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)

• Published in: Breast cancer research and treatment Vol. 165; no. 2; pp. 375 - 382
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2017; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer research; Clinical Trial; Combined Modality Therapy; Disease Progression; ErbB-2 protein; Female; Gene Amplification; Histone deacetylase; Humans; Hydroxamic acid; Hydroxamic Acids - administration & dosage; Immunotherapy; Kaplan-Meier Estimate; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Neoplasm Recurrence, Local; Neoplasm Staging; Oncology; Patient Compliance; Receptor, ErbB-2 - genetics; Retreatment; Solid tumors; Targeted cancer therapy; Thoracic Wall - pathology; Time Factors; Toxicity; Trastuzumab; Trastuzumab - administration & dosage; Treatment Outcome; Vorinostat; Resistance; Histone deacetylase; Tumor; Anticancer therapy; Toxicity
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4310-9

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.