth Israel Medical Center, New York, USA

  6. George W. Sledge

    Present address: Stanford University, Stanford, CA, USA

Authors and Affiliations

  1. Fox Chase Cancer Center, Philadelphia, PA, USA

    Lori J. Goldstein, Ramona F. Swaby, Neal J. Meropol & R. Katherine Alpaugh

  2. Dana Farber Cancer Institute – ECOG-ACRIN Biostatistics Center, Boston, MA, USA

    Fengmin Zhao & Molin Wang

  3. West Chester Medical Center, Valhalla, NY, USA

    Christine M. Pellegrino

  4. Georgia Regents University NCORP, Augusta, Georgia

    Kapil N. Bhalla

  5. University of Alabama, Birmingham, AL, England, UK

    Carla I. Falkson

  6. St. Vincent’s Comp. Cancer Center, New York, USA

    Paula Klein

  7. Indiana University Cancer Center, Indianapolis, IN, USA

    George W. Sledge

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  1. Lori J. Goldstein
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Correspondence to Lori J. Goldstein.

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Goldstein, L.J., Zhao, F., Wang, M. et al. 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 165, 375–382 (2017). https://doi.org/10.1007/s10549-017-4310-9

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