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)

Lori J. Goldstein, Fengmin Zhao, Molin Wang, Ramona F. Swaby, Joseph A. Sparano, Neal J. Meropol, Kapil N. Bhalla, Christine M. Pellegrino, R. Katherine Alpaugh, Carla I. Falkson, Paula Klein, George W. Sledge

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jun 16 2017
Externally publishedYes

Fingerprint

Thoracic Wall
Breast Neoplasms
Research
Neoplasms
vorinostat
Trastuzumab
Histone Deacetylase Inhibitors
Therapeutics
Survival

Keywords

  • Anticancer therapy
  • Histone deacetylase
  • Resistance
  • Toxicity
  • Tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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). / Goldstein, Lori J.; Zhao, Fengmin; Wang, Molin; Swaby, Ramona F.; Sparano, Joseph A.; Meropol, Neal J.; Bhalla, Kapil N.; Pellegrino, Christine M.; Katherine Alpaugh, R.; Falkson, Carla I.; Klein, Paula; Sledge, George W.

In: Breast Cancer Research and Treatment, 16.06.2017, p. 1-8.

Research output: Contribution to journalArticle

Goldstein, Lori J. ; Zhao, Fengmin ; Wang, Molin ; Swaby, Ramona F. ; Sparano, Joseph A. ; Meropol, Neal J. ; Bhalla, Kapil N. ; Pellegrino, Christine M. ; Katherine Alpaugh, R. ; Falkson, Carla I. ; Klein, Paula ; Sledge, George W. / 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). In: Breast Cancer Research and Treatment. 2017 ; pp. 1-8.
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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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T1 - 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

T2 - a trial of the ECOG-ACRIN Cancer Research Group (E1104)

AU - Goldstein, Lori J.

AU - Zhao, Fengmin

AU - Wang, Molin

AU - Swaby, Ramona F.

AU - Sparano, Joseph A.

AU - Meropol, Neal J.

AU - Bhalla, Kapil N.

AU - Pellegrino, Christine M.

AU - Katherine Alpaugh, R.

AU - Falkson, Carla I.

AU - Klein, Paula

AU - Sledge, George W.

PY - 2017/6/16

Y1 - 2017/6/16

N2 - 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.

AB - 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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KW - Toxicity

KW - Tumor

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