A Phase II Study of the Histone Deacetylase Inhibitor, Vorinostat, in Combination with Trastuzumab in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER-2 Amplified Breast Cancer Resistant to Transtuzumab-Containing Therapy: (E1104) a Trial of the Eastern Cooperative Oncology Group.
Authors: R. Swaby, M. Wang, J. Sparano, K. Bhalla, N. Meropol, C. Falkson, C. Pellegrino, P. Klein, L. Goldstein, G. Sledge, Jr
Journal: Cancer Research (2009)

Abstract BackgroundVorinostat, also known as suberoylanilide hydroxamic acid or SAHA, is a potent, small molecule, pan-inhibitor of histone deacetylase (HDAC) with excellent oral bioavailability, and is commercially approved for cutaneous T cell lymphoma. Pan HDAC inhibitors induce acetylation of histone tails, relaxing condensed chromatin for transcriptional regulation of specific genes and can also target non histone nuclear proteins. In pre-clinical studies of HER-2 overexpressing breast cancer cells, vorinostat(V) synergistically augmented the effects of trastuzumab(T) by downregulating Her-2, pAKT, pERK 1/2, reduced apoptosis by decreasing Bcl-2, Bcl-XL, XIAP and survivin levels, while inducing pro-apoptotic Bim and Bak. Therefore, we hypothesized that adding vorinostat to trastuzumab would reverse trastuzumab resistance in patients with HER-2 positive metastatic breast cancer.MethodsAn open label dose de-escalation schema for the initial portion of the trial was planned. V 200 mg bid continuous daily dosing with 6 mg/kg T every 21 days was administered. Eligible patients: HER-2 positive by IHC (3+) or FISH, subsequently centrally confirmed; measurable metastatic or chest wall disease; any number of prior therapies including endocrine, chemotherapy, prior treatment with T and/or lapatinib were allowed; evidence of progressive disease on prior T was required. The Phase II primary objective was response rate by RECIST criteria.ResultsMedian age - 54 (range 40-69); PS was 0 or 1; 6 patients - ER+; median number of prior therapies - 3 (range 2-6). Six patients were treated at the starting dose of 200 mg bid daily V combined with 6 mg/kg T every 21 days. There were no dose limiting adverse events at this dosing level, eliminating the need to de-escalate and this was determined to be the optimal Phase II dose. A total of 16 patients were enrolled. The most common AEs (all grades) were 62%-diarrhea, 37%-nausea, fatigue; 31%-anemia, anorexia, vomiting, elevated creatinine, hyperglycemia, hypokalemia; 25%-thrombocytopenia. Grade 3,4 toxicities were dyspnea(n=2) and thrombocytopenia(n=2). Of the 16 total enrolled, 10 were centrally confirmed to have HER-2 positive disease by the ECOG Pathology Coordinating Office, 5 were HER-2 negative and 1 had insufficient tissue. None of 11 patients with centrally confirmed HER-2 positive disease (or unknown) had an objective response. One of 5 patients with centrally confirmed HER-2 negative disease had an objective response.ConclusionsIn this heavily pre-treated population who had either relapsed or progressed during trastuzumab containing therapy (either alone or in combination with chemotherapy), we failed to confirm our hypothesis that adding the histone deacetylase inhibitor, vorinostat, could reverse trastuzumab resistance. Correlative studies including hyperacetylation status of PBMC, CTC enumeration and peripheral as well as tumor methylation are ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5084.